Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt/GSK-3β/β-catenin pathway / 中西医结合学报

OBJECTIVE@#Physical exercise, a common non-drug intervention, is an important strategy in cancer treatment, including hepatocellular carcinoma (HCC). However, the mechanism remains largely unknown. Due to the importance of hypoxia and cancer stemness in the development of HCC, the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer stemness.@*METHODS@#A physical exercise intervention of swimming (30 min/d, 5 d/week, for 4 weeks) was administered to BALB/c nude mice bearing subcutaneous human HCC tumor. The anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) detection of proliferating cell nuclear antigen (PCNA) and Ki67. The expression of stemness transcription factors, including Nanog homeobox (NANOG), octamer-binding transcription factor 4 (OCT-4), v-Myc avian myelocytomatosis viral oncogene homolog (C-MYC) and hypoxia-inducible factor-1α (HIF-1α), was detected using real-time reverse transcription polymerase chain reaction. A hypoxia probe was used to explore the intratumoral hypoxia status. Western blot was used to detect the expression of HIF-1α and proteins related to protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway. The IHC analysis of platelet endothelial cell adhesion molecule-1 (CD31), and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood perfusion. SMMC-7721 cells were treated with nude mice serum. The inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription factors. The hypoxia status was inferred by measuring the protein and mRNA levels of HIF-1α. Further, the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was detected.@*RESULTS@#Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC tumor. HE staining and IHC results showed a lower necrotic area ratio as well as fewer PCNA or Ki67 positive cells in mice receiving the swimming intervention. Swimming potently alleviated the intratumoral hypoxia, attenuated the cancer stemness, and inhibited the Akt/GSK-3β/β-catenin signaling pathway. Additionally, the desmin+/CD31+ ratio, rather than the number of CD31+ vessels, was significantly increased in swimming-treated mice. In vitro experiments showed that treating cells with the serum from the swimming intervention mice significantly reduced the formation of SMMC-7721 cell suspension sphere, as well as the mRNA expression level of stemness transcription factors. Consistent with the in vivo results, HIF-1α and Akt/GSK-3β/β-catenin signaling pathway were also inhibited in cells treated with serum from swimming group.@*CONCLUSION@#Swimming alleviated hypoxia and attenuated cancer stemness in HCC, through suppression of the Akt/GSK-3β/β-catenin signaling pathway. The alleviation of intratumoral hypoxia was related to the increase in blood perfusion in the tumor. Please cite this article as: Xiao CL, Zhong ZP, Lü C, Guo BJ, Chen JJ, Zhao T, Yin ZF, Li B. Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt/GSK-3β/β-catenin pathway. J Integr Med. 2023; 21(2): 184-193.

Aconite aqueous extract inhibits the growth of hepatocellular carcinoma through CCL2-dependent enhancement of natural killer cell infiltration / 中西医结合学报

OBJECTIVE@#Aconite is a traditional Chinese herbal medicine that has been found to inhibit the development of liver cancer; however, its exact molecular mechanisms in this process remain unclear. This study explores how aconite aqueous extract (AAE) inhibits hepatocellular carcinoma (HCC).@*METHODS@#An in vivo mouse model of subcutaneous liver cancer was established. After AAE treatment, immunohistochemistry (IHC) was used to determine the effect of AAE on natural killer (NK) cells. Subsequently, C57BL/6 mice were used to establish the subcutaneous tumor model, and a group of these mice were treated with anti-PK163 antibody to remove NK cells, which was verified by flow cytometry and IHC. The effect of AAE on the proliferation of HCC cells in vitro was determined using cell counting kit-8. The effect of AAE on chemokine production in HCC cells was measured using real-time quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay. The effect of AAE on the migration of NK cells was determined using a transwell assay. Finally, the molecular mechanism was investigated using the Western blotting method.@*RESULTS@#We demonstrated that the ability of AAE to induce overexpression of the cytokine C-C motif chemokine ligand 2 (CCL2) in HCC cells is fundamental to the infiltration of NK cells into the tumor bed. Mechanistically, we found that the upregulation of CCL2 was achieved by the activation of c-Jun N-terminal kinase but not extracellular regulated protein kinase or p38.@*CONCLUSION@#Our findings suggest that AAE can be used as an effective immune adjuvant to enhance antitumor immunity by increasing NK cell infiltration into tumors, which could help to improve the efficacy of HCC treatments. Please cite this article as: Yang KD, Zhang X, Shao MC, Wang LN. Aconite aqueous extract inhibits the growth of hepatocellular carcinoma through CCL2-dependent enhancement of natural killer cell infiltration. J Integr Med. 2023; 21(6): 575-583.

Cytotoxic effect of hydroalcoholic extract of Cota tinctoria (L) J. Gay on AGS and Hep-G2 cancer cell lines / Efecto citotóxico del extracto hidroalcohólico de Cota tinctoria (L) J. Gay sobre líneas celulares de cáncer AGS y Hep-G2

Cota tinctoria is a medicinal plant which has been used for management of cancer in folk medicine of various regions. The aim of present study is to investigate cytotoxic activity of different concentrations of hydroalcoholic extract of C. tinctoria flowers on gastric (AGS) and liver (Hep-G2) cancer cell lines as well as Human Natural GUM fibroblast (HUGU) cells. Cell mortality rates were examined after 24, 48 and 72 h incubations using the MTT assay. IC50of extract on AGS cells after 24, 48 and 72h was 1.46, 1.29 and 1.14 µg/mL respectively. The extract demonstrated IC50 of 5.15, 3.92 and 2.89 µg/mL on Hep-G2 cells after 24, 48 and 72 h respectively. No cytotoxic effect was detected on HUGU (Human Natural GUM fibroblast) cells. C. tinctoria seems to have a promising potential to be considered as a source for anticancer drug discovery. However, more experimental and clinical studies are required.

Cota tinctoria es una planta medicinal que se ha utilizado para el tratamiento del cáncer en la medicina popular de varias regiones. El objetivo del presente estudio es investigar la actividad citotóxica de diferentes concentraciones de extracto hidroalcohólico de flores de C. tinctoria en líneas celulares de cáncer gástrico (AGS) e hígado (Hep-G2), así como en células de fibroblasto GUM humano natural (HUGU). Se examinaron las tasas de mortalidad celular después de incubaciones de 24, 48 y 72 h utilizando el ensayo MTT. La CI50 del extracto en células AGS después de 24, 48 y 72 h fue de 1,46; 1,29 y 1,14 µg respectivamente. El extracto demostró una CI50 de 5,15, 3,92 y 2,89 µg/mL en células Hep-G2 después de 24, 48 y 72 h, respectivamente. No se detectó ningún efecto citotóxico en las células HUGU (fibroblasto GUM humano natural). C. tinctoria parece tener un potencial prometedor para ser considerada como una fuente de descubrimiento de fármacos contra el cáncer. Sin embargo, se requieren más estudios experimentales y clínicos.

Dahuang Zhechong pills inhibit liver cancer growth in a mouse model by reversing Treg/Th1 balance / 中国天然药物

The infiltration of immune cells into the hepatocellular carcinoma microenvironment is the main reason why hepatocellular carcinoma patients are prone to carcinoma recurrence and the disease are incurable. Notably, the infiltration of Treg cells is the main trigger. Dahuang Zhechong pill (DHZCP) is a traditional Chinese herbal compound successful in the treatment of hepatitis and hepatocellular carcinoma. DHZCP can heal and nourish while slowing the onset of the disease, thereby strengthening the body's immune function. It can localize tumors and ultimately achieve the goal of eliminating tumors. In this study, an orthotopic liver cancer model of mice was used to explore the mechanism of DHZCP enhancing anti-tumor immunity, which showed more Th1 cells in the peripheral blood and spleen after DHZCP treatment, while more IFN-γ was secreted to activate CD8+ T cells and Treg cell production was inhibited, thereby suppressing the growth of HCC. Finally, we also analyzed the potential components of DHZCP from the perspective of modern targets using network pharmacology methods and experimental results.

Prognostic factors affecting the success of conversion chemotherapy in patients with unresectable liver metastases from initially colorectal cancer / 中华胃肠外科杂志

Objective: To investigate the factors affecting the success of conversion therapy in patients with initially unresectable colorectal cancer liver metastases (CRLM) in order to provide evidence-based medical evidence for formulating individualized treatment strategies for patients. Methods: A retrospective case-control study was used in this study. Clinical data of 232 patients with initially unresectable CRLM receiving first-line systemic treatment in Sun Yat-sen University Cancer Center from January 2013 to January 2020 were collected, including 98 patients of successful conversion and 134 patients of failed conversion as control. Conversion therapy scheme: 38 patients received FOLFOXIRI regimen chemotherapy (irinotecan, oxaliplatin, calcium folinate and fluorouracil), 152 patients received FOLFOX regimen (oxaliplatin, calcium folinate and fluorouracil), 19 patients received FOLRIRI regimen (irinotecan, calcium folinate and fluorouracil), 23 patients received systemic chemotherapy combined with fluorouridine hepatic artery infusion chemotherapy; 168 patients received targeted therapy, including 68 of bevacizumab and 100 of cetuximab. Logistics analysis was used to compare the factors affecting the success of conversion therapy. The Kaplan-Meier method was used to calculate progression-free survival (PFS), and the Log-rank test was used for survival comparison. Results: Among 232 patients, 98 patients had successful conversions and 134 patients had failed conversions with a successful conversion rate of 42.2%, meanwhile 30 patients underwent simple hepatectomy and 68 underwent hepatectomy combined with intraoperative radiofrequency ablation. After first-line chemotherapy, 111 patients (47.8%) were partial remission, 57 patients (24.6%) were stable disease, and 64 patients (27.6%) were progression disease. During the median follow-up of 18.8 (1.0-87.9) months, 148 patients were dead or with tumor progression. The median PFS time of patients with successful conversion was longer than that of patients with failed conversion (31.0 months vs. 9.9 months, P<0.001). Univariate analysis found that the bilobar distribution of liver tumors (P=0.003), elevated baseline carcinoembryonic antigen (CEA) levels (P=0.024), tumor invasion of the portal vein (P=0.001), number of metastatic tumor>8 (P<0.001), non-FOLFOXIRI (P=0.005), and no targeted therapy (P=0.038) were high risk factors for the failed conversion therapy. The results of multivariate logistics analysis indicated that the number of metastatic tumor >8 (OR=2.422, 95%CI: 1.291-4.544, P=0.006), portal vein invasion (OR=2.727, 95%CI: 1.237-4.170, P=0.008) were the independent risk factors for failed conversion therapy, while FOLFOXIRI regimen (OR=0.300, 95%CI: 0.135-0.666, P=0.003) and targeted drugs (OR=0.411, 95%CI: 0.209-0.809, P=0.010) were independent protective factors for successful conversion therapy. Conclusions: The number of metastatic tumor and portal vein invasion are key factors that affect the outcomes of conversion therapy for initially unresectable CRLM. If a patient can tolerate chemotherapy, a combination program of three-drug and targeted therapy is preferred for the active conversion therapy.

Impact of nonsteroidal anti-inflammatory drugs on efficacy of anti-PD-1 therapy for primary liver cancer / 南方医科大学学报

OBJECTIVE@#To assess the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical outcomes of patients receiving anti-PD-1 immunotherapy for hepatocellular carcinoma.@*METHODS@#We conducted a retrospective study among 215 patients with primary liver cancer receiving immunotherapy between June, 2018 and October, 2020. The patients with balanced baseline characteristics were selected based on propensity matching scores, and among them 33 patients who used NSAIDs were matched at the ratio of 1∶3 with 78 patients who did not use NSAIDs. We compared the overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) between the two groups.@*RESULTS@#There was no significant difference in OS between the patients using NSAIDs (29.7%) and those who did not use NSAIDs (70.2%). Univariate and multivariate analyses did not show an a correlation of NSAIDs use with DCR (univariate analysis: OR=0.602, 95% CI: 0.299-1.213, P=0.156; multivariate analysis: OR=0.693, 95% CI: 0.330-1.458, P=0.334), PFS (univariate analysis: HR=1.230, 95% CI: 0.789-1.916, P=0.361; multivariate analysis: HR=1.151, 95% CI: 0.732-1.810, P=9.544), or OS (univariate analysis: HR=0.552, 95% CI: 0.208-1.463, P=0.232; multivariate analysis: HR=1.085, 95% CI: 0.685-1.717, P=0.729).@*CONCLUSION@#Our results show no favorable effect of NSAIDs on the efficacy of immunotherapy in patients with advanced primary liver cancer, but this finding still needs to be verified by future prospective studies of large cohorts.

Data Mining and Systems Pharmacology to Elucidate Effectiveness and Mechanisms of Chinese Medicine in Treating Primary Liver Cancer / 中国结合医学杂志

OBJECTIVE@#To identify specific Chinese medicines (CM) that may benefit patients with primary liver cancer (PLC), and to explore the mechanism of action of these medicines.@*METHODS@#In this retrospective, singlecenter study, prescription information from PLC patients was used in combination with Traditional Chinese Medicine Inheritance Supports System to identify the specific core drugs. A system pharmacology approach was employed to explore the mechanism of action of these medicines.@*RESULTS@#Taking CM more than 6 months was significantly associated with improved survival outcomes. In total, 77 putative targets and 116 bioactive ingredients of the core drugs were identified and included in the analysis (P<0.05). A total of 1,036 gene ontology terms were found to be enriched in PLC. A total of 75 pathways identified from Kyoto Encyclopedia of Genes and Genomes were also enriched in this disease, including fluid shear stress, interleukin-17 signaling, signaling between advanced glycan end products and their receptors, cellular senescence, tumor necrosis factor signaling, p53 signaling, cell cycle signaling, steroid hormone biosynthesis, T-helper 17 cell differentiation, and metabolism of xenobiotics by cytochrome. Docking studies suggested that the ingredients in the core drugs exert therapeutic effects in PLC by modulating c-Jun and interleukin-6.@*CONCLUSIONS@#Receiving CM for 6 months or more improves survival for the patients with PLC. The core drugs that really benefit for PLC patients likely regulates the tumor microenvironment and tumor itself.

Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma / 医学前沿

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

Exploration of the therapeutic mechanism of Yiqi Jiedu recipe for treatment of primary liver cancer based on network pharmacology and molecular docking / 南方医科大学学报

OBJECTIVE@#To explore the effective components of Yiqi Jiedu recipe and the main biological processes and signal pathways involved in the therapeutic mechanism of the recipe in treatment of primary liver cancer through network pharmacology and molecular docking approaches.@*METHODS@#TCMSP, Uniport, Genecards and String databases were searched to obtain the target genes of drugs and disease using Cytoscape 3.8.2 software. GO and KEGG enrichment analyses were performed to identify the common genes in the target genes of the drugs and disease. Using Pubcham, RCSB and Autoduck, the effective components of the drugs were connected with the final core genes. The effects of different concentrations of Yiqi Jiedu recipe on the expressions of the core genes DHX9, HNRNPK, NCL and PABPC1 in HepG2 cells were analyzed with Western blotting and real- time fluorescence quantitative PCR.@*RESULTS@#We finally identified 8 core genes from the drug and disease targets, including DDX5, HNRNPK, PABPC1, DHX9, RPS3A, RPS3, RPL13, and NCL. GO analysis showed that these core genes were involved mainly in the biological processes of adrenaline receptor signal communication, movement of cellular or subcellular components, blood particles, adhesion class and iron ion binding. KEGG analysis showed that the Ras signaling pathway had the greatest gene enrichment. The results of molecular docking suggested that the effective components of the recipe were capable of docking with the core genes under natural conditions, and PABPC1 and stigmasterol had the highest binding energy. In HepG2 cells, treatment with 10% medicated serum for 48 h had the strongest effect on the expression of DHX9, HNRNPK, NCL and PABPC1 (P < 0.05).@*CONCLUSION@#Yiqi Jiedu recipe is capable of regulating viral expression of primary liver cancer multiple effective components that bind to DHX9, HNRNPK, NCL and PABPC1.

Qualidade de vida de pacientes com metástase hepática em decorrência de câncer colorretal / Calidad de vida de los pacientes con metástasis hepática por cáncer colorrectal / Quality of life of patients with liver metastasis due to colorectal cancer

Objetivo: avaliar e correlacionar os domínios da qualidade de vida de pacientes com metástase hepática de câncer colorretal em tratamento quimioterápico. Método: estudo transversal, observacional, com 106 pacientes selecionados em três hospitais do Sul do Brasil. Os dados foram coletados com o Quality of Life Questionnaire Core 30 e Quality of Life Questionnaire Colorectal Liver Metastases, analisados descritivamente e pelo teste de correlação de Spearman. Resultados: a vida sexual (45,08%), função emocional (43,08%) e fadiga (40,15%) tiveram os piores escores com o Quality of Life Questionnaire Colorectal Liver Metastases. Todas as correlações entre os domínios são significativas, demonstrando que um domínio com escore baixo interfere em todos os demais. Conclusão: os pacientes com metástase hepática de câncer colorretal em tratamento quimioterápico apresentaram alteração nos domínios de qualidade de vida.

Objetivo: evaluar y correlacionar los dominios de calidad de vida de pacientes con metástasis hepática de cáncer colorrectal sometidos a quimioterapia. Método: estudio observacional transversal con 106 pacientes seleccionados en tres hospitales del sur de Brasil. Los datos fueron recolectados mediante el Quality of Life Questionnaire Core 30 y Quality of Life Questionnaire Colorectal Liver Metastases, analizados descriptivamente y mediante la prueba de correlación de Spearman. Resultados: la vida sexual (45,08%), la función emocional (43,08%) y la fatiga (40,15%) tuvieron las peores puntuaciones con el Quality of Life Questionnaire Colorectal Liver Metastases. Todas las correlaciones entre los dominios son significativas, demostrando que un dominio con una puntuación baja interfiere en todos los demás. Conclusión: los pacientes con metástasis hepática por cáncer colorrectal sometidos a quimioterapia mostraron cambios en los dominios de calidad de vida.

Objective: to evaluate and correlate the quality of life domains of patients with liver metastasis of colorectal cancer undergoing chemotherapy. Method: cross-sectional, observational study with 106 patients selected in three hospitals in southern Brazil. Data were collected using the Quality of Life Questionnaire Core 30 and Quality of Life Questionnaire Colorectal Liver Metastases, analyzed descriptively and by Spearman's correlation test. Results: sexual life (45.08%), emotional function (43.08%) and fatigue (40.15%) had the worst scores with the Quality of Life Questionnaire Colorectal Liver Metastases. All correlations between the domains are significant, demonstrating that a domain with a low score interferes in all others. Conclusion: patients with liver metastasis from colorectal cancer undergoing chemotherapy showed changes in quality of life domains.

Explore the antiproliferative phytocompounds from ethanolic extracts of Citrus paradisi against liver cancer cell line by chemical analysis using TLC and FT-IR spectroscopy / Explorar os fitocompostos antiproliferativos de extratos etanólicos de Citrus paradisi contra linhagem de células de câncer de fígado por análise química usando espectroscopia de TLC e FT-IR

The aim of the present study was to evaluate the in vitro antiproliferative activity of ethanolic extract of leaves and fruits Citrus paradisi plant on HepG-2 liver cell lines by MTT (3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2Hterazolium bromide) assay and to isolate and characterize the antiproliferative compounds by TLC (Thin layer chromatography) and FT-IR (Fourier transforms Infrared) spectroscopy. Qualitative phytochemical screening tests were performed to detect phytochemicals compounds from the crude extracts. Antioxidant activity of the plant extracts were characterized by using DPPH (2,2-Diphenyl-1-picrylhydrazyl) free radical scavenging method. The results showed that antioxidant activity using DPPH were found to be increased in a concentration dependent manner and decreased cell viability and cell growth inhibition in a dose dependent manner. The findings from this study indicated that fruit extract exhibited good antiproliferation and antioxidant potential. The seven functional groups of phytocompounds such as carboxylic acid, amine salt, aromatic compounds, cyclic alkene, aldehyde, fluoro compounds and alkene were detected by FT-IR which indicated that fruit extracts of Citrus paradisi possessed vast potential as a medicinal drug especially in liver cancer treatment.

O objetivo do presente estudo foi avaliar a atividade antiproliferativa in vitro do extrato etanólico de folhas e frutos da planta Citrus paradisi em linhagens de células hepáticas HepG-2 por MTT (3- (4, 5-dimetil-2-tiazolil) -2, Ensaio de brometo de 5-difenil-2H-terazólio) e isolar e caracterizar os compostos antiproliferativos por espectroscopia de TLC (cromatografia de camada fina) e FT-IR (infravermelho com transformadas de Fourier). Testes qualitativos de triagem fitoquímica foram realizados para detectar compostos fitoquímicos nos extratos brutos. A atividade antioxidante dos extratos vegetais foi caracterizada pelo método de eliminação de radicais livres DPPH (2,2-difenil-1-picrilhidrazil). Os resultados mostraram que a atividade antioxidante usando DPPH aumentou de uma maneira dependente da concentração e diminuiu a viabilidade celular e a inibição do crescimento celular de uma maneira dependente da dose. Os resultados deste estudo indicaram que o extrato de fruta exibiu bom potencial antiproliferação e antioxidante. Os sete grupos funcionais de fitocompostos, como ácido carboxílico, sal de amina, compostos aromáticos, alceno cíclico, aldeído, compostos de flúor e alceno, foram detectados por FT-IR, o que indicou que extratos de frutas de Citrus paradisi possuíam vasto potencial como medicamento, especialmente no tratamento de câncer do fígado.

Resultados del tratamiento del hepatoblastoma en los Andes Ecuatorianos / Results of the treatment of hepatoblastoma in the Ecuadorian Andes

RESUMEN: El hepatoblastoma (HB), es una neoplasia maligna, que se origina en el hígado. La supervivencia (SV) depende de la extensión de avance de la enfermedad. El objetivo de este estudio fue determinar diferencias en la SV actuarial global (SVAG) y libre de enfermedad (SVLE) en pacientes con HB, según la extensión de su enfermedad. Serie de casos con seguimiento. Se incluyeron pacientes de entre 4 y 160 meses de edad tratados en un centro oncológico de Los Andes ecuatorianos (2000-2019). Las variables resultado fueron: lóbulo afectado, metástasis pulmonar, infiltración vascular, estadio PRETEXT, riesgo, histología, niveles de alfafetoproteína (AFP), remisión completa (RC), SVAG y SVLE. Se utilizó estadística descriptiva y analítica (Chi2, exacto de Fisher y corrección por continuidad). Se realizaron análisis de SV con curvas de Kaplan Meier y log-rank. Fueron estudiados 28 pacientes (53,6 % hombres), con una mediana de edad de 40 meses. Se verificaron metástasis pulmonares e infiltración vascular en el 25,0 % y 35,7 % de los casos respectivamente. La histología, estadio clínico y riesgo alto fueron mayoritariamente tipo epitelial (42,8 %), PRETEXT II (50,0 %) y riesgo alto (67,8 %) respectivamente. La media de AFP al diagnóstico fue 1055712ng/ml y 9 pacientes alcanzaron RC. La SVAG y SVLE general a 19 años fue 33,1 % y 26,0 % respectivamente. Según su extensión, la SVAG y la SVLE para los pacientes de riesgo estándar y alto fueron 50,0 % y 25,4 % (p=0,148); y 50,0 % y 14,7 % (p=0,037) respectivamente. La SVAG y SVLE verificadas son menores a las reportadas en otros estudios. La SVLE según su extensión, presentó diferencia significativa, sin embargo, este resultado debe ser tomado con cautela debido al número pequeño de pacientes.

SUMMARY: Hepatoblastoma (HB), is a malignant neoplasm, which originates in the liver. Survival (SV) depends on the extent of disease progression. The objective of this study was to determine differences in overall SV (OS) and disease-free (DFS) in patients with HB, according to the extent of their disease. Case series with follow-up. Patients between 4 and 160 months of age treated at an oncology center in the Ecuadorian Andes (2000-2019) were included. The result variables were affected lobe, lung metastasis, vascular infiltration, PRETEXT stage, risk, histology, alpha-fetoprotein levels (AFP), complete remission (RC), OS and DFS. Descriptive and analytical statistics (Chi2, Fisher's exact and continuity correction) were used. SV analyzes were performed with Kaplan Meier and log-rank curves. In this analysis 28 patients (53.6 % men), with a median age of 40 months, were studied. Lung metastases and vascular infiltration were verified in 25.0 % and 35.7 % of the cases, respectively. Histology, clinical stage, and high risk were mainly epithelial type (42.8 %), PRETEXT II (50.0 %), and high risk (67.8 %), respectively. The mean AFP at diagnosis was 1055712 ng / ml and 9 patients achieved CR. OS and DFS at 19 years were 33.1 % and 26.0 % respectively. According to their extension, the OS and DFS for standard and high risk patients were 50.0 % and 25.4 % (p = 0.148); and 50.0 % and 14.7 % (p = 0.037) respectively. The verified OS and DFS are lower than those reported in other studies. DFS according to its extension, presented a significant difference, however, this result should be considered with caution due to the small number of patients.

Gene expression and apoptosis response in hepatocellular carcinoma cells induced by biocompatible polymer/magnetic nanoparticles containing 5-fluorouracil

BACKGROUND: Super-paramagnetic iron oxide nanoparticles (SPION) contain a chemotherapeutic drug and are regarded as a promising technique for improving targeted delivery into cancer cells. RESULTS: In this study, the fabrication of 5-fluorouracil (5-FU) was investigated with loaded Dextran (DEXSPION) using the co-precipitation technique and conjugated by folate (FA). These nanoparticles (NPs) were employed as carriers and anticancer compounds against liver cancer cells in vitro. Structural, magnetic, morphological characterization, size, and drug loading activities of the obtained FA-DEX-5-FUSPION NPs were checked using FTIR, VSM, FESEM, TEM, DLS, and zeta potential techniques. The cellular toxicity effect of FA-DEX-5-FU-SPION NPs was evaluated using the MTT test on liver cancer (SNU-423) and healthy cells (LO2). Furthermore, the apoptosis measurement and the expression levels of NF-1, Her-2/neu, c-Raf-1, and Wnt-1 genes were evaluated post-treatment using flow cytometry and RT-PCR, respectively. The obtained NPs were spherical with a suitable dispersity without noticeable aggregation. The size of the NPs, polydispersity, and zeta were 74 ± 13 nm, 0.080 and 45 mV, respectively. The results of the encapsulation efficiency of the nano-compound showed highly colloidal stability and proper drug maintenance. The results indicated that FA-DEX-5-FU-SPION demonstrated a sustained release profile of 5-FU in both phosphate and citrate buffer solutions separately, with higher cytotoxicity against SNU-423 cells than against other cells types. These findings suggest that FA-DEX-SPION NPs exert synergistic effects for targeting intracellular delivery of 5-FU, apoptosis induction, and gene expression stimulation. CONCLUSIONS: The findings proved that FA-DEX-5-FU-SPION presented remarkable antitumor properties; no adverse subsequences were revealed against normal cells.

Hepatectomía en dos tiempos por metástasis hepáticas bilobares de origen colorrectal: reporte de un caso / Two-stage hepatectomy for bilobar colorectal liver metastases: case report / Hepatectomia em dois estágios para metástases hepáticas bilobares de origem colorretal: relato de um caso

La mitad de los pacientes con cáncer de origen colorrectal desarrollan metástasis hepáticas durante el curso de su enfermedad y de esas el 80% son irresecables. La resecabilidad se define no por la extensión de la hepatectomía, sino por la función del hígado remanente, por lo que para pacientes con ciertos factores favorables se pueden realizar técnicas de remodelación hepática para aumentar el volumen del hígado remanente para que este sea suficiente. La hepatectomía en dos tiempos se basa en procedimientos secuenciales que buscan tratar metástasis hepáticas colorrectales consideradas inicialmente irresecables, logrando la resección completa de las mismas dejando un remanente hepático funcionante suficiente, lo cual no sería posible en un solo acto quirúrgico. El objetivo de este trabajo es presentar el caso clínico de un paciente portador de metástasis hepáticas sincrónicas de origen colorrectal irresecables, que luego de una quimioterapia de conversión, con el fin de aumentar el futuro remanente hepático y evitar falla hepática postoperatoria y realizar una resección oncológica, fue sometido a una hepatectomía en dos tiempos, técnica utilizada con baja frecuencia en nuestro medio, destacando una evolución favorable, con marcadores tumorales en valores normales y sin evidencia imagenológica de recaída local ni sistémica.

Half of colorectal cancer patients develop liver metastases during the course of their disease, 80% of which are unresectable. Resectability is defined not by the extent of the hepatectomy, but by the function of the liver remnant. Therefore, for patients with certain factors, liver remodeling techniques can be performed to increase volume of the remaining liver so that it is sufficient. Two-stage hepatectomy is performed on colorectal liver metastases which are initially considered unresectable in one stage resection procedures, in which sequential procedures are performed in order to achieve complete resection and preserve a sufficient functioning liver remnant. The objective of this paper is to present the case of a patient with unresectable synchronous colorectal liver metastases, in which after conversion chemotherapy, in order to increase the future liver remnant, avoid postoperative liver failure and perform an oncological resection underwent a two-stage hepatectomy, a technique used with low frequency in our setting, highlighting a favorable evolution, with tumor markers in normal values and without imaging evidence of local or systemic relapse.

Metade dos pacientes com câncer colorretal desenvolve metástases hepáticas durante o curso da doença e, desses, 80% são irressecáveis. A ressecabilidade é definida não pela extensão da hepatectomia, mas pela função do fígado remanescente; portanto, para pacientes com certos fatores favoráveis, técnicas de remodelação hepática podem ser realizadas para aumentar o volume do fígado remanescente de forma que seja suficiente. A hepatectomia em dois estágios é baseada em procedimentos sequenciais que buscam tratar metástases hepáticas colorretais inicialmente consideradas irressecáveis, obtendo ressecção completa, deixando um remanescente hepático funcional suficiente, o que não seria possível em um único ato cirúrgico. O objetivo deste trabalho é apresentar o caso clínico de um paciente com metástases hepáticas sincrônicas irressecáveis ​​de origem colorretal, que após quimioterapia de conversão, com o objetivo de aumentar o futuro remanescente hepático e evitar insuficiência hepática pós-operatória e realizar uma ressecção oncológica, foi submetido a dois Hepatectomia em estágio, técnica utilizada com baixa frequência em nosso meio, evidenciando evolução favorável, com marcadores tumorais em valores normais e sem evidências de imagem de recidiva local ou sistêmica.

Morphological and biochemical effects of carnosic acid on human hepatocellular carcinoma HepG2 cells / Efectos Morfológicos y Bioquímicos del ácido Carnósico en Células de Carcinoma Hepatocelular Humano HepG2

Background/aim: Autophagic cell death and apoptosis of tumor cells has become one of the main objectives in cancer treatment, whereas tumor cell lines are mainly used in studies for providing important data for the evaluation of potential anti cancer substances. In this study, our objective was to evaluate morphological and biochemical changes including rate of apoptosis and Alpha Fetoprotein (AFP) levels at different concentrations of Carnosic Acid (CA) on Human Hepatocellular Carcinoma HepG2 Cells.Materials and methods: Human Hepatocellular Carcinoma (7th passage HepG2 cells) Cell lines were cultured on 11 µM D263M schott glass coverslips placed in 12-well plates and were treated with DMSO, 1, 2.5, 5 and 10 µM concentrations of CA for 24, 48 and 72 hours. Morphological and biochemical data were recorded daily including apoptosis rates demonstrated by Caspase 3, Annexin V expressions under inverted light and Immunofluorescence microscopy, then data were analyzed for statistical significance. AFP, albumin and total protein levels were analyzed spectrophotometricaly for biochemical evaluation.Results: Our results showed that CA significantly inhibited HepG2 cell proliferation in a dose and time dependant manner and significantly caused the formation of autophagic vacuoles starting from 5µM and reaching significance at 10 µM concentrations. Significant decrease was observed in AFP when 48 and 72 hours expressions were examined, with the lowest level reached at 72 hours in the 10 µM CA group. Additionally, increase in albumin levels reached significance only in the 48 h group whereas non-significant increases were also observed in 24 h and 72 h groups.Conclusion: Our current study demonstrates significant increase in apoptosis rates by Carnosic Acid mainly at 10µM concentrations, supporting its anticancer effect on HepG2 cells. These findings are also supported by changes in biochemical analyses of Albumin and AFP levels at 10 µM concentrations.

Antecedentes / objetivos: La muerte celular autofágica y la apoptosis de células tumorales se ha convertido en uno de los principales objetivos en el tratamiento del cáncer, mientras que las líneas celulares tumorales se utilizan principalmente en estudios para proporcionar datos importantes para la evaluación de posibles sustancias anticancerígenas. En este estudio, nuestro objetivo fue evaluar los cambios morfológicos y bioquímicos, incluida la tasa de apoptosis y los niveles de alfa fetoproteína (AFP) a diferentes concentraciones de ácido carnósico (CA) en células de carcinoma hepatocelular humano HepG2.Materiales y métodos: Carcinoma hepatocelular humano (HepG2).Las líneas celulares se cultivaron en cubreobjetos de vidrio Schott D263M de 11 µM colocados en placas de 12 pocillos y se trataron con DMSO, concentraciones de CA 1, 2,5, 5 y 10 µM durante 24, 48 y 72 horas. Los datos morfológicos y bioquímicos se registraron diariamente, incluidas las tasas de apoptosis demostradas por Caspasa 3, las expresiones de Anexina V bajo luz invertida y microscopía de inmunofluorescencia, luego se analizaron los datos para determinar la significación estadística. Los niveles de AFP, albúmina y proteínas totales se analizaron espectrofotométricamente para evaluación bioquímica.Resultados: Nuestros resultados mostraron que CA inhibió significativamente la proliferación de células HepG2 de una manera dependiente de la dosis y el tiempo y causó significativamente la formación de vacuolas autofágicas comenzando desde 5 µM y alcanzando significancia a concentraciones de 10 µM. Se observó una disminución significativa en la AFP cuando se examinaron las expresiones de 48 y 72 horas, alcanzando el nivel más bajo a las 72 horas en el grupo de CA 10 µM. Además, el aumento en los niveles de albúmina alcanzó significación solo en el grupo de 48 h, mientras que también se observaron aumentos no significativos en los grupos de 24 hy 72 h.Conclusión: Nuestro estudio demuestra un aumento significativo en las tasas de apoptosis por el ácido carnósico principalmente a concentraciones de 10 µM, lo que respalda su efecto anticancerígeno en las células HepG2. Estos hallazgos también están respaldados por cambios en los análisis bioquímicos de los niveles de albúmina y AFP a concentraciones de 10 µM.

Chinese multidisciplinary expert consensus on combined immunotherapy based on immune checkpoint inhibitors for hepatocellular carcinoma(2021 version) / 中华肝脏病杂志

Combined immunotherapy based on immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma has achieved remarkable therapeutic effect in clinical research and practice. However, many problems that need to be resolved have also been recognized in the clinical promotion process. Therefore, the primary effort through the multidisciplinary experts' mutual discussion [Chinese multidisciplinary expert consensus on combined immunotherapy based on immune check point inhibitors for hepatocellular carcinoma (2021 version)] is to implement the principles and methods of clinical application of ICIs treatment, including the selection of indications, prescriptions, treatment methods, monitoring and management of treatment process and adverse reactions, and efficacy evaluation. In addition, the consensus aims to combine the latest research progress, summarize detailed clinical application rules and expert experience, so as to provide reference for health professionals.

Design of dual targeting immunomicelles loaded with bufalin and study of their anti-tumor effect on liver cancer / 中西医结合学报

OBJECTIVE@#Bufalin is an effective drug for the treatment of liver cancer. But its high toxicity, poor water-solubility, fast metabolism and short elimination half-life limit its use in tumor treatment. How to make the drug accumulate in the tumor and reduce side effects while maintaining its efficacy are urgent problems to be solved. The goal of this study is to solve these problems.@*METHODS@#A copolymer with tunable poly-N-isopropylacrylamide and polylactic acid was designed and synthesized. The corresponding dual targeting immunomicelles (DTIs) loaded with bufalin (DTIs-BF) were synthesized by copolymer self-assembly in an aqueous solution. The size and structure of DTIs-BF were determined by ZetaSizer Nano-ZS and transmission electron microscopy. Then, its temperature sensitivity, serum stability, critical micelle concentration (CMC), entrapment efficiency (EE), drug release and non-cytotoxicity of blank block copolymer micelles (BCMs) were evaluated. Next, the effects of DTIs-BF on cellular uptake, cytotoxicity, and tumor cell inhibition were evaluated. Finally, the accumulation of DTIs-fluorescein isothiocyanate (FITC) and the in vivo anti-tumor effect were observed using an interactive video information system.@*RESULTS@#DTIs-BF had a small size, spherical shape, good temperature sensitivity, high serum stability, low CMC, high EE, and slow drug release. The blank BCMs had very low cytotoxicity. Compared with free bufalin, the in vitro cellular internalization and cytotoxicity of DTIs-BF against SMMC-7721 cells were significantly enhanced, and the effects were obviously better at 40 °C than 37 °C. In addition, the therapeutic effect on SMMC-7721 cells was further enhanced by the programmed cell death specifically caused by bufalin. When DTIs-FITC were injected intravenously in BALB/c nude mice bearing liver cancer, the accumulation of FITC was significantly increased in tumors.@*CONCLUSION@#DTIs-BF is a potentially effective nano-formulation and has broad prospects in the clinical treatment of liver cancer.

Effect of Dahuang Zhechong Pills combined with TACE on VEGF, MMP-2, TGF-β1 and immune function of patients with primary liver cancer (blood stasis and collaterals blocking type) / 中国中药杂志

To investigate the effects of Dahuang Zhechong Pills combined with hepatic arterial chemoembolization(TACE) on tumor index and immune function of patients with primary liver cancer(blood stasis and collaterals blocking type), observe its application values in treatment of such patients, and provide effective treatment means for this disease. From June 2019 to December 2019, 79 patients with confirmed primary liver cancer(blood stasis and collaterals blocking type) treated in Wenzhou Hospital of Traditional Chinese Medicine were included in this study, all of which were grouped with random number table method before inclusion in this study. 40 patients in the control group were treated with TACE, while 39 patients in the observation group were treated with Dahuang Zhechong Pills combined with TACE. The efficacy was compared between two groups after 4 weeks of treatment. The immune function indexes of serum CD4~+ cells, CD4~+/CD8~+, CD3~+ cells of the observation group were higher than those in control group after treatment(P<0.05), and tumor indexes such as serum alpha-fetoprotein(AFP), carbohydrate antigen 199(CA199) and glutamic-pyruvic transaminase(ALT), total bilirubin(TBiL) levels were lower than those in the control group, with statistically significant differences(P<0.05). Plasma vascular endothelial growth factor(VEGF), transforming growth factor-β1(TGF-β1), and matrix metalloprotei-nase-2(MMP-2) levels in the observation group were lower than those in the control group after treatment, with statistically significant differences(P<0.05). The total effective rate of the observation group was 87.18%, higher than 67.50% in the control group, and the benefit rate was 94.87% in the observation group, higher than 85.00% in the control group(P<0.05). The total incidence of adverse reactions such as bone marrow suppression, gastrointestinal reaction, fever, renal function injury and peripheral nerve injury in the observation group was 48.72%, lower than 82.50% in the control group, with statistically significant difference(P<0.05). In summary, the combination of Dahuang Zhechong Pills with TACE could improve immunity, protect liver function, and reduce the risk of metastasis and the incidence of adverse reactions from chemotherapy, so it is worth popularizing for patients with primary liver cancer(blood stasis and collaterals blocking type).

Systematic evaluation of Huaier Granules adjuvant treatment of primary liver cancer / 中国中药杂志

To systematically evaluate the efficacy and safety of Huaier Granules in the adjuvant treatment of primary liver cancer. The databases of CNKI, Wanfang, VIP, CBMdisc, PubMed, Cochrane Library and EMbase were searched by computer to screen out the randomized controlled trial on Huaier Granules combined with Western medicine in the treatment of primary liver cancer from the establishment of the databases to January 2020. Data extraction and quality evaluation were conducted for the included literature. Meta-analysis was conducted with RevMan 5.3 software, and evidence quality evaluation was conducted for the outcomes by GRADE profiler software. A total of 24 articles were included, with a total sample size of 2 664 cases. Meta-analysis showed that as compared with Western medicine alone, Huaier Granules combined with Western medicine could improve the objective remission rate(RR=1.38, 95%CI[1.26, 1.51], P<0.000 01), disease control rate(RR=1.29, 95%CI[1.10, 1.52], P=0.002) and 6-month survival rate(RR=1.20, 95%CI[1.10, 1.32], P<0.000 1), 1-year survival rate(RR=1.39, 95%CI[1.23, 1.58], P<0.000 01), 2-year survival rate(RR=1.95, 95%CI[1.28, 2.96], P=0.002), KPS score(MD=17.15, 95%CI[6.47, 27.83], P=0.002) and the improvement rate of KPS score(RR=2.02, 95%CI[1.47, 2.77], P<0.000 1), AFP decline rate(RR=1.40, 95%CI[1.20, 1.62], P<0.000 1), CD3~+(MD=17.34, 95%CI[9.28, 25.40], P<0.000 1), CD4~+(MD=8.62, 95%CI[1.59, 15.64], P=0.02), CD8~+(MD=1.95, 95%CI[-3.93, 7.82], P=0.52), CD4~+/CD8~+(MD=0.42, 95%CI[-0.33, 1.17], P=0.27); reduce the level of AFP(MD=-71.57, 95%CI[-80.42,-62.72], P<0.000 01), recurrence rate(RR=0.76, 95%CI[0.67, 0.85], P<0.000 01), and incidence of adverse reactions(RR=0.60, 95%CI[0.41, 0.89], P=0.01) in patients with primary liver cancer. According to the GRADE system, the evidence for outcome measures was low to very low. The results show that Huaier Granules have certain efficacy and high safety in adjuvant treatment of primary liver cancer, but its effect in reducing adverse reactions and improve immunity remains to be verified. Due to the poor quality of the included studies and evidences, the conclusions still need to be further verified by multi-center, large sample, and randomized double-blind controlled studies.

Network Meta-analysis of oral Chinese patent medicine for adjuvant treatment of primary liver cancer / 中国中药杂志

Network Meta-analysis was used to evaluate the efficacy and safety of different oral Chinese patent medicines combined with transcatheter arterial chemoembolization(TACE) in the treatment of primary liver cancer. Randomized controlled trials of oral Chinese patent medicines for primary liver cancer were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library and EMbase databases from inception to May 2020. According to the Cochrane recommendation standard, the quality of the included articles was evaluated, and the data were analyzed by RevMan, R software and GeMTC software. A total of 10 kinds of oral Chinese patent medicines and 68 RCTs were included. Network Meta-analysis results showed that: as compared with TACE alone, 10 kinds of oral Chinese patent medicines combined with TACE showed advantages in effective rate, 1-year survival rate, 2-year survival rate, KPS score improvement rate and reduced adverse reaction incidence. In the pairwise comparison of oral Chinese patent medicines, the results showed that Cidan Capsules were superior to Jinlong Capsules and Xihuang Pills in 1-year survival rate. According to the probabi-lity ranking results: Shenyi Capsules and Ganfule were more obvious in improving the effective rate; Cidan Capsules and Shenyi Capsules were more effective in improving the 1-year survival rate; Pingxiao Capsules and Shenyi Capsules had better efficacy in improving 2-year survival rate; Huaier Granules and Shenyi Capsules had better efficacy in improving the quality of life; Huisheng Oral Liquid and Ganfule were more effective in reducing the incidence of adverse reactions(such as nausea, vomiting and leukocytosis). The current evidence showed that oral Chinese patent medicine combined with TACE was superior to TACE alone in efficacy and safety. In terms of the effective rate, 1-year survival rate, 2-year survival rate, KPS score improvement rate and reduced adverse reaction incidence, the optimal treatment measures were Shenyi Capsules, Cidan Capsules, Pingxiao Capsules, Huaier Granules and Huisheng Oral Liquid in turn. However, due to the limitations of the research, the current level of evidence is not high, and clear conclusions and evi-dence strength still need to be further verified and improved by high-quality researches.