Treatment Of Hepatoblastoma Research Articles

High-Resolution Magic-Angle-Spinning NMR in Revealing Hepatoblastoma Hallmarks.

Cancer is one of the leading causes of death in children and adolescents worldwide; among the types of liver cancer, hepatoblastoma (HBL) is the most common in childhood. Although it affects only two to three individuals in a million, it is mostly asymptomatic at diagnosis, so by the time it is detected it has already advanced. There are specific recommendations regarding HBL treatment, and ongoing studies to stratify the risks of HBL, understand the pathology, and predict prognostics and survival rates. Although magnetic resonance imaging spectroscopy is frequently used in diagnostics of HBL, high-resolution magic-angle-spinning (HR-MAS) NMR spectroscopy of HBL tissues is scarce. Using this technique, we studied the alterations among tissue metabolites of ex vivo samples from (a) HBL and non-cancer liver tissues (NCL), (b) HBL and adjacent non-tumor samples, and (c) two regions of the same HBL samples, one more centralized and the other at the edge of the tumor. It was possible to identify metabolites in HBL, then metabolites from the HBL center and the border samples, and link them to altered metabolisms in tumor tissues, highlighting their potential as biochemical markers. Metabolites closely related to liver metabolisms such as some phospholipids, triacylglycerides, fatty acids, glucose, and amino acids showed differences between the tissues.

Recent advances in surgical strategies and liver transplantation for hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although the development of treatment strategies with advances in chemotherapy has greatly improved the prognosis of HB, surgical resection and liver transplantation still play a vital role in the treatment of HB. In recent years, technological innovations have led to the development of new surgical approaches for HB. In this review, we describe the latest research on the surgical management of HB, including new imaging technologies, minimally invasive approaches, and the application of associating liver partition portal vein ligation for staged hepatectomy. We also discuss the current role of liver transplantation, use of ante-situm or ex-situ liver resection with auto-transplantation, and management of metastatic HB.

Inhibition of Heat Shock Factor 1 Signaling Decreases Hepatoblastoma Growth via Induction of Apoptosis

Although rare compared with adult liver cancers, hepatoblastoma (HB) is the most common pediatric liver malignancy, and its incidence is increasing. Currently, the treatment includes surgical resection with or without chemotherapy, and in severe cases, liver transplantation in children. The effort to develop more targeted, HB-specific therapies has been stymied by the lack of fundamental knowledge about HB biology. Heat shock factor 1 (HSF1), a transcription factor, is a canonical inducer of heat shock proteins, which act as chaperone proteins to prevent or undo protein misfolding. Recent work has shown a role for HSF1 in cancer beyond the canonical heat shock response. The current study found increased HSF1 signaling in HB versus normal liver. It showed that less differentiated, more embryonic tumors had higher levels of HSF1 than more differentiated, more fetal-appearing tumors. Most strikingly, HSF1 expression levels correlated with mortality. This study used a mouse model of HB to test the effect of inhibiting HSF1 early in tumor development on cancer growth. HSF1 inhibition resulted in fewer and smaller tumors, suggesting HSF1 is needed for aggressive tumor growth. Moreover, HSF1 inhibition also increased apoptosis in tumor foci. These data suggest that HSF1 may be a viable pharmacologic target for HB treatment.

Construction of a combined random forest and artificial neural network diagnosis model to screening potential biomarker for hepatoblastoma

The purpose of our study is to identify potential biomarkers of hepatoblastoma (HB) and further explore the pathogenesis of it. Differentially expressed genes (DEGs) were incorporated into the combined random forest and artificial neural network diagnosis model to screen candidate genes for HB. Gene set enrichment analysis (GSEA) was used to analyze the ARHGEF2. Student's t test was performed to evaluate the difference of tumor-infiltrating immune cells (TIICs) between normal and HB samples. Spearson correlation analysis was used to calculate the correlation between ARHGEF2 and TIICs. ARHGEF2, TCF3, TMED3, STMN1 and RAVER2 were screened by the new model. The GSEA of ARHGEF2 included cell cycle pathway and antigen processing presenting pathway. There were significant differences in the composition of partial TIICs between HB and normal samples (p < 0.05). ARHGEF2 was significantly correlated with memory B cells (Cor = 0.509, p < 0.05). These 5 candidate genes contribute to the molecular diagnosis and targeted therapy of HB. And we found "ARHGEF2-RhoA-Cyclin D1/CDK4/CDK6-EF2" is a key mechanism regulating cell cycle pathway in HB. This will be helpful in the treatment of HB. The occurrence of HB is related to abnormal TIICs. We speculated that memory B cells play an important role in HB.

Oncogenic Role of ADAM32 in Hepatoblastoma: A Potential Molecular Target for Therapy.

Simple SummaryHepatoblastoma (HBL) is a rare hepatic malignancy occurring mainly in early childhood. Although recently developed treatment regimens have improved prognosis, many refractory cases still exist, and the anticancer drug cis-diamminedichloroplatinum—cisplatin—primarily used in HBL treatment often induces severe side effects. Therefore, more effective and safer therapies are needed. In this study, we demonstrate that the expression level of ADAM32 is particularly high in HBL tissue samples and is associated with poor prognosis in various cancer types through the regulation of cancer cell proliferation, stemness, migration, invasion, and acquired resistance to chemotherapy. Our results thus indicate that ADAM32 could be a promising candidate therapeutic target molecule, and provide new insights into the molecular mechanisms of HBL carcinogenesis.Outcomes of pediatric hepatoblastoma (HBL) have improved, but refractory cases still occur. More effective and safer drugs are needed that are based on molecular mechanisms. A disintegrin and metalloproteases (ADAMs) are expressed with high frequency in various human carcinomas and play an important role in cancer progression. In this study, we analyzed expression of ADAMs in HBL with a cDNA microarray dataset and found that the expression level of ADAM32 is particularly high. To investigate the role of ADAM32 in cancer, forced expression or knockdown experiments were conducted with HepG2 and HBL primary cells. Colony formation, cell migration and invasion, and cell viability were increased in HepG2 expressing ADAM32, whereas knockdown of ADAM32 induced a decrease in these cellular functions. Quantitative RT-PCR demonstrated an association between ADAM32 expression and the expression of genes related to cancer stem cells and epithelial–mesenchymal transition (EMT), suggesting a role of ADAM32 in cancer stemness and EMT. Furthermore, knockdown of ADAM32 increased cisplatin-induced apoptosis, and this effect was attenuated by a caspase-8 inhibitor, suggesting that ADAM32 plays a role in extrinsic apoptosis signaling. We conclude that ADAM32 plays a crucial role in progression of HBL, so it might be a promising molecular target in anticancer therapy.

Abstract PO012: In silico drug repurposing identifies mebendazole as a treatment option for chemoresistant hepatoblastoma

Abstract Resistance to conventional chemotherapy remains a huge challenge in the clinical management and treatment of hepatoblastoma, the most common liver tumor of childhood. The in silico repurposing of drugs with known pharmacokinetics and safety profiles, which have been approved for other indications, represents a promising strategy to identify new drugs effective in chemoresistant hepatoblastoma. In this study, we integrated RNA sequencing-derived gene expression data into the pharmacologic perturbation prediction tool Connectivity Map (CMap) and identified the clinical widely used anthelmintic drug mebendazole as a putative drug to circumvent chemoresistance in hepatoblastoma. Consequently, we experimentally validated the efficacy of mebendazole in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. In contrast, similar mebendazole concentrations had little inhibitory effect on the growth of normal neonatal and adult skin fibroblasts. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin (cardiotoxic), the current standard treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony formation capability, induction of apoptosis, and cell cycle arrest of hepatoblastoma cells. Immunofluorescent staining of alpha-tubulin showed that mebendazole causes blockage of microtubule formation and subsequent RNA sequencing analyses confirmed the transcriptional downregulation of tubulins as the major mode of action of mebendazole treatment. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for doxorubicin in the treatment of chemoresistant hepatoblastoma. This could potentially not only improve outcome but also reduce severe long-term side effects. Citation Format: Qian Li, Salih Demir, Xuanwen Bao, Alexandra Wagner, Yanxin Fan, Stefano Cairo, Roland Kappler. In silico drug repurposing identifies mebendazole as a treatment option for chemoresistant hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO012.

Abstract PO014: Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model

Abstract Lack of relevant animal models and cell lines of hepatoblastoma hampers our understanding pathogenesis of and identifying therapeutic targets for this neoplasm. We report a liver-specific MYC-driven hepatoblastoma murine model that faithfully recapitulates the pathological features of mixed fetal and embryonal hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of human disease. Single-cell RNA-sequencing (scRNA-seq) and spatiotranscriptomics identified distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we mapped the cancer dependency genes using CRISPR-Cas9 screening and identified druggable targets shared with human hepatoblastoma (i.e., CDK7, CDK9, PRMT1, PRMT5). Our screen also revealed oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is the mainstay for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identified modifiers whose loss-of-function synergizes and antagonizes with the effect of chemotherapy. The combination of PRKDC inhibition and chemotherapy greatly enhances therapeutic efficacy. Our studies have provided and characterized useful resources including disease models and identified potential therapeutic targets of high-risk hepatoblastoma. Citation Format: Jun Yang. Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO014.

Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma.

Simple SummaryHepatoblastoma patients with tumors that do not respond to preoperative chemotherapy often experience incomplete surgical resection and thus poor outcomes. By analyzing the gene expression data of chemoresistant and responsive tumors using sophisticated drug prediction software we identified mebendazole, a medication usually used to treat parasitic worm infestations, as a putative drug to circumvent chemoresistance. We evaluated the efficacy of this drug in cell culture models of hepatoblastoma and found that both short- and long-term tumor cell growth were significantly inhibited upon treatment. Moreover, we identified the cellular and molecular consequences of mebendazole treatment to be the arrest of cell division and the induction of programmed cell death by the deregulation of genes involved in the unwindosome. Most importantly, mebendazole also proved effective when tested in a mouse model carrying a patient-derived tumor. Our results demonstrate the successful repurposing of mebendazole as a new treatment option for chemoresistant hepatoblastoma.Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes.

Invited Commentary on Vasudevan, et al: Outcomes of children with well differentiated fetal hepatoblastoma treated with surgery only: Report from Children's Oncology Group Trial, AHEP0731

Advances in hepatoblastoma treatment have improved survival but have been accompanied by the chronic toxicities of pediatric cancer therapy. Cisplatin is the cornerstone of chemotherapy treatment for hepatoblastoma. The most frequent long-term complication of hepatoblastoma treatment is cisplatin-related ototoxicity. Among children who receive cisplatin, 25-90% will exhibit measurable hearing loss, impacting language and social development [1]. Therefore, efforts to identify children eligible for reduction or elimination of cisplatin-based chemotherapy while maintaining excellent oncologic outcomes are paramount in reducing the long-term toxicities of hepatoblastoma cancer treatment.

Salvage Liver Transplant in the Treatment of a Child With Local Recurrence of Hepatoblastoma

Hepatoblastoma is the most common primary liver cancer of childhood, accounting for two-thirds of primary malignant hepatic neoplasms. Radical surgical removal combined with efficient chemotherapy is essential for cure. Despite a complete tumor resection, hepatoblastoma may recur as isolated local disease. Intrahepatic recurrence of hepatoblastoma after liver resection is among the indications for liver transplant. Here, we present a patient who underwent salvage liver transplant for the treatment of local recurrence of hepatoblastoma. A 13-year-old boy who was diagnosed with hepatocellular carcinoma arising from the left liver lobe and who had been treated with surgical resection was admitted to our outpatient oncology clinic for further evaluation because alpha-fetoprotein levels had started to increase after surgery. Histopathological reexamination of hemihepatectomy material showed a histological aspect of an epithelial hepatoblastoma. Magnetic resonance imaging revealed multifocal lesions in the right liver lobe compatible with local recurrence. Despite a favorable initial response to chemotherapy, the tumor showed progression with increased alpha-fetoprotein levels. The patient was deemed a viable candidate for an urgent liver transplant and underwent right lobe living donor liver transplant. He had excellent graft function without any complications or signs of malignancy in the last follow-up visit at 7 months posttransplant. Salvage liver transplant is a lifesaving and sometimes the only treatment option for patients with local recurrence of hepatoblastoma. Although transplant in the salvage setting has been associated with worse outcomes than primary transplant, recent data have indicated more favorable and acceptable outcomes. Further studies are warranted to better understand the role of salvage liver transplant in the treatment of hepatoblastoma. Early consultation with the liver transplant team is critical in children who are most likely to need extreme resection or liver transplant.

Hepatoblastoma: Derived Exosomal LncRNA NEAT1 Induces BMSCs Differentiation into Tumor-Supporting Myofibroblasts via Modulating the miR-132/MMP9 Axis.

Background Hepatoblastoma (HB) is the most common malignant tumor of the liver. MMP9 plays an essential role in HB. The purpose of our study was to screen for differentially expressed lncRNAs and miRNAs that targeted MMP9. Based on this, the role of lncRNA NEAT1/miR-132/MMP9 in HB and the mechanisms involved were discussed. Methods Bioinformatics analysis was used to screen the differentially expressed lncRNAs and miRNAs targeting MMP9. Exosomes were extracted from HB cells and normal liver cells for characterization and identification. Exosome uptake assay was conducted to determine whether exosomes were absorbed by bone marrow stromal cells (BMSCs). α-SMA, fibronectin, and s-100 expressions in tissues and cells were detected by IHC and ICC. lncRNA XIST, lncRNA NEAT1, miR-132, and MMP9 expressions were characterized by qRT-PCR. Western blot was performed to measure MMP9, α-SMA, and s-100 expressions. Flow cytometry was used to stain α-SMA, s-100. Bioinformatics and dual-luciferase reporter assay were applied to verify the interaction between lncRNA NEAT1 and miR-132, and miR-132 and MMP9. The effect of lncRNA NEAT1 on the development of HB in nude mice was studied. Results Differentially expressed lncRNA NEAT1/miR-132/MMP9 was obtained through bioinformatics analysis and cell verification. HB-derived exosomal lncRNA NEAT1 regulated miR-132 and MMP9 expression in BMSCs. In addition, HB-derived exosomal lncRNA NEAT1 promoted BMSCs differentiation toward invasive myofibroblast via miR-132/MMP9 axis. LncRNA NEAT1 regulated MMP9 through miR-132. Tumor formation experiments in nude mice showed that HB-derived exosomal lncRNA NEAT1 could affect the development of HB. Conclusion HB-derived exosomal lncRNA NEAT1 induced BMSCs differentiation into tumor-supporting myofibroblasts via modulating miR-132/MMP9 axis, which provided a new target for HB treatment.

54P Targeted treatment options for childhood hepatoblastoma using high-throughput drug screening

Hepatoblastoma (HB) is a pediatric malignancy with prevalence of 1:1 000 000 in Europe. Median age at diagnosis is one year. Current treatment entails chemotherapy (platinum-based alone or combined with doxorubicin) followed by surgery (tumor resection or liver transplantation). Survival rate of HB patients has improved; however, high-risk HB tumors are still difficult to treat with 20-30% of HB patients responding poorly to current treatment modalities. Furthermore, while current treatment modalities improve the prognosis, side effects of the chemotherapeutics have a significant effect on the life quality of HB survivors. Therefore, safer, more effective, and targeted treatment options are needed for improved patient care. Drug sensitivity and resistance testing (DSRT) was completed using 3D spheroids of five histologically different high-risk hepatoblastoma PDX-derived models. Cells were cultured with 527 approved or emerging oncological compounds and 1 drug combination for 72 h in five concentrations. Viability was assessed with Cell-Titer Glo. Pediatric primary hepatocytes were used to evaluate the general toxicity of the compounds. Selective drug sensitivity score (sDSS, calculated DSS(PDX) - DSS(control)) was calculated for each drug. sDSS score was used to evaluate the efficacy and tumor-sensitivity of each compound. Between 14 and 71 compounds with sDSS > 10 were identified for each HB model. These compounds represent a wide range of mechanisms of action and include kinase inhibitors, HSP inhibitors, apoptotic modulators, as well as conventional chemotherapeutics. Of these, 8 compounds were found to be effective in all five HB models. These were onalespib (a heat shock protein inhibitor (HSPI)), fimepinostat (PI3K/HDAC inhibitor), idasanutlin (MDM2-antagonist), cabazitaxel (microtubule inhibitor), filanesib (kinesin inhibitor), BIIB021 (HSPI), eribulin (microtubule inhibitor), and luminespib (HSPI). Interestingly, standard treatments in HB (carboplatin and doxorubicin) only demonstrated a minor effect. The screen revealed many new promising compounds for HB treatment. The efficacy of these agents should be confirmed in in vivo models in the future.

Withdrawal.

Background Hepatoblastoma (HB) is the most common malignant embryonic liver tumor in children. In this study, we used the NGS method to detect the genotype characteristics of HB, summarized the correlation between common mutation genotypes of HB and clinical treatment and prognosis. Methods Firstly, DNA was extracted from tumor tissue specimens and peripheral blood of 19 children patients with HB. Then, DNA panel and NGS methods were used to detect tumor diagnosis and treatment-related genes, followed by summary of genotype characteristics. Thirdly, In order to further study the application of immunotherapy in HB, we performed programmed cell PDL1 immunohistochemical detection. Finally, the clinical treatment effect and prognosis of the children patients were statistically analyzed according to the characteristics of the genotype. Results In this study, some mutated genes including NFE2L2, CTNNB1, MYCN, TP53, AXIN1 and APC were related to the pathogenesis of HB. The immunohistochemical results showed lower expression of PDL1. The complete remission (CR) rate of children patients in the gene abnormality group was lower than that of the non-reported disease-related gene abnormality group. Conclusion The CR rate of the children patients with altered genotype was lower than those children patients without altered genotype. In addition, low expression of PDL1 limited the immunotherapy of children patients with HB.

Long non-coding RNA Linc00205 promotes hepatoblastoma progression through regulating microRNA-154-3p/Rho-associated coiled-coil Kinase 1 axis via mitogen-activated protein kinase signaling

Hepatoblastoma (HB) is the most common pediatric liver tumor. The significant tumor heterogeneity of HB leads to varied prognoses among children with the disease. Recent studies have suggested that long non-coding RNAs (lncRNAs) can serve as novel therapies for HB treatment. Thus, in this study, we aimed to reveal the function and mechanism of the lncRNA Linc00205 in HB. Our results exhibited that, in both HB tissues and cell lines, levels of Linc00205 were significantly increased. In addition, knockdown of Linc00205 led to suppression of HB development. Moreover, we identified that Linc00205 was able to directly bind to miR-154-3p, thus isolating miR-154-3p from its target Rho-associated coiled-coil Kinase 1 (ROCK1). Further cellular behavioral experiments elucidated that the miR-154-3p inhibitor and ROCK1 overexpression were able to reverse the effect of downregulated Linc00205 on proliferation, migration, invasion, and apoptosis of HB cells by rescue assays via mitogen-activated protein kinase (MAPK) signaling. Our results demonstrated that Linc00205 enhanced HB progression by regulating ROCK1 expression via sponging miR-154-3p through MAPK signaling, which suggests a novel potential therapeutic target for HB.

Successful Surgical Resection and Chemotherapy for Unresectable Hepatoblastoma With Pulmonary Metastases and for Lung Recurrence After Liver Transplantation: A Case Report

Liver transplantation (LTx) is indicated for unresectable hepatoblastoma (HB) without distal metastasis. However, to our knowledge, there is no consensus on the management of unresectable HB with pulmonary metastases, or on the treatment of recurrent HB. We report a successful case of metastatic HB treated with repeated lung resection, chemotherapy, and LTx. This study strictly complied with the Helsinki Congress and the Istanbul Declaration regarding donor source. Our case was a 1-year-old boy who developed pre-treatment extent of disease (PRETEXT) Ⅲ HB with multiple pulmonary metastases. The liver tumor was unresectable because it involved all hepatic veins. After 3 cycles of chemotherapy (cisplatin/carboplatin plus doxorubicin), the remaining 2 pulmonary metastases were resected and living donor liver transplantation (LDLT) was performed. Five months after LDLT, a tumor recurrence was detected in the right lung. Repeat lung resection was performed followed by 1 cycle of chemotherapy (carboplatin plus doxorubicin). There has been no recurrence for 18 months since the last lung resection. Previous reports revealed that 14 patients, including the present case, underwent LTx after resection of metastatic HB pulmonary lesions. Of these patients, the 2-year survival rate after LTx was 91%. Recurrence was reported in 5 patients, 2 of whom were successfully treated with repeated resection of the metastatic lesions. LTx after resection of lung recurrence may be a potential treatment for unresectable HB with pulmonary metastases.

Pediatric liver tumors: clinical manifestations of various liver tumors and the challenging treatment of hepatoblastoma

Pediatric liver tumors: clinical manifestations of various liver tumors and the challenging treatment of hepatoblastoma

Knockdown of long non-coding MIR210HG inhibits cell proliferation, migration, and invasion in hepatoblastoma via the microRNA-608-FOXO6 axis.

ObjectiveHepatoblastoma is the most common liver tumor. Recent research has found that long non-coding (lnc)RNAs are involved in multiple types of cancers, but the potential mechanism of lncRNA MIR210HG in hepatoblastoma remains unknown. The present study explored the molecular mechanism of MIR210HG in hepatoblastoma progression.MethodsThe cell counting kit-8 was used to detect cell viability, and Transwell assays assessed cell migration and invasion. Luciferase reporter assays showed the relationship between MIR210HG and microRNA (miR)-608 and between miR-608 and forkhead box O6 (FOXO6). Functional tests were verified in vivo by a tumor xenograft model. The expression of MIR210HG, miR-608, FOXO6, E-cadherin, N-cadherin, and vimentin was determined by quantitative reverse transcription polymerase chain reaction and western blotting.ResultsMIR210HG was shown to be highly expressed in hepatoblastoma tissues and cell lines. Knockdown of MIR210HG reduced proliferation, migration, and invasion in liver cancer cells, and suppressed tumor growth in vivo. MIR210HG competitively combined with miR-608, and miR-608 decreased FOXO6 expression.ConclusionOur study demonstrated that knockdown of MIR210HG inhibits hepatoblastoma development through binding to miR-608 and downregulating FOXO6. Our results provide novel insights for hepatoblastoma treatment involving the MIR210HG–miR608–FOXO6 axis.

Factors influencing recurrence after complete remission in children with hepatoblastoma: A 14-year retrospective study in China.

ObjectiveAfter a complete remission to treatment for hepatoblastoma, some children still have recurrence. We identified and explored the factors that influence recurrence after complete remission in a retrospective study.MethodsOf 197 children with hepatoblastoma, 140 (71.1%) achieved initial complete remission and were enrolled in factor analysis. Variables consisted of age, sex, PRE-Treatment EXTent of tumor (PRETEXT) stage, pathologic type, metastatic disease, serum alpha-fetoprotein level, vascular involvement, and surgical margin status. We employed univariate and multivariate analyses to assess the relationship between each factor and tumor recurrence.ResultsOf 140 children who achieved initial complete remission, 42 (30%) had recurrent hepatoblastoma. The 5-year overall survival rates for the non-recurrence and recurrence group were 99.0% and 78.6%, respectively. The overall 1-year, 3-year, and 5-year recurrence-free survival (RFS) rates were 77.8%, 69.8%, and 69.8%, respectively. All recurrences occurred within 2 years from complete remission. The RFS rate was significantly higher in children younger than 3 years and in those with mixed pathological type, PRETEXT II and III, without metastatic disease, without vascular involvement, and microscopic negative margin than in that of children older than 3 years, with epithelial pathological type, PRETEXT IV, metastatic disease, vascular involvement, and macroscopic positive margin (P < 0.001, = 0.020, < 0.001, = 0.004, = 0.002, and < 0.001, respectively). The independent risk factors for recurrence after complete remission were age ≥3 years, PRETEXT IV, and metastatic disease (P < 0.05).ConclusionAge, PRETEXT stage, metastatic disease, vascular involvement, pathologic type, and surgical margin status might be associated with recurrent hepatoblastoma after complete remission; meanwhile, age ≥3 years, PRETEXT IV, and metastatic disease are independent risk factors of recurrence. Further research is needed on the causes of tumor recurrence, which may improve the long-term outcomes of children with hepatoblastoma.

Liver Transplantation Is Highly Effective in Children with Irresectable Hepatoblastoma.

Background and Objectives: In children, hepatoblastoma preferentially is managed by liver resection (LR). However, in irresectable cases, liver transplantation (LT) is required. The aim of our study was to compare short- and long-term results after LR and LT for the curative treatment of hepatoblastoma. Materials and Methods: Retrospective analysis of all patients treated surgically for hepatoblastoma from January 2000 until December 2019 was performed. Demographic and clinical data were collected before and after surgery. The primary endpoints were disease free survival and patient survival. Results: In total, 38 patients were included into our analysis (n = 28 for LR, n = 10 for LT) with a median follow-up of 5 years. 36 patients received chemotherapy prior to surgery. Total hospital stay and intensive care unit (ICU) stay were significantly longer within the LT vs. the LR group (ICU 23 vs. 4 days, hospital stay 34 vs. 16 days, respectively; p < 0.001). Surgical complications (≤Clavien–Dindo 3a) were equally distributed in both groups (60% vs. 57%; p = 1.00). Severe complications (≥Clavien–Dindo 3a) were more frequent after LT (50% vs. 21.4%; p = 0.11). Recurrence rates were 10.7% for LR and 0% for LT at 5 years after resection or transplantation (p = 0.94). Overall, 5-year survival was 90% for LT and 96% for LR (p = 0.44). Conclusions: In irresectable cases, liver transplantation reveals excellent outcomes in children with hepatoblastoma with an acceptable number of perioperative complications.

Propofol Suppresses Cell Progression by Inhibiting CCL18 Expression in Hepatoblastoma

Background Propofol is an anesthetic commonly used clinically and has been found to have antitumor activity in various cancers. The purpose of this study was to investigate the role of propofol in hepatoblastoma (HB). Methods CCK-8 and transwell were used to measure cell proliferation, migration, and invasion in HB cells. Cell apoptosis rate was measured by FCM. The expression of CCL18 in HB tissues and cells was detected by RT-qPCR. Western blotting was used to explore the protein expression of CCK18- and PI3K/AKT-related proteins. Results The expression of CCL18 in HB tissues and cells was overexpressed compared with control groups. CCL18 knockdown was found to notably block cell proliferation and progression, while enhancing cell apoptosis in HuH-6 and HepT1 cells. Furthermore, propofol suppressed the proliferation of HB cells in a dose-dependent manner. According to the results, we chose 5 μg/mL of propofol-treated cells for 48 hours as the subsequent experimental conditions. We found that propofol (5 μg/mL, 48 h) significantly blocked cell migration and invasion, but induced cell apoptosis in HuH-6 and HepT1 cells. In addition, CCK18 overexpression facilitated cell progression in HB cells, while propofol dramatically suppressed the effect of CCK18. Besides that, propofol suppressed the PI3K/AKT pathway. Conclusion Propofol suppressed the development of HB cells by inhibiting CCK18 expression and the PI3K/AKT pathway. Therefore, we infer that propofol plays a role in the treatment of HB.