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This study aimed to compare the effectiveness of liver resection (LR) and microwave ablation (MWA) in hepatocellular carcinoma (HCC) patients with early recurrence and varying stages of cirrhosis. This study analyzed patients with HCC who underwent hepatectomy and experienced early tumor recurrence (≤3 cm) between December 2002 and December 2020 at the Tongji Hospital. Treatment effectiveness was assessed using a propensity score matching (PSM) analysis. This study included 295 patients (106, LR; 189, MWA), 86 patients in each of the 2 groups were chosen for further comparison, after PSM. After PSM, both LR and MWA demonstrated similar recurrence-free survival (RFS) and overall survival (OS) rates (p = 0.060 and p = 0.118, respectively). However, the LR group had more treatment-related complications. In patients with moderate or severe cirrhosis, no significant differences in RFS or OS rates were found between the LR and MWA groups (p = 0.779 and p = 0.772, respectively). In patients without cirrhosis or with mild cirrhosis, LR showed better RFS and OS rates than MWA (p = 0.024 and p = 0.047, respectively). Multivariate analysis after PSM identified moderate or severe cirrhosis and recurrence intervals ≤12 months as independent predictors of poor RFS and OS in patients with early recurrence of HCC. LR is more effective than MWA for early recurrence of HCC in patients without cirrhosis or with mild cirrhosis, showing improved RFS and OS rates. In patients with moderate or severe cirrhosis, the OS and RFS were statistically equal between the two therapies. However, MWA may be preferred owing to its low complication rate. [ABSTRACT FROM AUTHOR]

Introduction: For patients with large unresectable hepatocellular carcinoma (HCC), the effectiveness of conventional transarterial chemoembolization (cTACE) remains suboptimal. This study investigated the efficacy and safety of modified TACE using low-dose chemotherapy with blank microspheres (BMS-TACE) plus low-dose lenvatinib (LD-LEN) and microwave ablation (MWA) in patients with large unresectable HCC. Methods: In this prospective, single-arm, phase 2 study, patients with unresectable HCC exceeding the up-to-seven criteria, with maximum tumor diameter ≥7 cm, and without macrovascular invasion or extrahepatic metastases, received initial BMS-TACE (lipiodol, low-dose doxorubicin, and lobaplatin up to 30 mg each, and blank microspheres; subsequently modified and repeated in most patients) plus LD-LEN (4–8 mg/day) and MWA. The primary endpoint was downstaging rate (DSR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: From November 2019 to March 2022, 43 patients were enrolled. Median follow-up was 21.2 months. Median largest tumor diameter was 11.2 cm (interquartile range [IQR], 7–25). Following BMS-TACE and LD-LEN, downstaging occurred in 37 (86.0%) patients, 32 of whom received MWA, and 8 of whom had a complete response (CR) without MWA. ORR was 93.0% (CR in 32 [74.4%] and partial response in 8 [18.6%] patients). The 1-, 2-, and 3-year PFS rates were 57.5%, 25.9%, and 18.1%, respectively (median PFS, 14.7 months [95% CI: 8.1–19.5]). The 1-, 2-, and 3-year OS rates were 85.8%, 67.7%, and 61.6%, respectively (median OS, 36.4 months [95% CI: 26.8-not reached]). After BMS-TACE, a significant decline in CD11b+/CD33+/HLA-DR- myeloid-derived suppressor cells and early elevation in CXCR5+/CD8+ and CXCR5+/CD4+ T cells were observed (both p < 0.05). Conclusion: BMS-TACE plus LD-LEN and MWA resulted in promising efficacy and tolerable toxicity in patients with large unresectable HCC exceeding the up-to-seven criteria with a maximum tumor diameter ≥7 cm and without macrovascular invasion or extrahepatic metastases. [ABSTRACT FROM AUTHOR]

Inspired by our previous finding that disesquiterpenoids showed more potent antihepatoma cytotoxicity than their corresponding parent monomers, natural product‐like guaianolide‐germacranolide heterodimers were designed and synthesized from guaianolide diene and germacranolides via a biomimetic Diels–Alder reaction to provide three antihepatoma active dimers with novel scaffolds. To explore the structure–activity relationship, 31 derivatives containing ester, carbamate, ether, urea, amide, and triazole functional groups at C‐14′ were synthesized and evaluated for their cytotoxic activities against HepG2, Huh7, and SK‐Hep‐1 cell lines. Among them, 25 compounds were more potent than sorafenib against HepG2 cells, 15 compounds were stronger than sorafenib against Huh7 cells, and 17 compounds were stronger than sorafenib against SK‐Hep‐1 cells. Compound 23 showed the most potent cytotoxicity against three hepatoma cell lines with IC50 values of 4.4 µM (HepG2), 3.7 µM (Huh7), and 3.1 µM (SK‐Hep‐1), which were 2.7‐, 2.2‐, and 2.8‐fold more potent than sorafenib, respectively. The underlying mechanism study demonstrated that compound 23 could induce cell apoptosis, prevent cell migration and invasion, cause G2/M phase arrest in SK‐Hep‐1 cells. Network pharmacology analyses predicted PDGFRA was one of the potential targets of compound 23, and surface plasmon resonance (SPR) assay verified that 23 had strong affinity with PDGFRA with a dissociatin constant (KD) value of 90.2 nM. These promising findings revealed that structurally novel guaianolide‐germacranolide heterodimers might provide a new inspiration for the discovery of antihepatoma agents. [ABSTRACT FROM AUTHOR]

Objective: To compare the short- and long-term outcomes of robot-assisted (RALR), laparoscopic (LLR), or open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC). Summary Background Data: Following the Balliol IDEAL classification, long-term oncological outcomes can be used to evaluate the value of minimally invasive techniques in the treatment of HCC, and to assess whether they should become a standard practice. Methods: Data from prospective cohorts of patients with BCLC stage 0-A HCC who underwent curative liver resection using OLR, LLR, or RALR at Tongji Hospital were reviewed. The short-term and long-term oncological outcomes of these 3 different surgical approaches after adequate follow-up were compared using propensity score matching to reduce selection bias. Results: Of 369 patients included in this study (71, RALR; 141, LLR; and 157, OLR), 56 patients in each of the 3 groups were chosen for further comparison, after propensity score matching. In the minimally invasive group (RALR+LLR), both the operative time and duration of Pringle's maneuver were significantly longer than those in the OLR group; however, the length of hospital stay was significantly shorter. There were no significant differences in the other intraoperative parameters and the incidence of postoperative complications among the 3 groups. HCC recurrence in the minimally invasive group when compared with the OLR group was characterized by a significantly higher proportion of single lesion or early-stage HCC. However, there were no significant differences in the 5-year disease-free survival (63.8%, 54.4%, and 50.6%) or overall survival rates (80.8%, 78.6%, and 75.7%, respectively) among the 3 groups. Clinically significant portal hypertension was the only risk factor that negatively affected the 5-year disease-free survival rate. Multivariate Cox regression analysis showed that clinically significant portal hypertension, serum alpha-fetoprotein level (≥400 ng/mL), and Edmondson-Steiner grading (III+IV) were independent risk factors for poor long-term survival. Conclusion: Both robotic and laparoscopic hepatectomies were safe and effective for patients with BCLC stage 0-A HCC when compared with open hepatectomy. [ABSTRACT FROM AUTHOR]

Background: Acid phosphatase type 6 (ACP6) is a mitochondrial lipid phosphate phosphatase that played a role in regulating lipid metabolism and there is still blank in the clinico-pathological significance and functional roles of ACP6 in human cancers. No investigations have been conducted on ACP6 in hepatocellular carcinoma (HCC) up to date. Methods: Herein, we appraised the clinico-pathological significance of ACP6 in HCC via organizing expression profiles from globally multi-center microarrays and RNA-seq datasets. The molecular basis of ACP6 in HCC was explored through multidimensional analysis. We also carried out in vitro and in vivo experiment on nude mice to investigate the effect of knocking down ACP6 expression on biological functions of HCC cells, and to evaluate the expression variance of ACP6 in xenograft of HCC tissues before and after the treatment of NC. Results: ACP6 displayed significant overexpression in HCC samples (standard mean difference (SMD) = 0.69, 95% confidence interval (CI) = 0.56–0.83) and up-regulated ACP6 performed well in screening HCC samples from non-cancer liver samples. ACP6 expression was also remarkably correlated with clinical progression and worse overall survival of HCC patients. There were close links between ACP6 expression and immune cells including B cells, CD8 + T cells and naive CD4 + T cells. Co-expressed genes of ACP6 mainly participated in pathways including cytokine-cytokine receptor interaction, glucocorticoid receptor pathway and NABA proteoglycans. The proliferation and migration rate of HCC cells transfected with ACP6 siRNA was significantly suppressed compared with those transfected with negative control siRNA. ACP6 expression was significantly inhibited by nitidine chloride (NC) in xenograft HCC tissues. Conclusions: ACP6 expression may serve as novel clinical biomarker indicating the clinical development of HCC and ACP6 might be potential target of anti-cancer effect by NC in HCC. [ABSTRACT FROM AUTHOR]

Stromal antigen 1 (STAG1), a component of cohesion, is overexpressed in various cancers, but it is unclear whether it has a role in the transcriptional regulation of hepatocellular carcinoma (HCC). To test this hypothesis, here, we screened global HCC datasets and performed multiscale embedded gene co‐expression network analysis to identify the potential functional modules of differentially expressed STAG1 co‐expressed genes. The putative transcriptional targets of STAG1 were identified using chromatin immunoprecipitation followed by high‐throughput DNA sequencing. The cohesin‐associated gene score (CAGS) was quantified using the The Cancer Genome Atlas HCC cohort and single‐sample gene set enrichment analysis. Distinct cohesin‐associated gene patterns were identified by calculating the euclidean distance of each patient. We assessed the potential ability of the CAGS in predicting immune checkpoint blockade (ICB) treatment response using IMvigor210 and GSE78220 cohorts. STAG1 was upregulated in 3313 HCC tissue samples compared with 2692 normal liver tissue samples (standard mean difference = 0.54). A total of three cohesin‐associated gene patterns were identified, where cluster 2 had a high TP53 mutated rate and a poor survival outcome. Low CAGS predicted a significant survival advantage but presaged poor immunotherapy response. Differentially expressed STAG1 co‐expression genes were enriched in the mitotic cell cycle, lymphocyte activation, and blood vessel development. PDS5A and PDGFRA were predicted as the downstream transcriptional targets of STAG1. In summary, STAG1 is significantly upregulated in global HCC tissue samples and may participate in blood vessel development and the mitotic cell cycle. A cohesin‐associated gene scoring system may have potential to predict the ICB response. [ABSTRACT FROM AUTHOR]

To determine the predictive value of preoperative inflammatory markers in hepatocellular carcinoma (HCC) prognosis after transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA). A total of 161 patients with HCC who underwent TACE combined with RFA were enrolled in this retrospective study. Receiver operating characteristic (ROC) curve analysis was used to decide the cutoff value of the neutrophil-to-lymphocyte ratio (NLR), the lymphocyte-to-monocyte ratio (LMR), the platelet-to-lymphocyte ratio (PLR), and the prognostic nutritional index (PNI). The relationship between preoperative NLR, LMR, PLR, PNI, and survival outcomes was analyzed using Kaplan–Meier curves and multivariate Cox regression analyses. The cutoff value of NLR for the best discrimination of HCC prognosis was 2.95. The median recurrence-free survival (RFS) of the low NLR (≤2.95) group was longer than that of the high NLR (>2.95) group (29 months vs. 20 months, p = 0.013). The median overall survival (OS) of the low NLR group was longer than that of the high NLR group (60 months vs. 38 months, p = 0.006). Multivariate analysis showed that the tumor size (≤3 cm vs. >3cm), tumor number (single vs. multiple), and NLR (≤2.95 vs. >2.95) were independent predictors of the PFS and OS. LMR, PLR, and PNI did not have any prognostic significance. NLR was confirmed as an independent predictive biomarker for hepatocellular carcinoma prognosis after TACE combined with RFA. [ABSTRACT FROM AUTHOR]

Background: Scalp and skull metastasis of hepatocellular carcinoma (HCC) is extremely rare. Modalities for the treatment of this disease include craniotomy, radiotherapy and chemotherapy, which are unsatisfactory. We report a case of HCC with scalp and skull metastasis and review similar cases from the literature to accumulate experience for better management of this type of HCC metastasis. Case Presentation: A 54-year-old female was diagnosed with advanced HCC with posterior portal vein tumor thrombus (PVTT) at admission. She received laparoscopic microwave therapy for a large tumor in Segment 6, which was then followed by sorafenib therapy. One year later, sorafenib resistance developed, metastasis occurred in the scalp and skull, left sacroiliac joint, and lung; PVTT extended into the main portal vein and alpha-feta protein (AFP) levels exceeded 65,000 ng/mL. Systemic therapy was then substituted by regorafenib combined with sintilimab. Three months later, AFP decreased to 2005 ng/mL; meanwhile, skull and lung metastatic lesions shrank significantly. Furthermore, both lump and limp disappeared. One year after the combination of regorafenib and sintilimab, skull and lung metastasis, and PVTT were completely relieved. Moreover, primary liver lesions showed no sign of activity. With comprehensive therapy, the patient has survived for 5 years and 7 months. Conclusion: Sorafenib-regorafenib sequential treatment combined with sintilimab is safe and effective when used to treat HCC skull metastasis, for which high-level evidence is needed to support this treatment strategy. [ABSTRACT FROM AUTHOR]

Background. Cirrhotic severity scoring (CSS) is a noninvasive method that can predict histological severity of cirrhosis. This study is aimed at assessing the predictive value of CSS on long-term outcomes after curative hepatectomy for patients with hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC) and Child-Pugh grade A liver function and further developing novel nomograms to preoperatively predict posthepatectomy recurrence and survival. Methods. Consecutive patients who underwent curative hepatectomy for HCC between 2008 and 2014 were retrospectively studied. According to the CSS, patients were subclassified into 3 groups: no/mild, moderate, and severe cirrhosis. The impact of CSS on recurrence-free survival (RFS) and overall survival (OS) was assessed. Furthermore, RFS and OS nomograms were developed. Results. The 5-year RFS and OS rates were 36.1% and 62.8% in the no/mild cirrhosis group, compared with 28.4% and 56.2% in the moderate cirrhosis group, and 16.2% and 33.0% in the severe cirrhosis group. Long-term survival outcomes were significantly worse with the increment of cirrhotic severity. CSS, alpha-fetoprotein level, tumor size, tumor number, and macrovascular invasion were identified as independent predictors of both RFS and OS. Besides, albumin-bilirubin grade was an independent risk factor of OS not RFS. RFS- and OS-predictive nomograms based on these preoperative variables were built. For these 2 nomograms, the C-indexes were 0.696 and 0.732, respectively. Calibration curves exhibited good agreement between actual observation and nomogram prediction. Conclusions. CSS was a predictor for long-term outcomes in HCC patients after curative hepatectomy. The novel nomograms exhibited accurate preoperative prediction of posthepatectomy recurrence and OS. [ABSTRACT FROM AUTHOR]

Background: Liver resection (LR) and percutaneous microwave coagulation therapy (PMCT) are both considered as radical treatments for small hepatocellular carcinoma (HCC). However, it is still unclear whether to select LR or PMCT in HCC patients with different degrees of liver cirrhosis. The purpose of this study was to compare the efficacy of LR and PMCT in the treatment of solitary and small HCC accompanied with different degrees of liver cirrhosis. Methods: In this study, 230 patients with solitary HCC lesions ≤ 3 cm and Child-Pugh A liver function were retrospectively reviewed. Among these patients, 122 patients underwent LR, and 108 received PMCT. The short- and long-term outcomes were compared between these two procedures. Severity of liver cirrhosis was evaluated by using clinical scoring system (CSS) as previously published. Subgroup analysis based on CSS was performed to evaluate the effect of severity of liver cirrhosis on surgical outcomes after LR and PMCT. Results: There was no mortality within 90 days in both groups. Major complications were significantly more frequent in the LR group than in the PMCT group (18.8% vs. 4.6%, p <0.001). However, LR provided better surgical outcomes than PMCT. The 5-year overall survival (OS) rates for the LR and PMCT groups were 65.2% and 42%, respectively (p =0.006), and the corresponding disease-free survival (DFS) rates were 51.7% and 31.5%, respectively (p =0.004). Nevertheless, subgroup analysis showed that PMCT provided long-term outcomes that were similar to LR and lower surgical complications in HCC patients with CSS score≥4. Conclusions: LR may provide better OS and DFS rates than PMCT for patients with solitary HCC lesions ≤ 3 cm and Child-Pugh A liver function irrespective of liver cirrhosis. PMCT should be viewed as the optimal treatment for solitary and small HCC with severe cirrhosis. [ABSTRACT FROM AUTHOR]

The incidence and mortality of hepatocellular carcinoma (HCC) are gradually increasing during the past years. Recently, some studies have reported that malic enzyme (ME) plays an important role in cancer development, while the involvement of ME2 in HCC remains still undetermined. Here, we demonstrated that ME2 played an oncogenic role in HCC. ME2 was overexpressed in HCC tissues. TCGA database showed that the ME2 transcript level was inversely associated with the survival of HCC patients. Loss‐of‐function and gain‐of‐function assays showed that ME2 promoted HCC cell growth and migration. Furthermore, the xenografted tumorigenesis of MHCC97H cells was retarded by ME2 knockdown. ME2 silencing also suppressed the cell cycle process and induced apoptosis. Mechanistically, ME2 potentiated triglyceride synthesis, inhibition of which suppressed the proliferation and migration. We propose that ME2 promotes HCC progression by increasing triglyceride production. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is usually associated with varying degrees of cirrhosis. Among cirrhotic patients with solitary HCC in the absence of macro-vascular invasion, whether tumor size drives prognosis or not after hepatectomy remains unknown. This study aimed to investigate the prognostic impact of tumor size on long-term outcomes after hepatectomy for solitary HCC patients with cirrhosis and without macrovascular invasion. A total of 813 cirrhotic patients who underwent curative hepatectomy for solitary HCC and without macrovascular invasion between 2001 and 2014 were retrospectively studied. We set 5 cm as the tumor cut-off value. Propensity score matching (PSM) was performed to minimize the influence of potential confounders including cirrhotic severity that was histologically assessed according to the Laennec staging system. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after PSM. Overall, 464 patients had tumor size ≤ 5 cm, and 349 had tumor size > 5 cm. The 5-year RFS and OS rates were 38.3% and 61.5% in the ≤ 5 cm group, compared with 25.1% and 59.9% in the > 5 cm group. Long-term survival outcomes were significantly worse as tumor size increased. Multivariate analysis indicated that tumor size > 5 cm was an independent risk factor for tumor recurrence and long-term survival. These results were further confirmed in the PSM cohort of 235 pairs of patients. In cirrhotic patients with solitary HCC and without macrovascular invasion, tumor size may significantly affect the prognosis after curative hepatectomy. [ABSTRACT FROM AUTHOR]

Although liver resection (LR) and liver transplantation (LT) are widely considered as potentially curative therapies for selected patients with hepatocellular carcinoma (HCC); however, there is still high risk of tumor recurrence in majority of HCC patients. Previous studies demonstrated that the presence of microvascular invasion (MVI), which was defined as the presence of tumor emboli within the vessels adjacent to HCC, was one of the key factors of early HCC recurrence and poor surgical outcomes after LR or LT. In this review, we evaluated the impact of current MVI status on surgical outcomes after curative therapies and aimed to explore the surgical strategies for HCC based on different MVI status with evidence from pathological examination. Surgical outcomes of HCC patients with MVI have been described as a varied range after curative therapies due to a broad spectrum of current definitions for MVI. Therefore, an international consensus on the validated definition of MVI in HCC is urgently needed to provide a more consistent evaluation and reliable prediction of surgical outcomes for HCC patients after curative treatments. We concluded that MVI should be further sub-classified into MI (microvessel invasion) and MPVI (microscopic portal vein invasion); for HCC patients with MPVI, local R0 resection with a narrow or wide surgical margin will get the same surgical results. However, for HCC patients with MI, local surgical resection with a wide and negative surgical margin will get better surgical outcomes. Nowadays, MVI status can only be reliably confirmed by histopathologic evaluation of surgical specimens, limiting its clinical application. Taken together, preoperative assessment of MVI is of utmost significance for selecting a reasonable surgical modality and greatly improving the surgical outcomes of HCC patients, especially in those with liver cirrhosis. [ABSTRACT FROM AUTHOR]

Severity of liver cirrhosis is distinct from clinical portal hypertension because there exist different degrees of liver cirrhosis in hepatocellular carcinoma (HCC) patients without significant clinical portal hypertension. Whether severity of cirrhosis affects surgical outcomes for HCC patients in absence of portal hypertension or not remains unclear. This study aims to analyze the effect of cirrhotic severity on surgical outcomes for HCC patients with hepatitis B virus (HBV) infection in absence of portal hypertension. This retrospective study enrolled 166 patients who underwent curative resection for a single HCC ≤5 cm in absence of portal hypertension between February 2011 and December 2013. Liver cirrhosis was sub-classified into no/mild (no/F4A) and moderate/severe (F4B/F4C) according to the Laennec scoring system. The surgical outcomes and complications were analyzed. The surgical mortality was zero in this study. Major complications were apparently higher in the F4B/F4C group than in the no/F4A group (17.0% vs 7.4%, p < 0.001). The 1-year, 3-year and 5-year overall survival (OS) rates were 98.5, 88.1 and 80%, respectively, in the no/F4A group, which were significantly higher than those in the F4B/F4C group (98.0, 69.2 and 54.7%, p = 0.001). Microscopic vascular invasion, absence of tumor capsule and severity of liver cirrhosis were independent risk factors of surgical outcomes for HCC patients without portal hypertension. In conclusion, severity of liver cirrhosis affected surgical outcomes for early-stage HCC patients independent of portal hypertension. [ABSTRACT FROM AUTHOR]

Most patients diagnosed with hepatocellular carcinoma (HCC) have advanced diseases, and many are not eligible for curative therapies. There is growing evidence suggesting that the combination treatment of PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors (TKIs) is becoming a prospective trend for advanced HCC. For those HCC patients with sorafenib resistance, the efficacy of regorafenib combined with PD-1/PD-L1 inhibitors remains unclear. Herein, we represent a case of HCC with lung metastasis in the setting of Hepatitis B virus (HBV)-induced liver cirrhosis responding dramatically to the sequential treatment with regorafenib followed by PD-1 inhibitor after initial liver resection. A 51-year-old man diagnosed with alpha fetoprotein (AFP)-negative HCC underwent liver resection in September 2015 and was found to have solitary liver recurrence and multiple lung metastases in March 2017. He received microwave coagulation therapy (MCT) and trans-arterial chemoembolization (TACE) for liver tumor and treatment was started with sorafenib 400 mg twice daily for controlling lung metastases. In December 2018, an abdominal computerized tomography (CT) scan showed two new lesions in the liver. In March 2019, disease progression of lung metastases was measured and he received 160 mg regorafenib once daily. After a short period of partial response, in December 2019, due to the progression of the disease, he started treatment with regorafenib 160 mg in combination with sintilimab (PD-1 inhibitor) (200 mg, 3 weeks as a cycle). Surprisingly, after five cycles of sintilimab injection, he showed complete response in target lesions. There was no clinical evidence of disease progression, and the side-effects were mild. The current overall survival (OS) is 58 months. Data from this clinical case report suggest that sequential treatment with regorafenib followed by PD-1 inhibitor is a promising therapeutic option for sorafenib-refractory cases of HCCs. [ABSTRACT FROM AUTHOR]

Objective: To investigate the safety and therapeutic efficacy of adjuvant cytokine-induced killer (CIK) cells to minimally invasive therapies in unresectable hepatocellular carcinoma (u-HCC).Materials and Methods: Hundred patients diagnosed with having u-HCC in our department from January 1, 2001, to July 31, 2018, were recruited. Forty-three patients received microwave ablation (MWA) and transcatheter arterial chemoembolization (TACE) together with autologous CIK cell treatment (TACE + MWA + CIK group), whereas 57 patients received TACE and MWA only (TACE + MWA group). Postprocedural complications and cumulative therapeutic effects were assessed in all patients. The disease control rate, median survival time (MST), and cumulative survival rate were compared between the cohorts using the Kaplan-Meier method and unpaired Student's t-tests.Results: The overall response (complete response [CR] + partial response [PR]) rate was 74.42% (32/43) and 77.19% (44/57) for TACE + MWA + CIK and TACE + MWA groups, respectively (P = 0.243). Those of the TACE + MWA + CIK group had better rates of disease control (CR + PR + stable disease) in contrast to the TACE + MWA group (87.72% vs. 79.07%, respectively) but this failed to achieve statistical significance (P = 0.748). Based on the Kaplan-Meier survival graphs, those of the TACE + MWA + CIK groups possessed markedly increased overall survival (41 months vs. 24 months, P = 0.002) and progression-free survival (17 months vs. 10 months, P = 0.023) rates in compared to the TACE + MWA group. Survival rates were raised also TACE + MWA + CIK group than in TACE + MWA group (P = 0.002), with a MST of 6.13 ± 0.83 months and 11.61 ± 1.59 months in the TACE + MWA + CIK and TACE + MWA groups, respectively. Patients in the TACE + MWA + CIK group were not reported to have any severe complications.Conclusion: CIK cell immunotherapy as an adjuvant to TACE and MWA enhanced long-term prognosis and improved quality of life in patients with u-HCC. This regimen may be recommended as a novel treatment regime in u-HCC patients. [ABSTRACT FROM AUTHOR]

Background: Bronchobiliary fistula is a rare, but life‐threatening complication after ablation of hepatocellular carcinoma. Few cases of bronchobiliary fistula have been reported and the treatment is controversial. Methods: From 2006 to 2019, a total of 11 patients were diagnosed with bronchobiliary fistula after ablation and received nonsurgical treatment. Results: All 11 patients presented with cough and bilioptysis. There were only two patients in which MRI revealed an obvious fistulous tract connecting the pleural effusion and biliary lesions. Pleural effusion, liver abscess and hepatic biloma were found in other patients. Three patients died of uncontrolled bronchobiliary fistula. Conclusions: Bronchobiliary fistula is a rare post‐ablation complication but should be taken into consideration in clinical decisions. Minimally invasive interventional treatment is a relatively effective means of dealing with bronchobiliary fistula, but as for the more severe cases, greater clinical experience is required. [ABSTRACT FROM AUTHOR]

Introduction: MIR22HG has a reported involvement in the tumorigenesis of a variety of cancers, including hepatocellular carcinoma (HCC). However, the exact molecular mechanism of MIR22HG in HCC has not been clarified. Methods: In the present study, we integrated data from in-house RT-qPCR, RNA-sequencing, microarray, and literature studies to conduct a comprehensive evaluation of the clinico-pathological and prognostic significance of MIR22HG in an extremely large group of HCC samples. We also explored the potential mechanism of MIR22HG in HCC by analyzing the alteration profiles of MIR22HG in HCC to predict transcription factors (TFs) that may interact with MIR22HG and to annotate the biological functions of genes co-expressed with MIR22HG. MIR22HG expression was also compared in HCC nude mice xenografts before and after a treatment with nitidine chloride. Results: We found that MIR22HG was downregulated in HCC and that this downregulation correlated with the malignant phenotype of HCC. Comprehensive analysis of the prognostic impact of MIR22HG in HCC revealed a beneficial effect of MIR22HG on the survival outcome of HCC patients. Seven cases of MIR22HG deep deletion occurred in 360 of the cancer genome atlas (TCGA) provisional HCC samples. A total of 22 MIR22HG-TF-mRNA triplets in HCC were predicted by the lncRNAmap. Co-expressed genes of MIR22HG, identified by weighted correlation network analysis (WGCNA), mainly participated in the pathways involving osteoclast differentiation, chemokine signaling pathways, and hematopoietic cell lineage. In vivo experiments demonstrated that nitidine chloride could stimulate MIR22HG expression in HCC xenografts. Conclusion: In summary, MIR22HG may play a tumor-suppressive role in HCC by coordinating with predicted TFs and co-expressed genes, such as NLRP3, CSF1R, SIGLEC10, and ZEB2, or by being controlled by nitidine chloride. [ABSTRACT FROM AUTHOR]

Partial hepatectomy has been used to treat patients with resectable hepatocellular carcinoma (HCC) which spontaneously ruptured. It is still controversial as to whether emergency partial hepatectomy (EmPH) should be carried out at the time of rupture, or the patients should initially be managed by operative or non-operative treatment to stop the bleeding, followed by staged early or delayed partial hepatectomy when the patient's condition becomes stable. Consecutive 10-year patients with ruptured HCC managed at our center were included in this study. Patients who underwent partial hepatectomy were further subdivided into the EmPH group, the staged early partial hepatectomy (SEPH) group, and the staged delayed partial hepatectomy (SDPH) group. Univariate and multivariate analyses of factors affecting overall survival(OS) were conducted before and after propensity score matching analyses amongst the included patients. OS, postoperative mortality, recurrence free survival (RFS), and peritoneal metastatic rates were compared. The risk factors of peritoneal metastases were determined using the COX regression analysis. The 130 patients who underwent partial hepatectomy were subdivided into the EmPH group (surgery at the time of rupture, n = 30), the SEPH group (surgery ≤ 8 days of rupture, n = 67), and the SDPH group (surgery > 8 days of rupture, n = 33). The remaining 86 patients underwent non-surgical treatment. Partial hepatectomy was an independent predictor of better OS (HR 2.792, P < 0.001). For resectable HCC, the 30-day mortality, OS, and RFS were similar between the EmPH group, and the staged partial hepatectomy (SPH) group which included the patients who underwent SEPH and SDPH. The SEPH group had significantly better OS and RFS. Multivariate COX regression analysis demonstrated that SDPH was strongly associated with postoperative peritoneal dissemination (OR 28.775, P = 0.003). Partial hepatectomy provided significantly better survival than non-surgical treatment for patients who presented with ruptured HCC. Early partial hepatectomy within 8 days of rupture which included EmPH (carefully selected) and SEPH, resulted in significantly less patients with peritoneal dissemination and better long-term survival outcomes (especially RFS) than SDPH. [ABSTRACT FROM AUTHOR]

Aims: To determine the sizes and shapes of ablation zones in 4-antenna microwave ablation in ex vivo bovine liver model under different conditions of power delivery patterns, antenna spacings, and ablation durations, for further using of multi-antenna MWA strategies in the treatment of large hepatocellular carcinoma.Methods: We tested protocols of eight ablations each on ex vivo bovine livers, involving simultaneous or sequential activation of four microwave antennas, spaced either 3 cm, 4 cm, or 5 cm apart, for either 10 or 15 min, at 60-W power. We determined the diameters, shapes, and temperatures of the ablation zones.Results: Compared to sequential power delivery, simultaneous power delivery resulted in significantly larger ablation zone diameters (P < .001). The temperatures in ablation zones were significantly higher for simultaneous than for sequential power delivery. The largest ablation diameter (7.45 ± 0.06 cm) resulted from simultaneous delivery for 15 min using 4-cm antenna spacing.Conclusions: Simultaneous 4-antenna microwave ablation results in larger ablation zones than sequential ablation, and 4-cm antenna spacing with a 15-minute ablation duration creates the largest ablation zone. This information may provide multi-antenna MWA strategies for large HCC in the further clinical practice. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the third leading cause of cancer‑associated mortality in the 21st century. microRNA (miR)‑23b has been shown to be involved in the pathogenesis of many cancers, including breast and prostate cancer. However, the role of miR‑23b in HCC remains unclear. The present study revealed a negative correlation between miR‑23b expression in HCC tissues and progression of carcinomas. Compared to normal tissues, miR‑23b expression was significantly downregulated in HCC tissues, whereas the expression of interleukin (IL)‑11 and IL‑11 receptor α (IL‑11Rα) was significantly upregulated, indicating that miR‑23b expression is negatively correlated with IL‑11 and IL‑11Rα expression. In addition, miR‑23b inhibited proliferation and promoted apoptosis of SMMC‑7721 cells. This effect was mediated by IL‑11, which was found to be the direct target of miR‑23b in this study. These results indicated that miR‑23b regulates IL‑11 and IL‑11Rα expression, and might act as an anti‑oncogenic agent in the progression of HCC by directly downregulating IL‑11 expression. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that the renin-angiotensin system (RAS) plays an important role in tumorigenesis. The interaction between Angiotensin II (AngII) and angiotensin type 1 receptor (AT1R) may have a pivotal role in hepatocellular carcinoma (HCC) and therefore, AT1R blocker and angiotensin I-converting enzyme (ACE) inhibitors may have therapeutic potential in the treatment of hepatic cancer. Although the involvement of AT1R has been well explored, the role of the angiotensin II Type 2 receptor (AT2R) in HCC progression remains poorly understood. Thus, the aim of this study was to explore the effects of AT2R overexpression on HCC cells in vitro and in mouse models of human HCC. An AT2R recombinant adenoviral vector (Ad-G-AT2R-EGFP) was transduced into HCC cell lines and orthotopic tumor grafts. The results indicate that the high dose of Ad-G-AT2R-EGFP–induced overexpression of AT2R in transduced HCC cell lines produced apoptosis. AT2R overexpression in SMMC7721 cells inhibited cell proliferation with a significant reduction of S-phase cells and an enrichment of G1-phase cells through changing expression of CDK4 and cyclinD1. The data also indicate that overexpression of AT2R led to apoptosis via cell death signaling pathway that is dependent on activation of p38 MAPK, pJNK, caspase-8 and caspase-3 and inactivation of pp42/44 MAPK (Erk1/2). Finally, we demonstrated that moderately increasing AT2R expression could increase the growth of HCC tumors and the proliferation of HCC cells in vivo. Our findings suggest that AT2R overexpression regulates proliferation of hepatocellular carcinoma cells in vitro and in vivo, and the precise mechanisms of this phenomenon are yet to be fully determined. [ABSTRACT FROM AUTHOR]

Transarterial chemoembolization (TACE) has therapeutic effects in patients with unresectable hepatocellular carcinoma (HCC), but its impact on the cellular immune response during disease progression is largely unknown. Here we conducted a prospective study to evaluate the effect of TACE on immune status and to identify prognostic immune markers governing treatment success. In this study, 51 stage III HCC patients, 28 stage I HCC patients (TNM classification) and 20 healthy donors were enrolled. Flow cytometry and cytometric bead array were used to evaluate the circulating immune cell subsets, including CD4+ T cells (Th1, Th17 and Treg cells), CD8+ T cells, NK cells, and NKT cells, and plasma cytokines before TACE and 30 days after TACE. Interestingly, among those immune parameters, the frequency of circulating Th17 cells was higher in stage III HCC patients than in stage I HCC patients (P = 0.015) and healthy donors (P<0.001). Moreover, an increased frequency of circulating Th17 cells was observed 30 days after TACE (Th17D30) compared with the baseline level (P = 0.036). Kaplan-Meier analysis demonstrated that Th17D30 was positively associated with overall survival (OS; P = 0.007) and time to progression (TTP; P = 0.009). Multivariate Cox analysis revealed that Th17D30 was an independent prognostic factor for OS (HR = 0.317, P = 0.032) and TTP (HR = 0.304, P = 0.010). These results provide a potential prognostic marker for stage III HCC patients undergoing TACE and may be useful for identifying patients who can benefit from adjuvant immunotherapies. [ABSTRACT FROM AUTHOR]

Objective To validate the efficacy of an innovative multimodality therapy with transcatheter arterial embolization ( TAE) plus octreotide and celecoxib in reducing neoangiogenesis and prolonging the survival of rabbits with hepatocellular carcinoma. Methods Rabbits with hepatic VX2 allografts were divided into four groups: control group, TAE group, octreotide + celecoxib ( O + C) group and the multimodality therapy ( TAE + O + C) group. Survival of the rabbits was analyzed using the Kaplan- Meier method and the expression of CD31 in tumor tissues was detected by immunohistochemistry. Results Rabbits in the TAE + O + C group lived nearly 20 days longer than those in the control group. The survival rate of the TAE + O + C group was 50% at day 80 and was the highest among the four groups ( P < 0.05). No VX2 allograft-bearing rabbits in the control group lived longer than 60 days. Compared with the control group, the survival time of the other two intervention groups were not prolonged significantly ( P > 0.05). The CD31 expression induced by TAE was reduced significantly in TAE + O + C group ( P < 0.05). Less metastasis was detected in TAE + O + C group. Conclusion TAE followed by the long-term administration of octreotide and celecoxib can synergistically prolong the survival of rabbits with hepatic VX2 allografts by inhibiting potential neoangiogenesis, tumor growth and metastasis. [ABSTRACT FROM AUTHOR]

Background/Aims: Coumarins are natural compounds found in many plants that possess medical value by itself and its modified derivatives. Method: Six novel coumarin derivatives were synthesized and examined for their potential anticancer cytotoxicity. Result: Among the 6 derivatives, 3,5-dimethyl-7H-furo[3,2-g]chromen-7-one (DMFC) presented the strongest cytotoxicity against human hepatoma HepG2 cells in vitro with an IC50 value of 8.46 ± 0.28 μM in a 48-hour treatment. Further experiments revealed that DMFC induced apoptosis in HepG2 cells through both extrinsic and intrinsic apoptotic pathways in a p53-dependent manner. Mechanistically, DMFC activated caspases 3, 8 and 9, depolarized mitochondrial membrane potential and induced cytochrome c and apoptosis-inducing factor release. DMFC-induced apoptosis was also characterized by DNA fragmentation, phosphatidylserine externalization and sub-G1 peak in DNA histograms. Moreover, both caspase 8 and 9 inhibitors suppressed the apoptosis induced by DMFC. Western blot analyses revealed that DMFC also significantly increased the expression levels of p53, Fas death receptor, Fas-associated death domain protein and proapoptotic Bcl-2 family members such as Bax, Bad and tBid, as well as decreased the levels of pro-survival members such as Bcl-2 and Bcl-xl. Conclusion: DMFC is potentially an effective therapeutic agent in liver cancer therapy. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) play an important regulatory role in carcinogenesis and cancer progression. Aberrant expression of miR‐497‐5p has been reported in various human malignancies. However, the role of miR‐497‐5p in hepatocellular carcinoma (HCC) remains unclear. Results: In this study, we found that miR‐497‐5p was downregulated in HCC tissues. The low level of miR‐497‐5p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. The overexpression of miR‐497‐5p significantly inhibited HCC cell proliferation, colony formation, and metastasis in vitro and vivo. Bioinformatics analysis further identified insulin‐like growth factor 1 (IGF1) as a novel target of miR‐497‐5p in HCC cells. Conclusion: Our study suggested that miR‐497‐5p regulates HCC cell survival, partially through downregulation of IGF1. Therefore, the miR‐497‐5p/IGF1 axis might serve as a novel therapeutic target in patients with HCC. [ABSTRACT FROM AUTHOR]

Background: In patients with a large, unresectable hepatocellular carcinoma (HCC), the primary recommendation is for transarterial chemoembolization (TACE) but used alone TACE is not typically curative. Combinations of TACE followed in a delayed fashion by single-applicator thermal ablation have also been suboptimal. As an alternative, we investigated the combination of TACE followed within 1–3 days by multi-antenna microwave ablation (MWA) in patients with a large HCC, to determine the feasibility, safety, local control, and short-term survival rates of this approach. Methods: We retrospectively studied 43 patients with a large HCC (mean diameter, 8.8 cm; SD, 2.8 cm) treated between July 2015 and July 2018, who underwent TACE followed within 3 days by multi-antenna simultaneous MWA. We measured the liver and renal function before and after treatment, recorded complications, used three-dimensional software and imaging to calculate tumor necrosis rates at 1 month after therapy, and calculated overall survival (OS) and progression-free survival (PFS) using the Kaplan–Meier method. Results: Mean follow up was 12.2 (range, 3.5–35.6) months. All patients completed the treatment protocol. At 1 month after combined therapy, tumor necrosis was complete in 16 (37.2%), nearly complete in 19 (44.2%), and partial in 8 (18.6%) patients. The 1- and 2-year OS rates were 64.0% and 46.8%, respectively, with a median OS of 23.0 months; and the 1- and 2-year PFS rates were 19.9% and 4.4%, respectively, with a median PFS of 4.2 months. A transient change in liver function occurred 3 days after MWA but resolved within 1 month. Only two patients had major complications, which were treatable and resolved. Conclusion: Multi-antenna MWA-oriented combined therapy is feasible and well tolerated, and it results in satisfactory initial local control and short-term survival in some but not all patients with a large HCC. [ABSTRACT FROM AUTHOR]

Abstract: Amphiphilic derivatives of poly(benzyl malate) were synthesized and characterized with the aim of being used as degradable and biocompatible building blocks for the design of functional nanoparticles (NPs). An anti-cancer model drug, doxorubicin, has been successfully encapsulated into the prepared NPs and its release profile has been evaluated in water and in culture medium. NPs bearing biotin molecules were prepared either for site-specific drug delivery via the targeting of biotin receptors overexpressed on the surface of several cancer cells, or for grafting biotinylated cyclic RGD peptide onto their surface using the strong and highly specific interactions between biotin and the streptavidin protein. We have shown that this binding did not affect dramatically the physico-chemical properties of the corresponding NPs. Cyclic RGD grafted fluorescent NPs were more efficiently uptaken by the HepaRG hepatoma cells than biotinylated fluorescent NPs. Furthermore, the targeting of HepaRG hepatoma cells with NPs bearing cyclic RGD was very efficient and much weaker for HeLa and HT29 cell lines confirming that cyclic RGD is a suitable targeting agent for liver cells. Our results also provide a new mean for rapid screening of short hepatotropic peptides in order to design NPs showing specific liver targeting properties. [Copyright &y& Elsevier]

Background Severity of liver cirrhosis plays a vital role in determining an appropriate surgical strategy for HCC treatment. However, preoperative evaluation of the severity of cirrhosis has not been established in a surgical setting. This study aims to develop a model to predict the severity of cirrhosis. Methods Overall, 604 patients with hepatocellular carcinoma (HCC) and hepatitis B virus–related cirrhosis undergoing liver resection from Jan 2005 to Jun 2013 were randomly divided into either the model building group ( n = 304) or the test group ( n = 300). The severity of cirrhosis of the resected specimens was pathologically staged according to the Laennec scoring system, which sub-classified cirrhosis into either stage F4A, F4B, or F4C. Results A logistic regression analysis showed that varicosity, portal vein diameter, spleen thickness, and platelet count were significantly associated with the histologic sub-classification of cirrhosis in the model building group. Based on these four parameters, a scoring model for predicting the severity of cirrhosis was established. The model was then verified in the test group, the areas under the ROC (AUROC) for predicting mild (F4A), moderate (F4B), and severe cirrhosis (F4C) were 0.861 (95% confidence interval [CI], 0.810-0.911), 0.860 (95% CI, 0.819-0.901), and 0.968 (95% CI, 0.951-0.985), respectively. The accuracy of this model in predicting mild, moderate, and severe cirrhosis is 79.3%, 81.0%, and 85.3%, respectively. Conclusions By using this model, the severity of cirrhosis can be reliably staged preoperatively, which will provide more information on cirrhotic livers in surgical settings for the treatment of hepatitis B virus–related HCC. [ABSTRACT FROM AUTHOR]

Some microRNAs (miRNAs) have been implicated in hepatocellular carcinoma (HCC) development and progression. However, the roles and mechanisms of several miRNAs in HCC remain poorly understood. Here, we report that miR-379-5p, which is down-regulated in HCC tissues and cell lines, is associated with advanced TNM stage and metastasis in HCC. The ectopic overexpression of miR-379-5p inhibited HCC cell migration, invasion, epithelial-to-mesenchymal transition (EMT) and metastasis both in vitro and in vivo. Conversely, miR-379 knockdown increased migration, invasion and EMT in HCC cells. Moreover, miR-379-5p exerted this function by directly targeting focal adhesion kinase (FAK) 3'-UTR and repressing FAK expression, thus leading to suppression of AKT signaling. Furthermore, the tumor suppressive effects of miR-379-5p in HCC cells were reversed by activating AKT signaling or restoring FAK expression. In clinical samples of HCC, miR-379-5p negatively correlated with FAK, which was up-regulated in HCC. Taken together, our findings highlight the important role of miR-379-5p in regulating the EMT and metastasis of HCC by targeting FAK/AKT signaling, suggesting that miR-379-5p may represent a novel potential therapeutic target and prognostic marker for HCC. [ABSTRACT FROM AUTHOR]

Background Liver resection is the mainstay of treatment for patients with hepatocellular carcinoma and compensated cirrhosis. We investigated the relationship between the morphologic severity of cirrhosis and post-hepatectomy liver failure (PHLF) and evaluated the role of cirrhosis staging in determination of the extent limit for liver resection. Methods The clinicopathologic data of 672 consecutive patients with Child–Pugh grade A liver function who underwent curative liver resection for hepatocellular carcinoma in Tongji Hospital from 2009 to 2013 were retrospectively reviewed. Severity of cirrhosis was staged morphologically and histologically. Risk factors for histologic cirrhosis and PHLF were analyzed. The extent limit of liver resection with reference to morphologic staging was studied. Results Morphologic and histologic stages were significantly correlated (τ = 0.809, P < 0.001). Multivariate analysis showed that morphologic staging was the most crucial factor for histologic cirrhosis (odds ratio = 26.99, 95% confidence interval = 16.88–43.14, P < 0.001) and PHLF (odds ratio = 11.48, 95% confidence interval = 6.04–21.82, P < 0.001). The incidence of PHLF was high in patients with mild cirrhosis after resection of four or more liver segments (13.6%), those with moderate cirrhosis after major resection (38.1%), and those with severe cirrhosis or severe portal hypertension after resection of two or more liver segments (63.2% and 50.0%, respectively). Conclusions Morphologic severity of cirrhosis is an independent predictor of PHLF. Resection of fewer than four liver segments is justified in patients with mild cirrhosis. Major resection is not recommended in patients with moderate cirrhosis. In patients with severe cirrhosis or severe portal hypertension, only resection of fewer than two liver segments can be safely performed. [ABSTRACT FROM AUTHOR]