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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]

Background & objective: It has been shown that the combined use of alcohol before radiofrequency ablation (RFA) helps to augment the therapeutic advantage of RFA. The present study was conducted to compare the outcome of treatment with RFA alone and RFA with alcohol as ablative technique in patients with small hepatocellular carcinomas (HCCs), who were not candidates for surgery. Methods: Fifty patients with chronic liver disease and concurrent HCC were enrolled in this prospective study. The patients were treated with either RFA alone (n=25) or RFA combined with alcohol (n=25). Patient outcome was evaluated, and the tumour recurrence and survival of the patients were assessed in the two groups. Results: The survival rates at six months in patients who completed at least six months of follow up were 84 and 80 per cent in patients treated with RFA alone and combination therapy, respectively. During the follow up period, 11 and four patients treated with RFA alone showed local and distant intrahepatic tumour recurrence, respectively. All local recurrences were at one to 18 months of the follow up period. The distant recurrences occurred at 6-36 months of the follow up period. During the follow up period, eight and six patients treated with combination therapy showed local and distant intrahepatic tumour recurrence, respectively. All local recurrences were at 1.5-15 months during the follow up period. The distant intrahepatic recurrences occurred at 6-72 months during the follow up period. Interpretation & conclusions: No significant difference was seen between the survival time of the patients treated with RFA alone and RFA with alcohol as well as in the local recurrences and distant intrahepatic recurrences in RFA compared to RFA and alcohol group patients. Combined use of RFA and alcohol did not improve the local tumour control and survival in patients with HCC compared to RFA alone. [ABSTRACT FROM AUTHOR]

Background and purpose To report the clinical usefulness of coiled fiducial markers as an internal surrogate in gated stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) using a real-time tumor-tracking radiotherapy (RTRT) system. Materials and methods Seventeen HCC patients with Child-Pugh (CP) scores of A or B received gated SBRT (45–50 Gy in 5–10 fractions) using an RTRT system and Visicoil markers. Local control (LC), progression-free (PFS), and overall survival (OS) rates were assessed using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria for Adverse Events, Version 4.0. Results Of the 17 patients, 14 had a CP score A. The mean planning target volume was 54.6 cc. Only 1 patient developed pneumothorax after marker implantation. Visicoil tracking during SBRT was possible in all cases. With a median follow-up of 16 months, 1-year LC, PFS, and OS rates were 100%, 53%, and 82%, respectively. Grade ≥ 2 late toxicity was observed in 2 patients (grade 2 duodenal ulcer and grade 3 temporary transaminase elevation). Conclusions Using an RTRT system and Visicoil markers, gated SBRT was well tolerated in patients with HCC. This can be considered a safe treatment strategy with potential for delivering favorable outcomes. [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. H 2 O 2 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 Ca 2+ 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 FROM AUTHOR]

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC-In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P= 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection. [ABSTRACT FROM AUTHOR]

Altered expression of TIP30, a tumor suppressor, has been observed in many cancers. In this study, we have evaluated the expression of TIP30 in the tissues of 209 hepatocellular carcinomas (HCC) and their adjacent tissues by using a high-density tissue microarray, and analyzed its correlation with the clinical pathological parameters of the patients. The results revealed negative or weak expression of TIP30 in 43.5% (91/209) of the HCC tissues, and in only 27% (56/209) of the adjacent tissues. The expression level of TIP30 in HCC was inversely correlated with serum alpha-fetoprotein (AFP) levels, HBV infection, and tumor differentiation. Multivariate analysis for survival indicated that serum HBV infection was the most significant predictor of poor prognosis in HCC ( P = 0.0023), and TIP30 expression and tumor differentiation were also independent indicators in this respect ( P = 0.0364 and P = 0.0397, respectively). Patients with medium or high expression levels of TIP30 (TIP30++/+++) had a better 5-year overall survival rate than those with low/negative (TIP30+/−) expression ( P < 0.001). TIP30+/−/HBV+ patients had the worst 5-year overall survival rate, whereas TIP30++/+++/HBV− patients had the best. To further explore the correlation between TIP30 and HBV infection in HCC, HBV+ hepatoblastoma cell-line HepG2 2.2.15 and HCC cell-line Hep3B were used. Upon silencing of HBV, we observed an upregulation of TIP30 and decreased cell proliferation. In the in vivo studies, we found that the mice inoculated with HepG2 2.2.15 cells with HBV silencing had a prolonged tumor latency and a longer life span, as compared to the control mice inoculated with untreated control cells. In conclusion, the results suggest that downregulation of TIP30 may result from HBV infection, and subsequently promotes the progression of HCC. [ABSTRACT FROM AUTHOR]

Combination therapies targeting two immune checkpoint regulators (PD-1 and CTLA-4) or PD-1 concurrently with the angiogenic pathway prolong the overall survival time to nearly twice that of patients receiving monotherapy ([3]; also reviewed by He et al. below). Keywords: Hepatocellular carcinomas; biomarkers; immune-checkpoint inhibitors; PD-1; PD-L1; immunotherapies; bioinformatics EN Hepatocellular carcinomas biomarkers immune-checkpoint inhibitors PD-1 PD-L1 immunotherapies bioinformatics 1 2 2 03/14/22 20220310 NES 220310 Hepatocellular carcinomas (HCCs), made up of 75-85% of primary liver cancers, remain the leading cause of new cancer cases (>0.7 million) and cancer deaths (>0.6 million) globally according to the data collected up to 2020 before the coronavirus disease 2019 (COVID-19) pandemic ([1]). Hepatocellular carcinomas, biomarkers, immune-checkpoint inhibitors, PD-1, PD-L1, immunotherapies, bioinformatics. [Extracted from the article]

The acquisition of stemness is a hallmark of aggressive human hepatocellular carcinoma (hHCC). The stem cell marker OCT4 is frequently expressed in HCCs, and its expression correlates with those of putative cancer stem cell (CSC) markers and CSC properties. Here, we describe a novel mechanism of CSC maintenance by SRY through OCT4. We previously reported that Sry is involved in tumor malignancy in rodent HCCs. However, the oncogenic function of SRY in hHCCs is poorly understood. Ectopic expression of SRY increased multiple stem cell factors, including OCT4 and CD13. The OCT4 promoter contained SRY-binding sites that were directly activated by SRY. In HCC-derived cells, SRY knockdown decreased OCT4 expression and cancer stem-like phenotypes such as self-renewal, chemoresistance, and tumorigenicity. Conversely, OCT4 and SRY overexpression promoted cancer stem-like phenotypes. OCT4 knockdown in SRY clones downregulated the self-renewal capacity and chemoresistance. These data suggest that SRY is involved in the maintenance of cancer stem-like characteristics through OCT4. Moreover, CSCs of HCC-derived cells differentiated into Tuj1-positive neuron-like cells by retinoic acid. Noteworthily, SRY was highly expressed in some hHCC patients. Taken together, our findings imply a novel therapeutic strategy against CSCs of hHCCs. S tem C ells 2015;33:2652-2663 [ABSTRACT FROM AUTHOR]

Purpose: This single-arm, multicenter, phase-II trial evaluated the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) using fine-powder cisplatin and iodized-oil suspension in patients with intermediate- and advanced-stage [Barcelona Clinic Liver Cancer (BCLC) stage-B and stage-C] hepatocellular carcinomas (HCCs). Methods: The Institutional Review Board approved this study and patients provided written informed consent. Thirty-five patients (24 men and 11 women, mean 74 ± 6 years [range 60-87 years]) with BCLC stage-B (57 %, 20/35) or stage-C (43 %, 15/35) HCCs who were not candidates for other locoregional treatments were enrolled. HAIC was performed using a suspension of fine-powder cisplatin with a maximum dose of 65 mg/m and iodized oil on demand. The primary endpoint was the response rate evaluated based on Response Evaluation Criteria in Solid Tumor (RECIST) and modified RECIST (mRECIST). Secondary endpoints were overall survival, progression-free survival, and safety. Results: The initial and best overall response rates at 4 weeks and 3 months, respectively, were 14 and 17 % based on RECIST, and 57 and 23 % based on mRECIST. The median overall and progression-free survival times were 18 and 4 months, respectively. The most frequent grade-3 or grade-4 adverse events were elevation of serum alanine (23 %) and aspartate aminotransferase (20 %), and thrombocytopenia (17 %). Conclusion: This HAIC provides promising therapeutic effects with acceptable safety to patients with intermediate-stage and advanced-stage HCCs. [ABSTRACT FROM AUTHOR]

The intestinal metabolites of ellagic acid (EA), urolithins are known to effectively inhibit cancer cell proliferation. This study investigates antiproliferative and antioxidant effects of urolithin A (UA) on cell survival of the HepG2 hepatic carcinomas cell line. The antiproliferative effects of UA (0–500 μM) on HepG2 cells were determined using a CCK assay following 12–36 h exposure. Effects on β-catenin and other factors of expression were assessed by using real-time PCR and Western blot. We found that UA showed potent antiproliferative activity on HepG2 cells. When cell death was induced by UA, it was found that the expression of β-catenin, c-Myc and Cyclin D1 were decreased and TCF/LEF transcriptional activation was notably down-regulated. UA also increased protein expression of p53, p38-MAPK and caspase-3, but suppressed expression of NF-κB p65 and other inflammatory mediators. Furthermore, the antioxidant assay afforded by UA and EA treatments was associated with decreases in intracellular ROS levels, and increases in intracellular SOD and GSH-Px activity. These results suggested that UA could inhibit cell proliferation and reduce oxidative stress status in liver cancer, thus acting as a viably effective constituent for HCC prevention and treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: The purpose of this study was to analyze the influence of age on both the risk of hepatectomy and the prognosis in patients with hepatocellular carcinoma (HCC). METHODS: Patients undergoing an initial hepatectomy for HCC were classified into 2 age groups: 75 years or over (n = 113) and less than 75 years (n = 499). RESULTS: A zero 90-day mortality was achieved in the elderly. Although the recurrence rate and recurrence sites were almost similar between the 2 groups, the 5-year survival rate in the elderly patients was significantly lower than that in the younger patients (46.0% vs 57.6%; P = .018), possibly because of the higher incidence of deaths from other causes (26.8% vs 10.4%; P = .011) in the elderly. CONCLUSION: Selected elderly HCC patients can undergo a hepatectomy safely and can benefit from long-term HCC control comparable with that of their younger counterparts. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a large family of post-transcriptional regulators of gene expression that control a number of developmental and cellular processes in eukary-otic organisms and are ~23 nucleotides in length. miRNA-122 is an abundant liver-specific miRNA, implicated in fatty acid and cholesterol metabolism, as well as in hepatitis C viral replication and is frequently suppressed in primary hepatocellular carcinomas. In the current study, the Hep3B cell line with stable overexpression of miR-122 was successfully established through gene transfection methods and drug screening. miR-122 was observed to alter cell morphology in vitro by stable overexpression in Hep3B cells. This alteration was viewed by light microscopy and transmission electron microscopy. These alterations included increases in the cell volume, the appearance of lipid granules and vacuoles, thickening of nuclear membrane, swelling of the mitochondria, cytoplasm vacuolization and a more prominent nucleolus. Furthermore, the study provided novel evidence that miR-122 function was dependent upon its expression level. In addition, it was observed to negatively regulate mitochondria. [ABSTRACT FROM AUTHOR]

Highlights: [•] HOXB9 is overexpressed in human HCC samples. [•] HOXB9 over expression had shorter survival time than down expression. [•] HOXB9 stimulated the proliferation of HCC cells. [•] Activation of TGF-β1 contributes to HOXB9-induced proliferation in HCC cells. [ABSTRACT FROM AUTHOR]

Using a meta-analysis on gene expression data of hepatocellular carcinomas (HCC) from the Oncomine database, we identified that the Notch3 gene ranked as the highest up-regulated Notch pathway member in HCC tissues compared with normal liver tissues. We further detected the expression of Notch3 in 95 cases of HCC samples by immunohistochemistry, and evaluated its clinicopathological and prognostic significance. We confirmed that Notch3 is overexpressed in HCC tissues compared with normal liver tissues, and a high expression level of Notch3 was significantly associated with bigger tumor size (p = 0.014), multiple tumors (p = 0.026), late tumor-node-metastasis (TNM) stage (p < 0.01) and shorter overall survival (p = 0.002). Furthermore, high Notch3 expression emerged as a significant independent prognostic factor in multivariate analysis. In conclusion, we identified a positive association between Notch3 expression with more aggressive traits and shorter survival in HCC. Our findings suggest that Notch3 might be an important regulator in the development of HCC, and a potential therapeutic target for patients with HCC. [ABSTRACT FROM AUTHOR]

Transcatheter arterial chemoembolization (TACE) is known to be an effective palliative treatment for unresectable hepatocellular carcinoma (HCC). Serious complications, such as neutropenic sepsis and hepatic decompensation, are well known. A HCC rupture following TACE is a rare complication: however, it can be life-threatening if it occurs. In a 75-year-old male patient who subsequently developed capsular rupture of the lipiodol laden mass and several free intraperitoneal chemoembolization agents with hemoperitoneum, we report a case of a ruptured HCC that superficially located arterial enhancing and early wash-out mass in the right hepatic dome following TACE. [ABSTRACT FROM AUTHOR]

Distinction of liver metastases from hepatocellular carcinoma (HCC) may present a diagnostic challenge. Arginase-1 (Arg-1) is a marker for HCC recently described in some literature. Immunohistochemical evaluation of Arg-1, hepatocyte paraffin-1 (HepPar-1), and glypican-3 expression was performed on 1,240 surgical specimens and 62 liver fine-needle aspiration specimens (29 HCCs, 28 metastatic tumors, and 5 benign liver cases). The staining results on tissue microarray sections showed that 2. 7% and 3.1% of nonhepatic tumor cases were positive for HepPar-1 and glypican-3, respectively; none was positive for Arg-1. For fine-needle aspiration specimens, 19 HCCs were positive for all 3 markers; 9 were positive for 1 or 2 markers; and only I case was negative for all 3 markers. These data demonstrate that Arg-1 is the most specific marker in differentiating a non-HCC from HCC. It is recommended to use 3 markers as a panel in distinguishing HCC from metastatic carcinoma. [ABSTRACT FROM AUTHOR]

Background & Aims: Substantial evidence indicates that inflammation is a critical component of tumor progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with extensive leukocyte infiltration. Neutrophils are the common inflammatory infiltrate in tumors, but their nature and regulation in human cancers remain elusive. Methods: A total of 238 HCC patients were enrolled randomly. Immunohistochemistry and SuperArray Real-Time PCR were used to analyze the distribution and clinical relevance of neutrophils in different microanatomical areas. The regulation and function of neutrophils were assessed by both in vitro and in vivo studies. Results: Neutrophils were enriched predominantly in peritumoral stroma of HCC tissues and their levels could serve as a powerful predictor for poor survival in HCC patients. Proinflammatory IL-17 is a critical mediator of the recruitment of neutrophils into peritumoral stroma of HCC tissues by epithelial cell-derived CXC chemokines. The accumulated peritumoral neutrophils were the major source of matrix metalloproteinase-9 in HCC tissues; this secreted protein stimulated proangiogenic activity in hepatoma cells. Accordingly, high infiltration of peritumoral neutrophils was positively correlated with angiogenesis progression at tumor-invading edge of HCC patients. Furthermore, we found that selective depletion of neutrophils effectively inhibited tumor angiogenesis and growth, in vivo. Conclusions: These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in distinct tumor milieu, which reroutes the inflammatory response into a tumor-promoting direction. [Copyright &y& Elsevier]

ginine deiminase (ADI), an arginine-degrading enzyme, has been studied as a potential anti-cancer agent for inhibiting arginine-auxotrophic tumors, such as melanomas and hepatocellular carcinomas. Based on our preliminary results, it was noticed that the optimum pH of ADI from Pseudomonas plecoglossicida (PpADI) was 6.0, and less than 10% of the activity was retained at pH 7.4 (pH of human plasma). Additionally, the K value for wild-type ADI (WT-ADI) was 2.88 mM (pH 6.0), which is over 20 times of the serum arginine level (100-120 μM). These are two major limitations for PpADI as a potential anti-cancer drug. A highly sensitive and efficient high-throughput screening strategy based on a modified diacetylmonoxime-thiosemicarbazide method was established to isolate ADI mutants with higher activity and lower K under physiological pH. Three improved mutants was selected from 650 variants after one round of ep-PCR, among which mutant 314 (M314: A128T, H404R, I410L) exhibiting the highest activity. Interestingly, sequence alignment shows that three amino acid substitutes in M314 are coincident with corresponding residues in ADI from Mycoplasma arginini. The specific activity of M314 (9.02 U/mg) is over 20-fold higher than that of WT-ADI (0.44 U/mg) at pH 7.4, and the K value was reduced to 0.65 mM (pH 7.4). Noticeably, the pH optimum was shifted from 6.0 to 6.5 in M314. Homology model of M314 was constructed to understand the molecular basis of the improved enzymatic properties. This work could provide promising drug candidate for curing arginine-auxotrophic cancers. [ABSTRACT FROM AUTHOR]

Background: Malignant transformation of hepatocellular adenomas (HCAs) into hepatocellular carcinomas (HCCs) has been reported repeatedly and is considered to be one of the main reasons for surgical treatment. However, its actual risk is currently unknown. Objective: To provide an estimation of the frequency of malignant transformation of HCAs and to discuss its clinical implications. Methods: A systematic literature search was conducted using the following databases: The Cochrane Hepatobiliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE and EMBASE. Results: One hundred and fifty-seven relevant series and 17 case reports (a total of 1635 HCAs) were retrieved, reporting an overall frequency of malignant transformation of 4.2%. Only three cases (4.4%) of malignant alteration were reported in a tumour smaller than 5 cm in diameter. Discussion: Malignant transformation of HCAs into HCCs remains a rare phenomenon with a reported frequency of 4.2%. A better selection of exactly those patients presenting with an HCA with an amplified risk of malignant degeneration is advocated in order to reduce the number of liver resections and thus reducing the operative risk for these predominantly young patients. The Bordeaux adenoma tumour markers are a promising method of identifying these high-risk adenomas. [ABSTRACT FROM AUTHOR]

Abstract: Biliary hamartomas or von-Meyenburg complexes form part of a spectrum of ductal plate malformation that includes polycystic liver disease, congenital hepatic fibrosis, and Caroli disease. These lesions are known to have neoplastic transformation. Development of intrahepatic cholangiocarcinoma is well described in these complexes. Rarely, hepatocellular carcinomas (HCCs) have been seen in association with bile duct hamartomas, however; it is not clear whether development of HCC is an epiphenomenon unrelated to the precursor lesion or biliary hamartomas may progress to liver cancers. We herein report 4 interesting cases of hepatitis C virus–, alcohol-, and nonalcoholic fatty liver disease–associated end-stage liver disease with coexisting HCC and multiple large von-Meyenburg complexes. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the efficacy and safety of percutaneous microwave coagulation treatment (PMCT) by a new microwave delivery system (Forsea Microwave™) in large hepatocellular carcinomas (HCC) (≥5 cm). Materials and methods: Four patients with 4 HCC lesions measuring ≥6 cm in the greatest dimension underwent PMCT by means of the Forsea Microwave™ microwave delivery system. Final therapeutic efficacy was evaluated with dynamic computer tomography (CT) scans performed within one month after PMCT. During and after PMCT, patients' complaints and any abnormal physical signs were recorded for safety assay. CT or ultrasound scan (US) performed immediately after the treatment was used to detect acute complications related to the treatment. Repeated dynamic CT scans were performed every three to four months thereafter to detect local disease recurrence and/or other recurrences. Results: Three of these patients achieved a complete ablation of the cancer nodules (two patients with two treatment sessions and one patient with three treatment sessions). One of these patients obtained a complete ablation of the cancer nodule with two treatment sessions except the lesion of portal vein tumour thrombus (PVTT). No obvious symptomatic complication was observed except abdominal pain during and after the treatment in two of these patients. All the patients remained asymptomatic and no recurrent tumour was observed during their follow-up (1-19 months). Conclusions: PMCT by the Forsea Microwave™ microwave delivery system could offer a satisfactory therapeutic effect and is applicable to the treatment of large HCC. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To prospectively assess the relationship between the time to peak enhancement of hepatocellular carcinomas (HCC) and that of the aorta at 64-detector computed tomography (CT). Materials and methods: The study prospectively included 43 patients with known HCC. All underwent abdominal CT imaging by using BodyPerfusion CT model. The CT data acquisition was initiated with a delay of 8–15s from the beginning of the contrast material administered. The time–density curves (TDC) of the HCC and the aorta were drawn. The times to peak enhancement of the HCC and the aorta were recorded and the correlation between the time to peak enhancement of the HCC and that of the aorta was analyzed. Results: There were three tendencies of TDC of the HCC enhancement, only 23.3% of them were similar to that of the aorta. The mean time to peak enhancement of the aorta and the HCC (86.1%) was 23.38s and 30.04s, respectively. The time to peak enhancement of most HCC was positively and linearly correlated with the time to peak aortic enhancement (r =0.662, P <0.05). Conclusion: The result may potentially allow scan delay optimization at contrast material-enhanced CT image in the detection of HCC according to interindividual variability. [Copyright &y& Elsevier]

Aim: Real-time virtual sonography (RVS) can synchronize B-mode ultrasound (US) images with multiplanar reconstruction (MPR)–computed tomography (CT) images on the same screen in real time. The purpose of this study was to evaluate the effectiveness of RVS for radiofrequency ablation therapy (RFA) of hepatocellular carcinomas (HCC) in which it was difficult to identify contours or margins by B-mode US. Methods: Sixty-three consecutive patients with a solitary HCC of less than 3.5 cm in diameter were enrolled in this study. Thirty-nine patients with HCC clearly detectable by B-mode US underwent conventional RFA, while the remaining 24 with obscure tumor lesions underwent RVS-guided RFA. A follow-up study of RFA treatment was performed every 3 months using enhanced CT imaging of the arterial and portal phase (at least 24 months). The accuracy of needle insertion was confirmed by measuring the gap between the needle insertion line and the center of the tumor from MPR–CT images. Results: The local recurrence rate of the RVS-guided RFA group was similar to that of the conventional RFA group (8.3% vs 7.7%), despite the difficulty of detecting tumor lesions in the former group. The mean gap between the needle insertion line and the center of the tumor was 1.6 mm (0–3.2 mm) in eight patients treated with RVS-guided RFA. Conclusion: RVS-guided RFA can be useful for treating HCC that are difficult to detect by B-mode US. [ABSTRACT FROM AUTHOR]

To maintain a tumour vasculature in proportion of the tumour growth, the endothelial cells proliferate and up-regulate the expression of the VEGF receptor 2 (VEGFR-2), whose expression is restricted to this cell type. This specificity implies that one therapeutically target the tumour endothelium. We investigated the use of immunoliposomes (IL), containing conjugated Fab' fragments of the monoclonal rat anti-VEGFR-2 antibody DC101 (DC101-IL) to cargo doxorubicin to the tumour endothelium. In vitro, fluorescein-labelled IL displayed a 7 fold better binding to VEGFR-2-positive 293T cells in comparison to unspecific liposomes. Balb/C mice were injected subcutaneously with syngeneic hepatocellular carcinoma cells. One set of animals was treated with DC101-IL filled with doxorubicin when the tumours were bigger than 400 mm3. A specific delivery of doxorubicin to endothelial cells of the tumour vessels could be demonstrated by the red fluorescence of doxorubicin with laser scanning microscopy, but neither a delay of tumour growth nor a shrinking of the tumour mass was observed. Yet necrosis in the tumours treated with doxorubicin containing vehicles was larger than in the tumours of the control groups. A second set of animals was treated with DC101-IL filled with doxorubicin when the tumours were smaller than 1 mm3. DC101-IL filled with doxorubicin led to a significant delay in tumour growth up to 7 weeks compared to empty DC101-IL, free doxorubicin, and HEPES/Glucose (HEPES/Glucose vs. DOX-DC101-IL, p = 0.001; unpaired, two-tailed Student's t-test) and to a higher amount of necrotic areas in the tumours (p = 0.053; 1 way ANOVA with 4 groups). These findings suggest that IL designed to bind specifically to VEGFR-2 can be used to deliver doxorubicin to the tumour endothelium and may impair the "angiogenic switch" of the tumours. [ABSTRACT FROM AUTHOR]

Purpose: To verify changes in the signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) of hypervascular hepatocellular carcinomas (HCCs) on ferucarbotran-enhanced dynamic T1-weighted MR imaging.Materials and Methods: Fifty-two patients with 61 hypervascular HCCs underwent ferucarbotran-enhanced dynamic MR imaging, and then hepatic resection. Hypervascular HCCs were identified when definite enhancement was noted during the arterial dominant phase of three-phase MDCT. Dynamic MR Images with T1-weighted fast multiplanar spoiled gradient-recalled echo sequence (TR200/TE4.2) were obtained before and 20 s, and 1, 3, 5, and 10 min, after bolus injection of ferucarbotran. We estimated the signal intensities of tumors and livers, and calculated the SNRs and CNRs of the tumors.Results: On ferucarbotran-enhanced dynamic MR imaging, SNR measurements showed a fluctuating pattern, namely, an increase in SNR followed by a decrease and a subsequent increase (or a decrease in SNR followed by a increase and a subsequent decrease) in 50 (82.0%) of 61 tumors, a single-peak SNR pattern (highest SNR on 20 s, 1, 3, or 5 min delayed images followed by a decrease) in seven (11.5%), and a decrease in SNR followed by an increase in four (6.6%). Maximum absolute CNRs with positive value were noted on 10 min delayed images in 41 (67.2%) tumors, and maximum absolute CNRs with negative value were observed on 20 s delayed images in 12 (19.7%) and on 1 min delayed images in eight (13.1%).Conclusion: Despite showing various SNR and CNR changes, the majority of hypervascular HCCs demonstrated a fluctuating SNR pattern on ferucarbotran-enhanced dynamic MR imaging and a highest CNR on 10 min delayed image, which differed from the classic enhancement pattern on multiphasic CT. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular carcinoma (HCC) is the third deadliest and fifth most common human cancer worldwide. Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections along with alcohol and aflatoxin B1 intake are widely recognized etiological agents in HCCs. It is anticipated that HCCs will constitute a major health problem in the next two decades because of the rising incidence of HCV infections in the US. The poor survival rate achieved by current surgical procedures and chemotherapy treatment has prompted the scientific community to gain a better understanding of the molecular events involved in hepatocarcinogenesis in order to define new targets for more effective treatment. Recent findings from several laboratories have implicated constitutive activation of the transcription factor NF-κB as one of the early key events involved in neoplastic progression of the liver. Data is summarized here from recently published studies illustrating a crucial role of NF-κB in bridging the action of growth factors and inflammation to hepatic oncogenesis. Although additional work is needed to fully understand the precise role of NF-κB in the regulation of the various transitions of HCC development, these new findings raise the intriguing possibility that pharmacologic inhibition of NF-κB in the liver could selectively eradicate malignant liver cells without affecting normal liver homeostasis. [Copyright &y& Elsevier]

Abstract: Chronic exposure to 2-butoxyethanol resulted in an increase in liver hemangiosarcomas and hepatic carcinomas in male mouse liver. No increase in liver neoplasia was observed in similarly exposed male and female rats or female mice. We have proposed that the production of liver neoplasia in the male mouse is the result of oxidative damage secondary to the hemolytic deposition of iron in the liver. Our working hypothesis is that the mode of action of butoxyethanol-induced mouse liver hemangiosarcomas and hepatic neoplasia involves the metabolism of 2-butoxyethanol to butoxyacetic acid which results in the induction of RBC hemolysis. This hemolytic response is translated into the accumulation of iron in both liver hepatocytes and Kupffer cells. The Kupffer cell response to this insult is two-fold: (1) the production of oxidative species—through both Kupffer cell activation and through the Fenton reaction involving iron and (2) the production of cytokines (for example TNF alpha). The induction of reactive oxygen species can, if not scavenged, produce oxidative DNA damage (the formation of OH8dG), as well as increase cell growth through modulation of gene expression. While the reactive oxygen species generation would occur in the both rats and mice, the ability of the rat to detoxify the reactive oxygen species would preclude the remaining steps from occurring. In contrast, in the mouse, the reactive oxygen species would override antioxidant defense mechanisms and allow the proposed mode of action to move forward. Our results to date in male B6C3F1 mice and male F344 rats treated with 2-butoxyethanol (via daily gavage; five times per week) at doses of 0, 225, 450, and 900mg/kg/day (mice) and 0, 225, 450mg/kg/day (rats), respectively, showed: an increase in hemolysis in 2-butoxyethanol treated rats and mice in a dose-dependent manner, in addition, an increase in the percent of iron stained Kupffer cells in the liver was observed following treatment with 450 and 900mg/kg of 2-butoxyethanol in mice and 225 and 450mg/kg of 2-butoxyethanol in rat. With the iron deposition, a biphasic increase in oxidative damage (OH8dG and malondialdehyde) was seen in mouse liver after treatment with 2-butoxyethanol. In contrast, no increase in oxidative damage was observed in the rat liver at any of the doses examined. Concomitant with the increase in oxidative damage, Vitamin E levels were similarly reduced by 2-butoxyethanol in both mice and rat liver. However, the basal level of Vitamin E in rat liver was 2.5-fold greater than in mouse liver. A biphasic induction of DNA synthesis was seen following 2-butoxyethanol in the mouse. In mouse liver, increased DNA synthesis was observed in hepatocytes at 90 days and in endothelial cells at 7 and 14 days at all doses. No change in DNA synthesis was seen in 2-butoxyethanol treated rat liver. No apparent differences in apoptosis and mitosis in the liver were observed in mouse and rat liver between 2-butoxyethanol treatment groups and untreated controls. These results suggest that the induction of DNA synthesis, possibly from oxidative stress and/or Kupffer cell activation, occurs selectively in the mouse liver, in endothelial cells and in hepatocytes following exposure to 2-butoxyethanol, and support the hypothesis proposed above. [Copyright &y& Elsevier]

Date M, Fukuchi K, Namiki Y, Okumura A, Morita S, Takahashi H, Ohura K. Therapeutic effect of photodynamic therapy using PAD-S31 and diode laser on human liver cancer cells. Liver International 2004: DOI: 10.1111/j.1478-3231.2004.0902.x. © Blackwell Munksgaard 2004 Photodynamic therapy (PDT) is an effective local cancer treatment which a photosensitizer is administered and the tumor is irradiated with light. We examined the effect of PDT using PAD-S31 as the photosensitizer, and the 670 nm diode laser on human hepatocellular carcinomas (HCCs). Huh-7, HepG2 and Hep3B cell lines were used in the all experiments. Cell viability was determined by a modified MTT assay. Two methods were used for the determination of apoptosis: terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling assay and detection of fragmented mono- and oligo-nucleosomes by enzyme-linked immunosorbent assay. The caspase activity was measured by fluorometric assay. Cytochrome c in cytosolic fraction was determined using a human cytochrome c immunoassay. Xenografts of human oral HCC cells were generated in KSN S1c nude mice. In vitro PDT showed excellent cytotoxicity that was a function of laser energy, drug concentration and time to the hepatoma cell lines. The combined use of PAD-S31 and laser irradiation showed excellent anti-tumor activity without severe side-effect against human hepatoma xenografts in nude mice. PDT-mediated cell death occurred predominantly by apoptosis in vitro and in vivo. Furthermore, this treatment initiates early cytochrome c release, followed by late caspase-3 and -9 activation. Our study demonstrates that PDT using PAD-S31 and the diode laser induces apoptosis that is mediated by cytochrome c release and caspase activation in human liver cancer cell lines. It is expected that this therapy will be clinically useful for the treatment of patients with HCC. [ABSTRACT FROM AUTHOR]

The fibroblast growth factor (FGF) function has been considered to contribute to various human tumors and malignant growth of neoplasm. Hepatocellular carcinoma (HCC) is a typical hypervascular tumor, and it is suggested that FGF may be involved in hepatocarcinogenesis. Therefore, the relationship between the progression of HCC and expression of FGFs and FGF receptors (FGFRs) was evaluated in this study. We investigated the expression of messenger ribonucleic acids (mRNAs) of FGFs and FGFRs by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in eight human hepatoma-derived cell lines (Hep3B, HLE, HLF, HUH6, HUH7, KIM1, Li7, and PLC/PRF/5), one hepatoblastome-derived cell line (HepG2), and human primary hepatocytes. In addition, effects of FGF-1, FGF-2, and FGF-7 on the growth of hepatoma-derived cell lines were studied in serum-free defined culture conditions. An RT-PCR analysis revealed that all cell lines except PLC/PRF/5 expressed all FGFR MRNAs: FGF-R1 (IIIc),-R2 (IIIb),-R3 (IIIb),-R3 (IIIc), and-R4 mRNAs. In contrast, human primary hepatocytes expressed FGF-R1 (IIIc),-R3 (IIIc), and-R4 mRNAs but not mRNAs of FGF-R2 (IIIb),-R2 (IIIc), and-R3 (IIIb). All cell lines except HUH6 and HUH7 expressed FGF-1 and FGF-2 mRNAs. Addition of exogenous FGF-1 or FGF-2 (or both) to culture stimulated cell proliferation in several cell lines, but FGF-7 exhibited no growth stimulation in all cells. Hepatoma cells may posses a proliferation mechanism regulated by an autocrine mechanism, a paracrine mechanism, or both, which are mediated by FGF-1/FGFR or FGF-2/FGFR (or both). In addition, a gain of FGF-R2 (IIIb),-R2 (IIIc), and-R3 (IIIb) may be associated with malignant transformation of liver tumor and may eventually serve as useful diagnostic and prognostic indicators. [ABSTRACT FROM AUTHOR]

We examined the chromosomal changes of 22 hepatocellular carcinomas (HCCs) by comparative genomic hybridization (CGH) analysis and compared the results with that of allelotype by polymerase chain reaction based loss of heterozygosity (PCR-LOH) analysis. By CGH analysis, frequent chromosomal losses were noted in the chromosomal region of 4q (59%), 8p (77%), and 16q (50%), whereas gains were noted in 1q (86%) and 8q (77%). All of these chromosomal arms were revealed to have frequent allelic imbalances by PCR-LOH analysis, however, 9% of chromosomal aberrations were detected only by CGH analysis and 2% were detected only by PCR-LOH analysis. Our results suggest that CGH analysis gives more precise results for the screening of chromosomal aberrations in HCCs than that of PCR-LOH analysis with randomly selected microsatellite markers. [Copyright &y& Elsevier]

As a source of various compounds, natural products have long been important and valuable for drug development. Kaempferol (KP) is the most common flavonol with bioactive activity and has been extracted from many edible plants and traditional Chinese medicines. It has a wide range of pharmacological effects on inflammation, oxidation, and tumour and virus regulation. The liver is an important organ and is involved in metabolism and activity. Because the pathological process of liver diseases is extremely complicated, liver diseases involving ALD, NASH, liver fibrosis, and HCC are often complicated and difficult to treat. Fortunately, there have been many reports that KP has a good pharmacological effect on a series of complex liver diseases. To fully understand the mechanism of KP and provide new ideas for its clinical application in the treatment of liver diseases, this article reviews the pharmacological mechanism and potential value of KP in different studies involving various liver diseases. In the trilogy of liver disease, high concentrations of ROS stimulate peroxidation and activate the inflammatory signal cascade, which involves signalling pathways such as MAPK/JAK-STAT/PERK/Wnt/Hipp, leading to varying degrees of cell degradation and liver damage. The development of liver disease is promoted in an inflammatory environment, which is conducive to the activation of TGF-β1, leading to increased expression of pro-fibrosis and pro-inflammatory genes. Inflammation and oxidative stress promote the formation of tumour microenvironments, and uncontrolled autophagy of cancer cells further leads to the development of liver cancer. The main pathway in this process is AMPK/PTEN/PI3K-Akt/TOR. KP can not only protect liver parenchymal cells through a variety of antioxidant and anti-apoptotic mechanisms but also reduces the immune inflammatory response in the liver microenvironment, thereby preventing cell apoptosis; it can also inhibit the ER stress response, prevent inflammation and inhibit tumour growth. KP exerts multiple therapeutic effects on liver disease by regulating precise signalling targets and is expected to become an emerging therapeutic opportunity to treat liver disease in the future. The role of kaempferol in the progression of the trilogy of liver disease [Display omitted] [ABSTRACT FROM AUTHOR]

Chronic infection of woodchucks with woodchuck hepatitis virus (WHV) was associated with the development of hepatitis, foci of altered hepatocytes and hepatocellular adenomas and carcinomas. The cytomorphological and cytochemical analysis permitted the identification of three different types of focal lesions; namely, glycogen-storage foci, mixed-cell foci and intermediatecell foci, each showing a characteristic pattern. The cells of the glycogen-storage foci had clear to acidophilic cytoplasm, and were overloaded with glycogen. They showed a marked elevation in the activity of glucose-6-phosphate dehydrogenase (G6PDH) and malate dehydrogenase (MDH), increased activity of succinate dehydrogenase (SDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glycerol-3-phosphate dehydrogenase (G3PDH), reduction in the activity of glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), adenosine triphosphatase (ATPase) and adenyl cyclase (ADC), and unchanged activity of glycogen synthase (SYN) and γ-glutamyl transferase (GGT). The mixed-cell foci mainly consisted of basophilic cells poor in glycogen, but were intermingled with cells containing glycogen. These foci were characterized by a marked decrease in activity of PHO, SYN, G6Pase, G6PDH, ATPase and ADC, and increased activity of GGT, SDH, MDH and GAPDH. The intermediate-cell foci consisted of cells with both basophilic and glycogenotic cytoplasmic compartments, and showed a similar enzyme histochemical profile to the mixed-cell foci, with slight differences in the degree of elevation or reduction of some enzymes. The phenotypic similarities and the close spatial relationship between the foci of altered hepatocytes, and the hepatocellular adenomas and carcinomas in WHV-infected woodchucks, suggest that these lesions are preneoplastic. The focal morphological and metabolic aberrations emerging during hepatocarcinogenesis in WHV-infected woodchuck, are in principle similar to those identified in the course of chemical hepatocarcinogenesis in various species. The focal metabolic aberrations apparently represent a general biological response of the liver parenchyma to oncogenic agents and are closely linked to neoplasic transformation of the hepatocytes. [ABSTRACT FROM AUTHOR]

In 19 patients (34 applications) radioembolisation with Y-90 resin particles applied superselectively with microcatheters was carried out as a palliative treatment of liver cell carcinoma. The calculations of tumour dose and of exposure to the liver parenchyma and lung were made following angioscintigraphy with Tc-MAP. In 27 patients the tumour dose was between 50 and 470 Gy, in 5 patients < 50 Gy and in 2 patients > 800 Gy. The adjacent liver parenchyma was exposed to 13% of the targeted tumour dose (mean 34 Gy). The lung shunt in 31 applications was between 0 and 8%, in three instances between 12 and 14%. Complications due to shunt or reflux were observed in 2 patients. Small solitary hypervascularised tumours showed the most improvement (high dose/low-volume embolisation). In multisegmental/lobar tumours, radioembolisation with smaller doses ( < 100 Gy) showed good palliative effects (medium dose/limited-volume embolisation). [ABSTRACT FROM AUTHOR]

In the United States, 80%-90% of primary hepatic tumors are hepatocellular carcinomas and 10%-15% are cholangiocarcinomas (CCA), both with high mortality rate, particularly CCA, which portends a worse prognosis. Traditional management with surgery has good outcomes in appropriately selected patients; however, novel ablative treatment options have emerged, such as radiofrequency ablation (RFA), which can improve the prognosis of both hepatic and biliary tumors. RFA is aimed to generate an area of necrosis within the targeted tissue by applying thermal therapy via an electrode, with a goal to completely eradicate the tumor while preserving surrounding healthy tissue. Role of RFA in management of hepatic and biliary tumors forms the focus of our current mini-review article., Competing Interests: Conflict-of-interest statement: The authors have no disclosures or conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Yes-associated protein-1 (YAP1) is a potent transcriptional co-activator and functions as an important downstream effector of the Hippo signaling pathway, which is key to regulating cell proliferation, apoptosis, and organ growth. YAP1 has been implicated as an oncogene for various human cancers including gastrointestinal cancers and hepatocellular carcinoma (HCC). YAP1 promotes tumorigenesis and cancer progression by multiple mechanisms, such as by promoting malignant phenotypes, expanding cancer stem cells, and inducing epithelial-mesenchymal transition. YAP1 overexpression or its activated forms are associated with advanced pathological grades and poor prognosis of cancer, and therefore targeting YAP1 may open a fertile avenue for cancer therapy. In this review, we summarize the recent evidence regarding the role of YAP1 in the carcinogenesis of gastrointestinal cancers and HCC., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest regarding this article

Abstract: Trichinella spiralis infection confers effective resistance to tumor cell expansion. In this study, a T7 phage cDNA display library was constructed to express genes encoded by T. spiralis. Organic phase multi-cell screening was used to sort through candidate proteins in a transfected human chronic myeloid leukemia cell line (K562) and a human hepatoma cell line (H7402) using the display library. The protein encoded by the A200711 gene was identified and analyzed using protein analysis software. To test the antitumor effects of A200711, variations in cell proliferation and apoptosis were monitored after recombinant pEGFP-N1-A200711 was transfected into H7402 cells. The results show that the expressed target gene successfully induced apoptosis in H7402 cells as measured by Hoechst-PI staining, MTT assay (p <0.05). This study warrants further investigation into the therapeutic use of A200711 for anti-hepatocellular carcinomas. [Copyright &y& Elsevier]