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Aim: We previously reported that abdominal aortic calcification is associated with poor overall and recurrence‐free survival after hepatectomy for hepatocellular carcinoma (HCC). However, the effect of abdominal aortic calcification on cancer‐specific prognosis in very old patients with several comorbidities remains unknown. This multicenter study aimed to evaluate the impact of abdominal aortic calcification on the cumulative recurrence rate and recurrence‐free survival in patients with HCC aged >80 years. Methods: We retrospectively analyzed the data of 128 patients (aged ≥80 years) who underwent liver resection for hepatocellular carcinoma at seven hospitals belonging to Hiroshima Surgical Study Group of Clinical Oncology between January 2014 and December 2018. Patients were divided into two groups: high and low abdominal aortic calcification groups. The primary endpoints were cumulative recurrence rate and recurrence‐free survival. Results: Kaplan–Meier survival curve analysis demonstrated that the cumulative recurrence rate in the high abdominal aortic calcification group was significantly higher than that in the low abdominal aortic calcification group, and the high abdominal aortic calcification group had a significantly lower recurrence‐free survival rate. In the multivariate analysis, high abdominal aortic calcification (p = 0.03), high des‐gamma‐carboxyprothrombin score (p = 0.04), and multiple tumors (p < 0.01) were independent predictive factors for recurrent HCC, and high abdominal aortic calcification (p = 0.01) and high des‐gamma‐carboxyprothrombin (p = 0.01) were independent predictive factors for poor cancer‐specific survival. Conclusions: Our results indicate that the abdominal aortic calcification score is associated with cumulative recurrence rate and recurrence‐free survival in very old patients with HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of death in which the molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations in oncogenes, DNA repair genes, and tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory of harmful epigenetic modifications in DNA and chromatin—impacting the expression of genes involved in cellular proliferation, differentiation, genome stability, cell-cycle control, and DNA repair—are now acknowledged across various biological contexts that contribute to cancer etiology. Notably, the dynamic hypermethylation and hypomethylation in enhancer and promoter regions that promote activation or silencing of the master regulatory genes of the epigenetic programs is often altered in tumor cells due to mutation. Genome instability is one of the cancer hallmarks that contribute to transdifferentiation and intratumoral heterogeneity. Thus, it is broadly accepted that tumor tissue is dominated by genetically and epigenetically distinct sub-clones which display a set of genetic and epigenetic mutations. Here we summarize some functions of key genetic and epigenetic players and biochemical pathways leading to liver cell transformation. We discuss the role of the potential epigenetic marks in target genes thought to be involved in sequential events following liver lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, and finally hepatocellular carcinoma. We also briefly describe new findings showing how epigenetic drugs together with chemotherapy and immunotherapy can improve overall responses in patients with hepatic tumors. [ABSTRACT FROM AUTHOR]

Abstract Aim We previously reported that abdominal aortic calcification is associated with poor overall and recurrence‐free survival after hepatectomy for hepatocellular carcinoma (HCC). However, the effect of abdominal aortic calcification on cancer‐specific prognosis in very old patients with several comorbidities remains unknown. This multicenter study aimed to evaluate the impact of abdominal aortic calcification on the cumulative recurrence rate and recurrence‐free survival in patients with HCC aged >80 years. Methods We retrospectively analyzed the data of 128 patients (aged ≥80 years) who underwent liver resection for hepatocellular carcinoma at seven hospitals belonging to Hiroshima Surgical Study Group of Clinical Oncology between January 2014 and December 2018. Patients were divided into two groups: high and low abdominal aortic calcification groups. The primary endpoints were cumulative recurrence rate and recurrence‐free survival. Results Kaplan–Meier survival curve analysis demonstrated that the cumulative recurrence rate in the high abdominal aortic calcification group was significantly higher than that in the low abdominal aortic calcification group, and the high abdominal aortic calcification group had a significantly lower recurrence‐free survival rate. In the multivariate analysis, high abdominal aortic calcification (p = 0.03), high des‐gamma‐carboxyprothrombin score (p = 0.04), and multiple tumors (p

Hepatocellular carcinoma (HCC) is one of the leading causes of death in which the molecular tumorigenesis and cellular heterogeneity are poorly understood. The genetic principle that specific driver mutations in oncogenes, DNA repair genes, and tumor-suppressor genes can independently drive cancer development has been widely explored. Additionally, a repertory of harmful epigenetic modifications in DNA and chromatin—impacting the expression of genes involved in cellular proliferation, differentiation, genome stability, cell-cycle control, and DNA repair—are now acknowledged across various biological contexts that contribute to cancer etiology. Notably, the dynamic hypermethylation and hypomethylation in enhancer and promoter regions that promote activation or silencing of the master regulatory genes of the epigenetic programs is often altered in tumor cells due to mutation. Genome instability is one of the cancer hallmarks that contribute to transdifferentiation and intratumoral heterogeneity. Thus, it is broadly accepted that tumor tissue is dominated by genetically and epigenetically distinct sub-clones which display a set of genetic and epigenetic mutations. Here we summarize some functions of key genetic and epigenetic players and biochemical pathways leading to liver cell transformation. We discuss the role of the potential epigenetic marks in target genes thought to be involved in sequential events following liver lipid metabolism dysregulation, inflammation, fibrosis, cirrhosis, and finally hepatocellular carcinoma. We also briefly describe new findings showing how epigenetic drugs together with chemotherapy and immunotherapy can improve overall responses in patients with hepatic tumors.

Background: Several studies have demonstrated a relationship between genetic polymorphisms of interleukin‐1 beta (IL‐1β) and cancer development; however, their influence on cancer prognosis is unknown. In the present study, we aimed to evaluate the impact of IL‐1β single nucleotide polymorphisms on the hematogenous dissemination and prognosis of hepatocellular carcinoma. Methods: We conducted a retrospective cohort study including patients with hepatocellular carcinoma who underwent primary liver resection at our hospital between April 2015 and December 2018. The primary endpoints were overall and recurrence‐free survival. Secondary endpoints were microscopic portal vein invasion and number of circulating tumor cells. Results: A total of 148 patients were included, 32 with rs16944 A/A genotype. A/A genotype was associated with microscopic portal vein invasion and number of circulating tumor cells (p =.03 and.04). In multivariate analysis, A/A genotype, alpha‐fetoprotein level, and number of circulating tumor cells were associated with microscopic portal vein invasion (p =.01,.01, and <.01). A/A genotype, Child‐Pugh B, and intraoperative blood loss were independent predictive factors for overall survival (p =.02, <.01, and <.01). Conclusions: Our results indicate that the IL‐1β rs16944 A/A genotype is involved in number of circulating tumor cells, microscopic portal vein invasion, and prognosis in HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is a refractory tumor with poor prognosis and high mortality. Many oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma. Based on previous studies, we constructed a recombinant GM-CSF-carrying Sindbis virus, named SINV-GM-CSF, which contains a mutation (G to S) at amino acid 285 in the nsp1 protein of the viral vector. The potential of this mutated vector for liver cancer therapy was verified at the cellular level and in vivo, respectively, and the changes in the tumor microenvironment after treatment were also described. The results showed that the Sindbis virus could effectively infect hepatocellular carcinoma cell lines and induce cell death. Furthermore, the addition of GM-CSF enhanced the tumor-killing effect of the Sindbis virus and increased the number of immune cells in the intra-tumor microenvironment during the treatment. In particular, SINV-GM-CSF was able to efficiently kill tumors in a mouse tumor model of hepatocellular carcinoma by regulating the elevation of M1-type macrophages (which have a tumor-resistant ability) and the decrease in M2-type macrophages (which have a tumor-promoting capacity). Overall, SINV-GM-CSF is an attractive vector platform with clinical potential for use as a safe and effective oncolytic virus. [ABSTRACT FROM AUTHOR]

Diffusion‐derived vessel density (DVDD) is a physiological surrogate of the area of microvessels per unit tissue area. DDVD is calculated according to DDVD(b0b2) = Sb0/ROIarea0 – Sb2/ROIarea2, where Sb0 and Sb2 refer to the liver signal when b is 0 or 2 s/mm2. Pathohistological studies and contrast‐enhanced CT/MRI data showed higher blood volume in hepatocellular carcinoma (HCC) relative to native liver tissue. With intravoxel incoherent motion (IVIM) imaging, most authors paradoxically reported a decreased perfusion fraction of HCC relative to the adjacent liver. This study applied DDVD to assess the perfusion of HCC. MRI was performed with a 3.0‐T magnet. Diffusion‐weighted images with b‐values of 0 and 2 s/mm2 were acquired in 72 HCC patients. Thirty‐two patients had microvascular invasion (MVI(+)) and 40 patients did not have microvascular invasion (MVI(−)). Fifty‐eight patients had Edmondson–Steiner grade I or II HCC, and 14 patients had Edmondson–Steiner grade III or IV HCC. DDVD measurement was conducted on the axial slice that showed the largest HCC size. DDVD(b0b2) T/L = HCC DDVD(b0b2)/liver DDVD(b0b2). DDVD(b0b2) T/L median (95% confidence interval) of all HCCs was 2.942 (2.419–3.522), of MVI(−) HCCs was 2.699 (2.030–3.522), of MVI(+) HCCs was 2.988 (2.423–3.990), of Edmondson–Steiner grade I/II HCCs was 2.873 (2.277–3.465), and of Edmondson–Steiner grade III/IV HCCs was 3.403 (2.008–4.485). DDVD(b0b2) T/L approximately agrees with contrast agent dynamically enhanced CT/MRI literature data, whereas it differs from earlier IVIM study results, where HCC perfusion fraction was paradoxically lower relative to native liver tissue. A weak trend was noted with MIV(+) HCCs had a higher DDVD(b0b2) T/L than that of MVI(−) HCCs, and a weak trend was noted with the poorly differentiated group of HCCs (Edmondson–Steiner grade III and IV) had a higher DDVD(b0b2) T/L than that of the better differentiated group of HCCs (Edmondson–Steiner grade I and II). [ABSTRACT FROM AUTHOR]

Summary: Background: Loss of heterozygosity (LOH) diminishes genetic diversity within cancer genomes. A tumour arising in an individual heterozygous for a functional and a loss-of-function (LoF) allele of a gene occasionally retain only the LoF allele. This can result in deficiency of specific protein activities in cancer cells, creating unique differences between tumour cells and normal cells of the individual. Such differences may constitute vulnerabilities that can be exploited through allele-specific therapies. Methods: To discover frequently lost genes with prevalent LoF alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. From these, the variant rs3892097 in the liver enzyme CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types including hepatocellular cancers. To evaluate the relationship between CYP2D6 activity and the toxicities of anticancer agents, we screened 525 compounds currently in clinical use or undergoing clinical trials using cell model systems with or without CYP2D6 activity. Findings: We identified 12 compounds, AZD-3463, CYC-116, etoposide, everolimus, GDC-0349, lenvatinib, MK-8776, PHA-680632, talazoparib, tyrphostin 9, VX-702, and WZ-3146, using an engineered HEK293T cell model. Of these, talazoparib and MK-8776 demonstrated consistently heightened cytotoxic effects against cells with compromised CYP2D6 activity in engineered hepatocellular cancer cell models. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids. Interpretation: Exploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment. Funding: This work was funded by Barncancerfonden (T.S, PR2022-0099 and PR2020-0171, X.Z, TJ2021-0111), Cancerfonden (T.S, 211719Pj and D.G, 222449Pj), Vetenskapsrådet (T.S, 2020-02371 and D.G, 2020-04707), and the Erling Persson Foundation (T.S, 2020-0037 and T.S, 2023-0113).

Abstract Background Increasing evidence suggests that hepatocellular carcinoma (HCC) stem cells (LCSCs) play an essential part in HCC recurrence, metastasis, and chemotherapy and radiotherapy resistance. Multiple studies have demonstrated that stemness-related genes facilitate the progression of tumors. However, the mechanism by which stemness-related genes contribute to HCC is not well understood. Here, we aim to construct a stemness-related score (SRscores) model for deeper analysis of stemness-related genes, assisting with the prognosis and individualized treatment of HCC patients.Further, we found that the gene LPCAT1 was highly expressed in tumor tissues by immunohistochemistry, and sphere-forming assay revealed that knockdown of LPCAT1 inhibited the sphere-forming ability of hepatocellular carcinoma cells. Methods We used the TCGA-LIHC dataset to screen stemness-related genes of HCC from the MSigDB database. Prognosis, tumor microenvironment, immunological checkpoints, tumor immune dysfunction, rejection, treatment sensitivity, and putative biological pathways were examined. Random forest created the SRscores model. The anti-PD-1/anti-CTLA4 immunotherapy, tumor mutational burden, medication sensitivity, and cancer stem cell index were compared between the high- and low-risk score groups. We also examined risk scores for different cell types using single-cell RNA sequencing data and correlated transcription factor activity in cancer stem cells with SRscores genes. Finally, we tested core marker expression and biological functions. Results Patients can be divided into two subtypes (Cluster1 and Cluster2) based on the TCGA-LIHC dataset's identification of 11 stemness-related genes. Additionally, a SRscores was developed based on subtypes. Cluster2 and the group with the lowest SRscores had superior survival and immunotherapy response than Cluster1 and the group with the highest SRscores. The group with a high SRscores was significantly more enriched in classical tumor pathways than the group with a low SRscores. Multiple transcription factors and SRscores genes are correlated. The core gene LPCAT1 is highly expressed in rat liver cancer tissues and promotes tumor cell sphere formation. Conclusion A SRscores model can be utilized to predict the prognosis of HCC patients as well as their response to immunotherapy.

Background: Increasing evidence suggests that hepatocellular carcinoma (HCC) stem cells (LCSCs) play an essential part in HCC recurrence, metastasis, and chemotherapy and radiotherapy resistance. Multiple studies have demonstrated that stemness-related genes facilitate the progression of tumors. However, the mechanism by which stemness-related genes contribute to HCC is not well understood. Here, we aim to construct a stemness-related score (SRscores) model for deeper analysis of stemness-related genes, assisting with the prognosis and individualized treatment of HCC patients.Further, we found that the gene LPCAT1 was highly expressed in tumor tissues by immunohistochemistry, and sphere-forming assay revealed that knockdown of LPCAT1 inhibited the sphere-forming ability of hepatocellular carcinoma cells. Methods: We used the TCGA-LIHC dataset to screen stemness-related genes of HCC from the MSigDB database. Prognosis, tumor microenvironment, immunological checkpoints, tumor immune dysfunction, rejection, treatment sensitivity, and putative biological pathways were examined. Random forest created the SRscores model. The anti-PD-1/anti-CTLA4 immunotherapy, tumor mutational burden, medication sensitivity, and cancer stem cell index were compared between the high- and low-risk score groups. We also examined risk scores for different cell types using single-cell RNA sequencing data and correlated transcription factor activity in cancer stem cells with SRscores genes. Finally, we tested core marker expression and biological functions. Results: Patients can be divided into two subtypes (Cluster1 and Cluster2) based on the TCGA-LIHC dataset's identification of 11 stemness-related genes. Additionally, a SRscores was developed based on subtypes. Cluster2 and the group with the lowest SRscores had superior survival and immunotherapy response than Cluster1 and the group with the highest SRscores. The group with a high SRscores was significantly more enriched in classical tumor pathways than the group with a low SRscores. Multiple transcription factors and SRscores genes are correlated. The core gene LPCAT1 is highly expressed in rat liver cancer tissues and promotes tumor cell sphere formation. Conclusion: A SRscores model can be utilized to predict the prognosis of HCC patients as well as their response to immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Kinetic estimation provides fitted parameters related to blood flow perfusion and fluorine-18-fluorodeoxyglucose (18F-FDG) transport and intracellular metabolism to characterize hepatocellular carcinoma (HCC) but usually requires 60 min or more for dynamic PET, which is time-consuming and impractical in a busy clinical setting and has poor patient tolerance. Methods This study preliminarily evaluated the equivalence of liver kinetic estimation between short-term (5-min dynamic data supplemented with 1-min static data at 60 min postinjection) and fully 60-min dynamic protocols and whether short-term 18F-FDG PET-derived kinetic parameters using a three-compartment model can be used to discriminate HCC from the background liver tissue. Then, we proposed a combined model, a combination of the maximum-slope method and a three-compartment model, to improve kinetic estimation. Results There is a strong correlation between the kinetic parameters K 1 ~ k 3, HPI and $${{\varvec{V}}}_{{\varvec{b}}}$$ V b in the short-term and fully dynamic protocols. With the three-compartment model, HCCs were found to have higher k 2, HPI and k 3 values than background liver tissues, while K 1, k 4 and $${{\varvec{V}}}_{{\varvec{b}}}$$ V b values were not significantly different between HCCs and background liver tissues. With the combined model, HCCs were found to have higher HPI, K 1 and k 2, k 3 and $${{\varvec{V}}}_{{\varvec{b}}}$$ V b values than background liver tissues; however, the k 4 value was not significantly different between HCCs and the background liver tissues. Conclusions Short-term PET is closely equivalent to fully dynamic PET for liver kinetic estimation. Short-term PET-derived kinetic parameters can be used to distinguish HCC from background liver tissue, and the combined model improves the kinetic estimation. Clinical relevance statement Short-term PET could be used for hepatic kinetic parameter estimation. The combined model could improve the estimation of liver kinetic parameters. Graphical Abstract

Growing concern about photothermal tumor therapy (PTT) as a promising alternative to conventional liver cancer treatment, which is a treatment strategy that utilizes near‐infrared (NIR) light‐induced photothermal agents (PTAs) to yield photothermal effects to localize thermal damage for tumors. Herein, given the gap between experimental research and clinical application, this review seeks to timely summarize and highlight the recent progress of PTAs used for photothermal treatment of liver cancer in vivo and in vitro in the last five‐year. The implications of various PTAs on the multifunctional photothermal conversion capability, the structure‐performance correlations of PTT, together with the evaluation of their potential in application are systematically dissected to further dig out what the buried mechanism is. Besides, higher requirements are put forward for the discrepancies and crucial issues faced by different PTAs in PTT with related medical technical obstacles being conquered, which lays a solid theoretical foundation for the medical field of oncology treatment as a whole, especially liver cancer. Finally, it is expected that this review can present valuable guidance for the design of efficient, photostability, and biosafety‐aware PTAs for anticancer therapy while stepping into the fast traffic lane for the conversion from bench to bedside in the foreseeable future. [ABSTRACT FROM AUTHOR]

Tobacco contains many harmful chemicals, toxins, and carcinogens which cause serious health hazards. Mycotoxins and Aflatoxins are present in all tobacco including chewing and smokeless tobacco. We detected and isolated the aflatoxins-producing fungi Aspergillus sp. by microbial and molecular-based techniques. 50 samples were collected randomly and grown on SDA media by spread plate method. Isolates of A. flavus were analyzed for Aflatoxin production by Ammonia vapor test and the DNA of isolates was extracted and subjected for further molecular identification. Different fungal genera were observed including the most common Aspergillus while the other were Penicillium, Rhizopus, candida, and Trichophyton. Aspergillus flavus was isolated and characterized as a white soft velvety surface. The diameter of colonies was observed as 50 - 70 mm. Coconut-based medium detection by UV light of 365 nm showed the production of blue-green fluorescence on the reverse of colonies on coconut agar medium. DNA extracted from all the strains producing aflatoxins was quantified by VICAM. High levels of Aflatoxin ranging from 21 - 47 ug/kg were detected in 10 different samples while the remaining samples had a range of 10 - 20 ug/kg. the study showed both quantitative and qualitative techniques for the detection of aflatoxin-producing fungi in chewing tobacco. aflR and aflS were observed as potential candidates for the detection of aflatoxigenic fungi. [ABSTRACT FROM AUTHOR]

Background: The expression level of Ribonuclease H2, subunit A (RNASEH2A) in hepatocellular carcinoma (HCC) has been reported, but the function of RNASEH2A on HCC cells development and the related molecular mechanisms remain unclear. Herein, we intend to explore the upstream regulator of RNASEH2A and its role in the HCC progression. Methods: GEPIA website was employed to determine the level of RNASEH2A in HCC tissues and get a survival analysis. After reducing RNASEH2A expression by RNA interference, cell counting kit-8, colony formation, Western blot, Transwell and wound healing assays were performed to estimate the malignant properties of HCC cells. The transcriptional factor of RNASEH2A was predicted by UCSC and JASPAR database and confirmed by dual luciferase assay and Ch-IP assay. The expression level of EMT pathway related molecules was determined by western blotting. Results: An increased expression of RNASEH2A was presented in HCC and predicted worse prognosis of HCC patients. Functionally, the results demonstrated that depletion of RNASEH2A suppressed HCC cell proliferation, cell cycle, migration and invasion. Moreover, we illustrated that SP1 targeted to the promoter of RNASEH2A and modulated its expression in HCC cell lines. RNASEH2A knockdown counteracted the function of SP1 overexpression in modulating HCC cell growth, cell cycle, and mobility. Then, our data showed that the SP1/RNASEH2A axis affected the malignant behaviors of HCC cells by regulating EMT process. Conclusions: In summary, these results demonstrated that RNASEH2A promoted HCC cells development through regulating EMT process and was transcriptionally modulated by SP1.

Background: Kinetic estimation provides fitted parameters related to blood flow perfusion and fluorine-18-fluorodeoxyglucose (18F-FDG) transport and intracellular metabolism to characterize hepatocellular carcinoma (HCC) but usually requires 60 min or more for dynamic PET, which is time-consuming and impractical in a busy clinical setting and has poor patient tolerance. Methods: This study preliminarily evaluated the equivalence of liver kinetic estimation between short-term (5-min dynamic data supplemented with 1-min static data at 60 min postinjection) and fully 60-min dynamic protocols and whether short-term 18F-FDG PET-derived kinetic parameters using a three-compartment model can be used to discriminate HCC from the background liver tissue. Then, we proposed a combined model, a combination of the maximum-slope method and a three-compartment model, to improve kinetic estimation. Results: There is a strong correlation between the kinetic parameters K1 ~ k3, HPI and V b in the short-term and fully dynamic protocols. With the three-compartment model, HCCs were found to have higher k2, HPI and k3 values than background liver tissues, while K1, k4 and V b values were not significantly different between HCCs and background liver tissues. With the combined model, HCCs were found to have higher HPI, K1 and k2, k3 and V b values than background liver tissues; however, the k4 value was not significantly different between HCCs and the background liver tissues. Conclusions: Short-term PET is closely equivalent to fully dynamic PET for liver kinetic estimation. Short-term PET-derived kinetic parameters can be used to distinguish HCC from background liver tissue, and the combined model improves the kinetic estimation. Clinical relevance statement: Short-term PET could be used for hepatic kinetic parameter estimation. The combined model could improve the estimation of liver kinetic parameters. Key points: Short-term PET could be used for hepatic kinetic parameter estimation. Short-term PET was very similar to full dynamic PET in the estimation of liver kinetic parameters. The combined models could improve the estimation of liver kinetic parameters. [ABSTRACT FROM AUTHOR]

Objectives: To comprehensively evaluate the reporting quality, risk of bias, and radiomics methodology quality of radiomics models for predicting microvascular invasion in hepatocellular carcinoma. Methods: A systematic search of available literature was performed in PubMed, Embase, Web of Science, Scopus, and the Cochrane Library up to January 21, 2022. Studies that developed and/or validated machine learning models based on radiomics data to predict microvascular invasion in hepatocellular carcinoma were included. These studies were reviewed by two investigators and the consensus data were used for analyzing. The reporting quality, risk of bias, and radiomics methodological quality were evaluated by Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD), Prediction model Risk of Bias Assessment Tool, and Radiomics Quality Score (RQS), respectively. Results: A total of 30 studies met eligibility criteria with 24 model developing studies and 6 model developing and external validation studies. The median overall TRIPOD adherence was 75.4% (range 56.7–94.3%). All studies were at high risk of bias with at least 2 of 20 sources of bias. Furthermore, 28 studies showed unclear risks of bias in up to 5 signaling questions because of the lack of specified reports. The median RQS score was 37.5% (range 25–61.1%). Conclusion: Current radiomic models for MVI-status prediction have moderate to good reporting quality, moderate radiomics methodology quality, and high risk of bias in model development and validation. Key Points: • Current microvascular invasion prediction radiomics studies have moderate to good reporting quality, moderate radiomics methodology quality, and high risk of bias in model development and validation. • Data representativeness, feature robustness, events-per-variable ratio, evaluation metrics, and appropriate validation are five main aspects futures studies should focus more on to improve the quality of radiomics. • Both Radiomics Quality Score and Prediction model Risk of Bias Assessment Tool are needed to comprehensively evaluate a radiomics study. [ABSTRACT FROM AUTHOR]

Objective: Primary liver tumors are rare pediatric malignancies. Knowledge of the epidemiology of pediatric liver tumors is limited. This study aims to present the national incidence trends of pediatric liver tumors over 18 years, according to sociodemographic and histological subtype variation. Methods: The Surveillance, Epidemiology, and End Results registry was queried from 2000 to 2017 for 1,099 patients between ages 0 and 19 with liver tumors. Age-standardized incidence rates by age, sex, and race/ethnicity were examined among histological subtypes. Annual percentage change (APC) was calculated via joinpoint regression for various sociodemographic and histotype subgroups. Results: An increase of age-adjusted incidence rate of pediatric hepatic cancers was observed between 2000 and 2017 (APC, 1.7% [95% confidence interval or CI: 0.6%–2.8%], p-value = 0.006), which may likely attribute to the increasing incidence of hepatoblastoma and mesenchymal tumors (APC, 2.5% [95% CI: 1.1%–3.8%], p-value = 0.001). The incidence trend of hepatocellular carcinoma remained stable in the study period. The non-Hispanic Asian/Pacific Islander children and adolescents had a higher risk of hepatic tumors (incidence rate ratio or IRR, 1.42 [95% CI: 1.16–1.72], p-value = 0.0007) when compared with the non-Hispanic white subgroup, while a non-Hispanic black child was associated with a lower incidence rate (IRR, 0.64 [95% CI: 0.50–0.80], p-value < 0.0001). Significantly lower hepatic tumor incidence occurred in females than males, with an incidence rate ratio of 0.69 (95% CI: 0.61–0.78; p-value < 0.0001). Hepatic tumor incidence was also significantly lower in those aged 1–4 years (IRR, 0.47 [95% CI: 0.40–0.54]; p-value < 0.001) and 5–19 years (IRR, 0.09 [95% CI: 0.08–0.10]; p–value < 0.001) when compared with the youngest age group aged less than 1 year. These significant differences were also detected for the subgroup of hepatoblastoma and mesenchymal liver tumors but less among hepatocellular carcinomas (all p-values less than 0.0001). Conclusion: Continued increasing incidence of pediatric hepatoblastoma and mesenchymal liver tumors was discovered and warranted further investigation. Additional findings include a lower incidence of hepatic cancer among non-Hispanic black individuals and higher incidence of hepatic cancer in non-Hispanic Asian/Pacific Islander, male, and aged 1–4-year children and adolescents. [ABSTRACT FROM AUTHOR]

DNA glycosylases promote genomic stability by initiating base excision repair (BER) in both the nuclear and mitochondrial genomes. Several of these enzymes have overlapping substrate recognition, through which a degree of redundancy in lesion recognition is achieved. For example, OGG1 and NEIL1 both recognize and release the imidazole-ring-fragmented guanine, FapyGua as part of a common overall pathway to cleanse the genome of damaged bases. However, these glycosylases have many differences, including their differential breadth of substrate specificity, the contrasting chemistries through which base release occurs, the subsequent steps required to complete the BER pathway, and the identity of specific protein-binding partners. Beyond these differences, the complexities and differences of their in vivo biological roles have been primarily elucidated in studies of murine models harboring a knockout of Neil1 or Ogg1, with the diversity of phenotypic manifestations exceeding what might have been anticipated for a DNA glycosylase deficiency. Pathologies associated with deficiencies in nuclear DNA repair include differential cancer susceptibilities, where Ogg1-deficient mice are generally refractory to carcinogenesis, while deficiencies in Neil1-deficient mice confer cancer susceptibility. In contrast to NEIL1, OGG1 functions as a key transcription factor in regulating inflammation and other complex gene cascades. With regard to phenotypes attributed to mitochondrial repair, knockout of either of these genes results in age- and diet-induced metabolic syndrome. The adverse health consequences associated with metabolic syndrome can be largely overcome by expression of a mitochondrial-targeted human OGG1 in both wild-type and Ogg1-deficient mice. The goal of this review is to compare the roles that NEIL1 and OGG1 play in maintaining genomic integrity, with emphasis on insights gained from not only the diverse phenotypes that are manifested in knockout and transgenic mice, but also human disease susceptibility associated with polymorphic variants. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficiency of radiomics signatures in predicting the response of transarterial chemoembolization (TACE) therapy based on preoperative contrast-enhanced computed tomography (CECT).Materials: This study consisted of 111 patients with intermediate-stage hepatocellular carcinoma who underwent CECT at both the arterial phase (AP) and venous phase (VP) before and after TACE. According to mRECIST 1.1, patients were divided into an objective-response group (n = 38) and a non-response group (n = 73). Among them, 79 patients were assigned as the training dataset, and the remaining 32 cases were assigned as the test dataset.Methods: Radiomics features were extracted from CECT images. Two feature ranking methods and three classifiers were used to find the best single-phase radiomics signatures for both AP and VP on the training set. Meanwhile, multi-phase radiomics signatures were built upon integration of images from two CECT phases by decision-level fusion and feature-level fusion. Finally, multivariable logistic regression was used to develop a nomogram by combining radiomics signatures and clinic-radiologic characteristics. The prediction performance was evaluated by AUC on the test dataset.Results: The multi-phase radiomics signature (AUC = 0.883) performed better in predicting TACE therapy response compared to the best single-phase radiomics signature (AUC = 0.861). The nomogram (AUC = 0.913) showed better performance than any radiomics signatures.Conclusion: The radiomics signatures and nomogram were developed and validated for predicting responses to TACE therapy, and the radiomics model may play a positive role in identifying patients who may benefit from TACE therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Accumulating evidence suggests that light at night (LAN) disrupts circadian rhythms and may increase risk of liver cancer. However, there is no population-based study that examined LAN and liver cancer risk. Therefore, we aimed to investigate the association between outdoor LAN and liver cancer risk in a prospective cohort.Methods: Residential outdoor LAN level was measured from satellite imagery in the NIH-AARP Diet and Health Study, a prospective cohort of 451,945 men and women, 50-71 years old. Relative risks (RR) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models that adjusted for known risk factors for liver cancer and neighborhood characteristics.Results: During an average 12.2 years of follow-up, 897 liver cancers, 603 of which were hepatocellular carcinomas (HCC), were diagnosed. Residential outdoor LAN was not associated with risk of liver cancer (RRQ5 vs Q1 = 0.96, 95% CI: 0.77-1.20, p trend = 0.771) or HCC (RRQ5 vs Q1 = 0.82, 95% CI: 0.62-1.07, p trend = 0.425).Conclusion: No association between outdoor LAN and risk of liver cancer or HCC may in part be due to limitations in LAN assessment. More studies on the relationship between light intensity, duration, timing, and wavelength and liver cancer are warranted. [ABSTRACT FROM AUTHOR]

Highlight 1. High BMI combined with HBV infection has a negative impact on the PFS and OS of HCC patients treated with TACE. 2. Irrespective of TACE, the average HMGB1 in hepatitis and obesity patients was higher than that in normal individuals, which was not upregulated after TACE. 3. Patients without overweight and HBV infection had a low level of serum concentration of HMGB1 before TACE that was upregulated after TACE. Compared to others, these patients have severe changes in HMGB1 in the peripheral blood after treatment, indicating a higher risk of acute liver injury. 4. Upregulated HMGB1 elevated the prognosis after TACE, but obesity and HBV infection resulted in the negative effect by inhibiting HMGB1 expression. 5. For advanced HCC, overweight combined HBV infection, PVTT, multiple lesions, and larger tumor diameter are negative factors for TACE.

Purpose: To evaluate the diagnostic performance of LR‐5 for diagnosing poorly differentiated hepatocellular carcinoma (p‐HCC). To build a contrast‐enhanced ultrasound (CEUS) signature for improving the differential diagnostic performance between p‐HCC and intrahepatic cholangiocarcinoma (ICC). Methods: The B‐mode ultrasound (BUS) and CEUS features of 60 p‐HCCs and 56 ICCs were retrospectively analyzed. The CEUS LI‐RADS category was assigned according to CEUS LI‐RADS v2017. A diagnostic CEUS signature was built based on the independent significant features. An ultrasound (US) signature combining both BUS and CEUS features was also built. The diagnostic performances of the CEUS signature, US signature, and LR‐5 were evaluated by receiver operating characteristic (ROC) analysis. Results: One (1.7%) p‐HCC and 26 (46.4%) ICC patients presented cholangiectasis or cholangiolithiasis (P <.001). Fifty‐four (90.0%) p‐HCCs and 8 (14.3%) ICCs showed clear boundaries in the artery phase (P <.001). The washout times of p‐HCCs and ICCs were 81.0 ± 42.5 s and 34.7 ± 8.6 s, respectively (P <.001). The AUC, sensitivity, and specificity of the CEUS signature, US signature, and LR‐5 were 0.955, 91.67%, and 90.57% versus 0.976, 96.67%, and 92.45% versus 0.758, 51.67%, and 100%, respectively. The AUC and sensitivity of CEUS LI‐RADS were much lower than those of the CEUS and US signatures (P <.001). Conclusion: LR‐5 had high specificity but low sensitivity in diagnosing p‐HCC. When the washout time and tumor boundary were included in the CEUS signature, the sensitivity and AUC were remarkably increased in the differentiation between p‐HCC and ICC. [ABSTRACT FROM AUTHOR]

Hypoxia in the tumor microenvironment (TME) is the leading cause of metastasis and chemoresistance in cancer cells. Numerous 3D in vitro models have been proposed to study hypoxic stress, but none have enabled sufficient analysis of hepatocellular carcinoma (HCC). Herein, a 3D in vitro tumor vasculature model for HCC is introduced to investigate cellular responses and drug resistance under hypoxic conditions through high‐content screening. The hypoxic TME of vascularized HCC can be established by maintaining the platform in a hypoxia chamber and is used to analyze the diverse physiological responses of the TME to normoxia, hypoxia, and drug treatment. The proposed platform also demonstrates the hypoxic status naturally induced by 3D HCC spheroids for comparison with single HCC cells cultured in the hypoxia chamber. The results show that hypoxic stress in the HCC vasculature promotes angiogenesis, hypoxia‐inducible factor 1 (HIF‐1) expression, and proliferation; it also enhances drug resistance. The hypoxic tumor vasculature of the model generates cellular responses that are also expressed in the physiological hypoxic microenvironment of HCC. These findings suggest that our high‐content microfluidic platform can be applied as a powerful tool to develop anticancer therapeutics, which have remained elusive because of hypoxia in the TME.

Laparoscopic ablation (LA) of liver tumors is an increasingly performed procedure. However, LA is technically demanding, with inherent difficulties making LA more complex than percutaneous and open surgery ablations. This study aimed to characterize the learning curve (LC) of LAs. All consecutive LAs of malignant liver tumors performed with curative intent by a single surgeon were identified from a prospective database. A risk-adjusted cumulative summative (RA-CUSUM) analysis was used for evaluating the LC of LAs. Incomplete ablation (IA) was the outcomes measure. Performance trends were analyzed using broken-line modeling. From June 2007 to February 2018, 241 lesions underwent LA during 151 procedures. RA-CUSUM analysis demonstrated an LC of 93 LAs (p < 0.001), with an IA rate decreasing from 12.9% to 4.7% (p = 0.027). Lesions in the posterosuperior segment and those in cirrhotic livers showed an LC of 34 and 45 tumor ablations, respectively (p=<0.001 each). Open ablations performed during the same period showed steady outcomes, indicating already acquired proficiency. Completion of a steep LC is needed to gain proficiency in LAs. Dedicated training should be warranted to novices to smooth the LC and decrease LA failures. [ABSTRACT FROM AUTHOR]

Background: Transarterial chemoembolization (TACE) is an effective treatment for patients with hepatocellular carcinoma (HCC). However, the impact of hepatitis B viral (HBV) infection and body mass index (BMI) on TACE is controversial. The present study aimed to compare the influence of HBV and high BMI on TACE outcomes in advanced HCC.Methods: Based on HBV infection history and BMI, patients were assigned to different subgroups. Blood samples were collected and analyzed by an enzyme-linked immunosorbent assay (ELISA) kit. The primary endpoint was progression-free survival (PFS) and the overall survival (OS) in the population.Results: Compared to overweight combined HBV patients who received TACE, people with normal weight or no viral infection had significantly better OS and PFS. Sex, age, portal vein tumor thrombus, BCLC, ECOG, and tumor diameter are the main risk factors affecting PFS and OS. Except for the postoperative fever, no significant difference was detected in adverse reactions. Irrespective of TACE, the average expression of HMGB1 in hepatitis or obesity patients was higher than that in normal individuals and did not show upregulation after TACE. Patients without overweight or HBV infection had a low expression of serum HMGB1 that was substantially upregulated after TACE.Conclusions: In this study, overweight combined HBV infection patients had shorter PFS and OS than other HCC patients. Thus, HBV and BMI maybe two factors affecting the efficacy of TACE via upregulated HMGB1. [ABSTRACT FROM AUTHOR]

Background: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) represents an aggressive form of hepatocellular carcinoma and is associated with poor survival outcomes. Aims: This study aimed to develop a radiomics nomogram based on contrast-enhanced MRI for preoperative prediction of MTM-HCC. Methods: This study enrolled 88 patients with histologically confirmed HCC, including 32 MTM-HCCs and 56 Non-MTM-HCCs. The clinical and gadobenate dimeglumine (Gd)-enhanced MRI features were retrospectively reviewed by two abdominal radiologists. The regions of interest (ROIs) on the largest cross-sectional image and two adjacent images of the tumor, from which radiomics features were extracted via MaZda software and a radiomics score (Rad-score) was calculated via Python software. Combined with the Rad-score and independent imaging factors, a radiomics nomogram was constructed using R software. Nomogram performance was estimated with calibration curve. Results: A total of eleven top weighted radiomics features were selected among five sequences of MR images. There was a significant difference in Rad-score between MTM-HCC and non-MTM-HCC patients (P < 0.001), where patients with MTM-HCC generally had higher Rad-scores (absolute value). After multivariate analysis, radiomics score (OR = 7.794, P < 0.001) and intratumor fat (OR = 9.963, P = 0.014) were determined as independent predictors associated with MTM-HCC. The area under the receiver operating characteristic (ROC) curve of the selected model was 0.813 (95% CI 0.714–0.912) and the optimal cutoff value was 0.60. The nomogram showed overall satisfactory prediction performance (AUC = 0.785 [95% CI 0.684–0.886]). Conclusions: A contrast-enhanced MRI-based radiomics nomogram may be useful for preoperative prediction of MTM-HCC in primary HCC patients, allowing opportunity to improve the treatment course and patient outcomes. [ABSTRACT FROM AUTHOR]

Abstract The physical microenvironment is a critical mediator of tumor behavior. However, detailed biological and mechanistic insight is lacking. The present study reveals the role of chemotherapy‐enriched CD133+ liver cancer stem cells (CSCs) with THBS2 deficiency. This subpopulation of cells contributes to a more aggressive cancer and functional stemness phenotype in hepatocellular carcinoma (HCC) by remodeling the extracellular matrix (ECM) through the regulation of matrix metalloproteinase (MMP) activity, collagen degradation, and matrix stiffness. The local soft spots created by these liver CSCs can enhance stemness and drug resistance and provide a route of escape to facilitate HCC metastasis. Interestingly, a positive feed‐forward loop is identified where a local soft spot microenvironment in the HCC tumor is enriched with CD133 expressing cells that secrete markedly less ECM‐modifying THBS2 upon histone H3 modification at its promoter region, allowing the maintenance of a localized soft spot matrix. Clinically, THBS2 deficiency is also correlated with low HCC survival, where high levels of CSCs with low THBS2 expression in HCC are associated with decreased collagen fiber deposits and an invasive tumor front. The findings have implications for the treatment of cancer stemness and for the prevention of tumor outgrowth through disseminated tumor cells.

The physical microenvironment is a critical mediator of tumor behavior. However, detailed biological and mechanistic insight is lacking. The present study reveals the role of chemotherapy‐enriched CD133+ liver cancer stem cells (CSCs) with THBS2 deficiency. This subpopulation of cells contributes to a more aggressive cancer and functional stemness phenotype in hepatocellular carcinoma (HCC) by remodeling the extracellular matrix (ECM) through the regulation of matrix metalloproteinase (MMP) activity, collagen degradation, and matrix stiffness. The local soft spots created by these liver CSCs can enhance stemness and drug resistance and provide a route of escape to facilitate HCC metastasis. Interestingly, a positive feed‐forward loop is identified where a local soft spot microenvironment in the HCC tumor is enriched with CD133 expressing cells that secrete markedly less ECM‐modifying THBS2 upon histone H3 modification at its promoter region, allowing the maintenance of a localized soft spot matrix. Clinically, THBS2 deficiency is also correlated with low HCC survival, where high levels of CSCs with low THBS2 expression in HCC are associated with decreased collagen fiber deposits and an invasive tumor front. The findings have implications for the treatment of cancer stemness and for the prevention of tumor outgrowth through disseminated tumor cells. [ABSTRACT FROM AUTHOR]

Background: Several studies have demonstrated a relationship between genetic polymorphisms of interleukin-1 beta (IL-1β) and cancer development; however, their influence on cancer prognosis is unknown. In the present study, we aimed to evaluate the impact of IL-1β single nucleotide polymorphisms on the hematogenous dissemination and prognosis of hepatocellular carcinoma., Methods: We conducted a retrospective cohort study including patients with hepatocellular carcinoma who underwent primary liver resection at our hospital between April 2015 and December 2018. The primary endpoints were overall and recurrence-free survival. Secondary endpoints were microscopic portal vein invasion and number of circulating tumor cells., Results: A total of 148 patients were included, 32 with rs16944 A/A genotype. A/A genotype was associated with microscopic portal vein invasion and number of circulating tumor cells (p = .03 and .04). In multivariate analysis, A/A genotype, alpha-fetoprotein level, and number of circulating tumor cells were associated with microscopic portal vein invasion (p = .01, .01, and <.01). A/A genotype, Child-Pugh B, and intraoperative blood loss were independent predictive factors for overall survival (p = .02, <.01, and <.01)., Conclusions: Our results indicate that the IL-1β rs16944 A/A genotype is involved in number of circulating tumor cells, microscopic portal vein invasion, and prognosis in HCC., (© 2024 The Author(s). Journal of Hepato‐Biliary‐Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Patients with HCC receiving TACE have various clinical outcomes. Several prognostic models have been proposed to predict clinical outcomes for patients with hepatocellular carcinomas (HCC) undergoing transarterial chemoembolization (TACE), but establishing an accurate prognostic model remains necessary. We aimed to develop a radiomics signature from pretreatment CT to establish a combined radiomics-clinic (CRC) model to predict survival for these patients. We compared this CRC model to the existing prognostic models in predicting patient survival. This retrospective study included multicenter data from 162 treatment-naïve patients with unresectable HCC undergoing TACE as an initial treatment from January 2007 and March 2017. We randomly allocated patients to a training cohort (n = 108) and a testing cohort (n = 54). Radiomics features were extracted from intra- and peritumoral regions on both the arterial phase and portal venous phase CT images. A radiomics signature (Rad-signature) for survival was constructed using the least absolute shrinkage and selection operator method in the training cohort. We used univariate and multivariate Cox regressions to identify associations between the Rad- signature and clinical factors of survival. From these, a CRC model was developed, validated, and further compared with previously published prognostic models including four-and-seven criteria, six-and-twelve score, hepatoma arterial-embolization prognostic scores, and albumin-bilirubin grade. The CRC model incorporated two variables: The Rad-signature (composed of features extracted from intra- and peritumoral regions on the arterial phase and portal venous phase) and tumor number. The CRC model performed better than the other seven well-recognized prognostic models, with concordance indices of 0.73 [95% confidence interval (CI) 0.68–0.79] and 0.70 [95% CI 0.62–0.82] in the training and testing cohorts, respectively. Among the seven models tested, the six-and-12 score and four-and-seven criteria performed better than the other models, with C-indices of 0.64 [95% CI 0.58–0.70] and 0.65 [95% CI 0.55–0.75] in the testing cohort, respectively. The CT radiomics signature represents an independent biomarker of survival in patients with HCC undergoing TACE, and the CRC model displayed improved predictive performance.

Arsenic, a human carcinogen, causes various human cancers, including those of the skin, lung, and liver. Hepatocellular carcinomas (HCCs), which have high mortality, are common malignancies worldwide. Tumor-associated macrophages (TAMs), which are considered to be similar to M2-polarized macrophages, promote tumor invasion and progression. Small non-coding RNAs (miRNAs) regulate expression of genes involved in progression of various malignancies. Extracellular vesicles (EVs), as mediators of cell communication, pass specific miRNAs directly from TAMs to tumor cells, promoting tumor pathogenesis and metastasis. In HCCs, large tumor suppressor kinase 1 (LATS1), functions as a tumor suppressor. However, the molecular mechanism by which miRNA modulates LATS1 expression in HCCs remains unclear. The results show that exposure to arsenite, increased miR-15b levels and induced M2 polarization of THP-1 cells. Elevated levels of miR-15b were transferred from arsenite-treated-THP-1 (As-THP-1) cells to HCC cells via miR-15b in EVs inhibited activation of the Hippo pathway by targeting LATS1, and was involved in promoting the proliferation, migration, and invasion of HCC cells. In conclusion, miR-15b in EVs from As-THP-1 cells is transferred to HCC cells, in which it targets and downregulates LATS1 expression and promotes the proliferation, migration, and invasion of HCC cells. [ABSTRACT FROM AUTHOR]

Patients with HCC receiving TACE have various clinical outcomes. Several prognostic models have been proposed to predict clinical outcomes for patients with hepatocellular carcinomas (HCC) undergoing transarterial chemoembolization (TACE), but establishing an accurate prognostic model remains necessary. We aimed to develop a radiomics signature from pretreatment CT to establish a combined radiomics-clinic (CRC) model to predict survival for these patients. We compared this CRC model to the existing prognostic models in predicting patient survival. This retrospective study included multicenter data from 162 treatment-naïve patients with unresectable HCC undergoing TACE as an initial treatment from January 2007 and March 2017. We randomly allocated patients to a training cohort (n = 108) and a testing cohort (n = 54). Radiomics features were extracted from intra- and peritumoral regions on both the arterial phase and portal venous phase CT images. A radiomics signature (Rad-signature) for survival was constructed using the least absolute shrinkage and selection operator method in the training cohort. We used univariate and multivariate Cox regressions to identify associations between the Rad- signature and clinical factors of survival. From these, a CRC model was developed, validated, and further compared with previously published prognostic models including four-and-seven criteria, six-and-twelve score, hepatoma arterial-embolization prognostic scores, and albumin-bilirubin grade. The CRC model incorporated two variables: The Rad-signature (composed of features extracted from intra- and peritumoral regions on the arterial phase and portal venous phase) and tumor number. The CRC model performed better than the other seven well-recognized prognostic models, with concordance indices of 0.73 [95% confidence interval (CI) 0.68–0.79] and 0.70 [95% CI 0.62–0.82] in the training and testing cohorts, respectively. Among the seven models tested, the six-and-12 score and four-and-seven criteria performed better than the other models, with C-indices of 0.64 [95% CI 0.58–0.70] and 0.65 [95% CI 0.55–0.75] in the testing cohort, respectively. The CT radiomics signature represents an independent biomarker of survival in patients with HCC undergoing TACE, and the CRC model displayed improved predictive performance. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the efficacy and safety of microwave ablation (MWA) in small hepatocellular carcinomas sized ≤ 3 cm, determine long-term survival, and identify prognostic factors for survival rates. Material and methods: In this study, the radiological and laboratory findings obtained from 31 consecutive patients who underwent MWA were retrospectively evaluated. The survival periods and complication rates were analysed. Results: Microwave ablation was applied to 42 hepatocellular carcinoma nodules in 31 patients. The mean age of the patients was 61 ± 7.3 (median 62, range 46-78) years. The mean overall survival (OS) was 47.4 ± 3.3 months. The rates of cumulative OS in the first, second, and third years were 95.2%, 91.8%, and 79.2%, respectively. The mean disease-free survival (DFS) rate was 24.1 ± 2.5 months. The cumulative DFS rates in the first, second, and third years were 75.6%, 52.5%, and 28.2%, respectively. The number of tumours and tumour distribution were determined as prognostic factors. No major complication was detected, but six patients (13.9%) developed minor complications after MWA. Conclusions: Microwave ablation in patients with hepatocellular carcinoma is a safety treatment modality with very low rates of complications. It offers an effective treatment with a high rate of complete response and local disease control according to the short-term results. In the long term, it prolongs the survival time of the treated patients. The number of tumours and tumour distribution were determined as prognostic factors affecting survival rates. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is very common globally prevalent cancer. Due to its poor clinical prognosis, increasing the diagnostic rate of HCC is urgently needed. Herein, we validate discovered metabolomic biomarkers to distinguish Hepatitis B virus (HBV)-related HCC, including alpha-fetoprotein (AFP) negative (AFP–) and positive (AFP+) individuals.Methods: We recruited 130 HCC subjects (independent case-control, randomized clinical cohorts) to our study. We separated the subjects randomly into two panels: (1) 58 individuals for the discovery panel; and (2) 72 individuals for the validation panel. For each panel, gender and age-matched hepatitis B group (HBG) and healthy group were included as controls. Plasma samples were collected for metabolic profiling by liquid chromatography—mass spectrometry—based metabolomics assays. We applied both non-targeted metabolomics analyses and targeted metabolomics analyses. Significantly changed metabolites (SCMs) were identified. The power of SCMs to discriminate HCC and HBG or healthy group was determined by receiver operating characteristic curve (ROC) analysis.Results: Ten SCMs were selected form the discovery panel, and further verified in the validation panel. ROC analyses indicated that 1 SCMs (LysoPC (24:0)) could discriminate HCC from HBG (AUC = 0.765). Further, 8 SCMs including (LysoPC (17:0), LysoPC (20:4(8Z,11Z,14Z,17Z)), LysoPC (22:0), LysoPC (24:0), PE (P-16:0/22:4(7Z,10Z,13Z,16Z)), SM (d18:1/22:1(13Z)), Creatinine, and L-Isoleucine) displayed a heightened ability to discriminate between HCC and healthy controls (AUC were more than 0.800). Most of these SCMs were important in lipid metabolism.Conclusions: LysoPC (24:0) could distinguished HCC from HBG, and 8 SCMs distinguished HCC from healthy controls. LysoPC and other metabolites have the potential to serve as non-invasive biomarkers for HBV related AFP– and AFP+ HCC.

Hepatocellular carcinoma (HCC) is a prototype of inflammation-related cancer, harboring M1-like and M2-like tumor-associated macrophages. M1 macrophages are thought to be tumoricidal, but some studies report its pro-tumor role. The programmed cell death-ligand (PD-L) 1 expressed in HCC cells is a critical checkpoint molecule to mediate immune escape of HCC. The PD-L1 expression in HCC cells is inducible. In the present study, we ask whether M1 macrophages induce the expression of PD-L1 in HCC cells. First, an association between M1 macrophage infiltration and PD-L1 expression in HCC tissues was determined by bioinformatics and immunohistochemistry experiments. The enrichment score of M1 macrophages was correlated to PD-L1 expression in 90 HCC samples from GEO database. Besides, infiltration of CD68+HLA-DR+ M1-like macrophages correlated with PD-L1 expression level in HCC cells. Moreover, M1-conditioned media was prepared from M1 macrophages derived from THP-1 cell, RAW264.7 cell or murine bone marrow. These supernatants induced expression of PD-L1 in HCC cells. Furthermore, inflammatory cytokine IL-1β in the supernatants was identified to account for the inducible PD-L1 expression by siRNA assay and receptor blockade assay. Additionally, transcription factor p65 and IRF1 in the HCC cells were revealed by CHIP assay to mediate the inducible PD-L1 expression. All the results demonstrate that M1 macrophages induced expression of PD-L1 in HCC cells, supporting the pro-tumor role of M1 macrophages.

Objective: To explore the Clinical value of transcatheter arterial chernoembolization (TACE) followed by percutaneous microwave ablation (MWA) for hepatocellular carcinomas, and to analyze the efficacy. Methods: A retrospective analysis of 96 patients with primary liver cancer treated at the First People's Hospital of Shanghai Jiaotong University from January 2016 to July 2018, 42 patients underwent TACE sequential combined with B-ultrasound/CT－guided MWA treatment (Combined group), another 54 patients were treated with TACE alone (TACE group). CT, MRI, AFP and liver function were enhanced at 1 month, 3 months, 6 months, 1 year and 2 years after treatment Tumor necrosis, recurrence, progression and survival were compared between the two groups. The efficacy of the two groups was evaluated. Results: The tumor necrosis rate was 92.9 % in the combined group and 48.1 % in the TACE group, the difference was statistically significant (P<0.05). The tumor recurrence rate was 7.1 % in the combined group and 24.1 % in the TACE group, the difference was statistically significant (P<0.05). The tumor progression rate was 19.1 % in the combined group and 27.8 % in the TACE group, the difference was not statistically significant (P>0.05). The median progression time was 13.2 months in the combined group and 7.6 months in the TACE group, the difference was statistically significant (p<0.05). The 1-year survival rate of the combined group was 83.3 % and 57.4 % in the TACE group, the difference was statistically significant (P<0.05). The 2-year survival rate of the combined group was 62 % and 31.5 % in the TACE group, the difference was statistically significant (P<0.05). The median survival time was 28.9 months in the combined group and 16.9 months in the TACE group, the difference was statistically significant (P<0.05). ConcIusions TACE sequential MWA is safe and effective in the treatment of liver cancer, and can complement each other. It is a new model for comprehesive treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is very common globally prevalent cancer. Due to its poor clinical prognosis, increasing the diagnostic rate of HCC is urgently needed. Herein, we validate discovered metabolomic biomarkers to distinguish Hepatitis B virus (HBV)-related HCC, including alpha-fetoprotein (AFP) negative (AFP–) and positive (AFP+) individuals. Methods: We recruited 130 HCC subjects (independent case-control, randomized clinical cohorts) to our study. We separated the subjects randomly into two panels: (1) 58 individuals for the discovery panel; and (2) 72 individuals for the validation panel. For each panel, gender and age-matched hepatitis B group (HBG) and healthy group were included as controls. Plasma samples were collected for metabolic profiling by liquid chromatography—mass spectrometry—based metabolomics assays. We applied both non-targeted metabolomics analyses and targeted metabolomics analyses. Significantly changed metabolites (SCMs) were identified. The power of SCMs to discriminate HCC and HBG or healthy group was determined by receiver operating characteristic curve (ROC) analysis. Results: Ten SCMs were selected form the discovery panel, and further verified in the validation panel. ROC analyses indicated that 1 SCMs (LysoPC (24:0)) could discriminate HCC from HBG (AUC = 0.765). Further, 8 SCMs including (LysoPC (17:0), LysoPC (20:4(8Z,11Z,14Z,17Z)), LysoPC (22:0), LysoPC (24:0), PE (P-16:0/22:4(7Z,10Z,13Z,16Z)), SM (d18:1/22:1(13Z)), Creatinine, and L-Isoleucine) displayed a heightened ability to discriminate between HCC and healthy controls (AUC were more than 0.800). Most of these SCMs were important in lipid metabolism. Conclusions: LysoPC (24:0) could distinguished HCC from HBG, and 8 SCMs distinguished HCC from healthy controls. LysoPC and other metabolites have the potential to serve as non-invasive biomarkers for HBV related AFP– and AFP+ HCC. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies and growing challenges of global health. In this study, for the first time in Iran, we investigated the 5-year survival rate and prognostic factors in patients with HCC. Materials and Methods: In this historical cohort study, we examined the medical records of 227 HCC patients who were registered in the central tumor registry of our institution from September 2007 to September 2017. Demographic data, clinical parameters, received treatments, and survival curves from time of diagnosis were evaluated. Kaplan-Meier was used for univariate analysis, and multivariable analysis was performed by Cox regression. Results: A total of 208 (91.63%) patients were dead. The 5-year survival rate was estimated 19 (8.37%). The average follow-up in this study was 14.3 months. Overall median survival rate was 12.1 months. Univariate analysis showed that tumor size, metastasis, number of involved lymph node, hepatitis type, and treatment were significantly related to the survival rate, and Cox regression analysis revealed that the tumor size >3 cm (hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.68-4.97; P = 0.027), involved lymph nodes >2 (HR = 4.12, 95% CI = 2.66-6.38; P = 0.001), metastasis (HR = 3.87, 95% CI = 3.13-6.54; P = 0.011), combination therapy with surgery and chemotherapy (HR = 0.4, 95% CI = 0.15-0.79; P = 0.023), and coinfection with hepatitis B virus and hepatitis C virus (HR = 2.11, 95% CI = 1.81-4.6; P = 0.036) are the most relevant prognostic factors with 5-year survival rate in patients with HCC. Conclusion: Results of this study will help estimate survival rates for patients with HCC according to their clinical status. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a prototype of inflammation-related cancer, harboring M1-like and M2-like tumor-associated macrophages. M1 macrophages are thought to be tumoricidal, but some studies report its pro-tumor role. The programmed cell death-ligand (PD-L) 1 expressed in HCC cells is a critical checkpoint molecule to mediate immune escape of HCC. The PD-L1 expression in HCC cells is inducible. In the present study, we ask whether M1 macrophages induce the expression of PD-L1 in HCC cells. First, an association between M1 macrophage infiltration and PD-L1 expression in HCC tissues was determined by bioinformatics and immunohistochemistry experiments. The enrichment score of M1 macrophages was correlated to PD-L1 expression in 90 HCC samples from GEO database. Besides, infiltration of CD68+HLA-DR+ M1-like macrophages correlated with PD-L1 expression level in HCC cells. Moreover, M1-conditioned media was prepared from M1 macrophages derived from THP-1 cell, RAW264.7 cell or murine bone marrow. These supernatants induced expression of PD-L1 in HCC cells. Furthermore, inflammatory cytokine IL-1β in the supernatants was identified to account for the inducible PD-L1 expression by siRNA assay and receptor blockade assay. Additionally, transcription factor p65 and IRF1 in the HCC cells were revealed by CHIP assay to mediate the inducible PD-L1 expression. All the results demonstrate that M1 macrophages induced expression of PD-L1 in HCC cells, supporting the pro-tumor role of M1 macrophages. [ABSTRACT FROM AUTHOR]

In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids (MitoHCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH∙− and ROO∙− induced lipid peroxidation. H2O2 production was decreased significantly by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines (HepG2, L02 and WI38) indicated that the MitoHCAs were selective for cancer cells. Interestingly, the MitoHCAs both with or without Ca2+ triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore (mPTP), cyclosporin A, attenuated mitochondrial damage and cell apoptosis, indicating that mPTP may be involved in the antiproliferative activity of MitoHCAs. Further studies focused on structural optimization of these compounds are onging.

Abstract: Hepatocellular carcinoma is the most frequent primary liver cancer worldwide. The use of antioxidants as cancer prevention and treatment agents has become a focus of research in recent years due to their limited adverse effects. Alpha lipoic acid (ɑ‐LA) is synthesized in the liver and is considered a naturally occurring antioxidant. In this study, a total of 4446 differentially expressed genes (2097 down‐regulated and 2349 up‐regulated) were identified via RNA‐Seq in HepG2 cells after exposure to α‐LA for 24 hrs. Moreover, GO and KEGG pathway analyses showed that cancer‐relevant cell membrane proteins were significantly affected. An interaction network analysis predicted that Grb2 might mediate the key target pathways activated by exposure to ɑ‐LA. Verification of the RNA‐Seq and iTRAQ results confirmed that Grb2 mediated the ɑ‐LA‐induced inhibition of cell proliferation in vitro. Furthermore, the analysis of human hepatocellular carcinoma specimens obtained from the GEO database showed that the expression of EGFR and Met correlated with that of Grb2. These findings provide a novel mechanism through which ɑ‐LA regulates cell proliferation via the down‐regulation of growth factor‐stimulated Grb2 signalling. [ABSTRACT FROM AUTHOR]

Clinical benefit from immunotherapy of B7-H1/PD-1 checkpoint blockade indicates that it is important to understand the regulatory mechanism of B7-H1 expression in cancer cells. As an adaptive response to the endogenous antitumor immunity, B7-H1 expression is up-regulated in HCC cells. B7-H1 expression is induced mainly by IFN-γ released from tumor-infiltrating T cells in HCC. In addition, HCC is a prototype of inflammation-related cancer and TNF-α is a critical component of inflammatory microenvironment of HCC. In the present study, we asked whether TNF-α can promote the expression of B7-H1 induced by IFN-γ in HCC cells. We found that JAK/STAT1/IRF1 was the primary pathway responsible for induction of B7-H1 expression by IFN-γ in human HCC cell lines. TNF-α and IFN-γ synergistically induced the expression of B7-H1 in the HCC cells. Moreover, the mechanism of the synergy was that TNF-α enhanced IFN-γ signaling by upregulating the expression of IFN-γ receptors. Furthermore, B7-H1 expression induced synergistically by TNF-α and IFN-γ in murine HCC cells facilitated tumor growth in vivo. Our findings suggest that TNF-α may enhance the adaptive immune resistance mediated by IFN-γ-induced B7-H1 in HCC cells. [ABSTRACT FROM AUTHOR]

Objective To carry out a prospective cohort study of combined intra-operative radiotherapy for centrally located hepatocellular carcinomas (HCC) and to observe the safety and postoperative complications. Methods A total of 79 patients with centrally located HCC who underwent hepatectomy were divided into two groups: experimental group (combined with targeted intra-operative radiotherapy, 32 cases) and control group (single surgical operation, 47 cases). Patients in the experimental group received intra-operative electron radiotherapy after tumor resection, while patients in the control group received to intra-operative electron radiotherapy.The haemorrhagia amount and operation time during the operation, intra-operative liver function and the recovery of liver and gastrointestinal tract of patients in these two groups were compared. Results No postoperative 30-day mortality was observed in all of the patients. The average total operation time of patients in the experimental group was (319±76) min, significantly longer than (233±76) min of the control group (P<0.001). The average aspartate transaminase (AST) level of patients in the experimental group at postoperative day 1 was 562.5 U/L, significantly higher than 347.0 U/L of control group (P=0.031). However, the average prothrombin activity levels of patients in the experimental group at postoperative day 3 and day 7 were (68.3±17.9)% and (73.4±10.2)%, respectively, significantly lower than (78.9±15.9)% and (80.0±10.6)% of control group (both P<0.05). There were no significant differences of tumor volume, differentiation degree, satellite lesion, dorsal membrane invasion, microvascular invasion between these two groups (all P>0.05). There were no significant differences of hospital stay, ventilation time, the incidence of hepatic insufficiency, ascites, pleural effusion, infection, biliary fistula between these two groups (all P>0.05). There were no significant differences of alanine aminotransferase (ALT), albumin, total bilirubin between these two groups at postoperative day 1, 3, 5 and 7 (all of P>0.05). Conclusion The resection of centrally located HCC combined with intra-operative radiotherapy may increase the total operation time, delay the early postoperative recovery of liver function, but it is still safe and feasible. [ABSTRACT FROM AUTHOR]