BACKGROUND Sorafenib has been the conventional treatment for advanced hepatocellular carcinoma(HCC)since 2008.While radiological complete responses are extremely rare,improved supportive care and multidisciplinary app...BACKGROUND Sorafenib has been the conventional treatment for advanced hepatocellular carcinoma(HCC)since 2008.While radiological complete responses are extremely rare,improved supportive care and multidisciplinary approaches in clinical practice may explain the recent increase in case reports and retrospective series documenting such responses.CASE SUMMARY This case series describes 3 patients with advanced HCC who achieved durable complete responses using first-line sorafenib therapy,even in the presence of portal vein thrombosis or extrahepatic spread,and highlights the potential for sustained remission in selected patients.Dermatologic toxicity and non-viral etiology may correlate with favorable outcomes;however,reliable predictive biomarkers for sorafenib response are lacking.CONCLUSION Future research into the etiology and molecular differences in HCC is necessary to develop more personalized therapy options.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients...BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients with advanced HCC.Different patterns of treatment responsiveness have been identified in differentiated hepatoblastoma HepG2 cells and metastatic HCC SNU449 cells.AIM To define the long non-codingRNA-microRNA-mRNA(lncRNA-miRNA-mRNA)predicted signatures related to selected hallmarks of cancer(apoptosis,autophagy,cell stress,cell dedifferentiation and invasiveness)in RNAseq studies using Sorafenib-treated HepG2 and SNU449 cells.Various available software analyses allowed us to establish the lncRNA-miRNA-mRNA regulatory axes following treatment in HepG2 and SNU449 cells.METHODS HepG2 and SNU449 cells were treated with Sorafenib(10μmol/L)for 24 hours.Total RNA,including small and long RNA,was extracted with a commercial miRNeasy kit.RNAseq was carried out for the identification of changes in lncRNA-miRNA-mRNA regulatory axes.RESULTS MALAT,THAP9-AS1 and SNGH17 appeared to coordinately regulate miR-374b-3p and miR-769-5p that led to upregulation of SMAD7,TIRARP,TFAP4 and FAXDC2 in HepG2 cells.SNHG12,EPB41 L4A-AS1,LINC01578,SNHG12 and GAS5 interacted with let-7b-3p,miR-195-5p and VEGFA in SNU449 cells.The axes MALAT1/hsamir-374b-3p/SMAD7 and MALAT1/hsa-mir-769-5p/TFAP4 were of high relevance for Sorafenib response in HepG2 cells,whereas PVT1/hsa-miR-195-5p/VEGFA was responsible for the differential response of SNU449 cells to Sorafenib treatment.CONCLUSION Critical lncRNAs acting as sponges of miRNA were identified that regulated mRNA expression,whose proteins mainly increased the antitumor effectiveness of the treatment(SMAD7,TIRARP,TFAP4,FAXDC2 and ADRB2).However,the broad regulatory axis leading to increased VEGFA expression may be related to the side effect of Sorafenib in SNU449 cells.展开更多
Sorafenib(Sora)not only has an inhibitory effect on angiogenesis via indirectly inhibiting tumor growth through antiangiogenesis,but also can inactivate the glutathione peroxidase 4(GPX4)to induce ferroptosis.Nonethel...Sorafenib(Sora)not only has an inhibitory effect on angiogenesis via indirectly inhibiting tumor growth through antiangiogenesis,but also can inactivate the glutathione peroxidase 4(GPX4)to induce ferroptosis.Nonetheless,the therapeutic efficacy is hampered by a plethora of factors,including low bioavailability and tumor microenvironment(TME).Of particular note is the hypoxic and reductive TME,which acts as a significant impediment and poses formidable challenges to attain the most optimal treatment outcomes.Herein,we developed a novel therapeutic platform based on Sora-loaded mesoporous ferromanganese nanoparticles(PMFNs@Sora).PMFNs mimics both catalase and GPX activities.The self-sustained catalase activity enables continuous decomposition of hydrogen peroxide to generate oxygen,which alleviates hypoxia microenvironment.The GPX activity simultaneously amplifies the therapeutic efficacy of Sora.The as-synthesized PMFNs@Sora demonstrates significantly enhanced antitumor effect in vitro through apoptosis-ferroptosis,revealed by Western blot.Furthermore,PMFNs@Sora also showed effective tumor growth inhibition in vivo.This multifunctional nanoplatform offers a promising strategy for modulating the TME and enhancing cancer treatment in clinical application.展开更多
BACKGROUND Lenvatinib and sorafenib are tyrosine kinase inhibitors that are effective in the treatment of unresectable hepatocellular carcinoma(uHCC).The efficacy of which of them is better suited to combine transarte...BACKGROUND Lenvatinib and sorafenib are tyrosine kinase inhibitors that are effective in the treatment of unresectable hepatocellular carcinoma(uHCC).The efficacy of which of them is better suited to combine transarterial chemoembolization(TACE)for the treatment of uHCC is ripe.RESULTS A total of six studies involving 547 patients were included,248 in the TACE-lenvatinib group and 299 in the TACE-sorafenib group.Meta-analysis results showed that TACE-lenvatinib was more effective than TACE-sorafenib in complete response[relative risk(RR)=1.81,95%confidence interval(CI):1.11-2.96,P=0.02],partial response(RR=1.38,95%CI:1.12-1.70,P=0.002),objective response rate(RR=1.47,95%CI:1.24-1.74,P<0.0001)and disease control rate(RR=1.22,95%CI:1.00-1.49,P=0.05).TACE-lenvatinib was significantly lower than TACE-sorafenib in progressive disease rate(RR=0.54,95%CI:0.39-0.74,P=0.002).No significant difference was found in stable disease rate(RR=0.89,95%CI:0.60-1.33,P=0.58)between the two groups.TACE-lenvatinib was significantly more effective than TACE-sorafenib in overall survival(hazard ratio=2.00,95%CI:1.59-2.50,P<0.05)and progression free survival(hazard ratio=2.04,95%CI:1.49-2.86,P<0.05).As regards adverse events,TACE-lenvatinib was better in reducing the incidence of hypertension than TACE-sorafenib,while no significant difference was found in overall adverse events,abdominal pain,fever,fatigue,nausea and vomiting,decreased appetite,liver dysfunction,hand-foot skin reaction,diarrhea,thrombocytopenia,and rash between the two groups.CONCLUSION In patients with uHCC,TACE-lenvatinib induced a better tumor response rate and survival outcome than TACE-sorafenib,while TACE-lenvatinib resulted in a higher incidence of hypertension than TACE-sorafenib.However,these conclusions are derived from currently available medical evidence,and further confirmation by more rigorously designed randomized controlled studies is still needed.展开更多
BACKGROUND The combination of sorafenib with transarterial chemoembolization(TACE)is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma(HCC).AIM To evaluate the efficacy of t...BACKGROUND The combination of sorafenib with transarterial chemoembolization(TACE)is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma(HCC).AIM To evaluate the efficacy of this combined treatment strategy in enhancing overall survival(OS)and progression-free survival(PFS)compared to monotherapies.METHODS A systematic review was conducted following the PRISMA guidelines.A comprehensive search was performed across PubMed,EMBASE,Web of Science,and the Cochrane Library up to May 8,2024.Studies were included if they compared sorafenib plus TACE to sorafenib alone or TACE alone in adults with advanced HCC.Primary outcomes were OS,PFS,response rates,and safety profiles.Data extraction and quality assessment were independently performed by two reviewers.Heterogeneity was assessed using the I^(2)statistic,and a random-effects model was applied for pooling data.Sensitivity analysis and publication bias assessment were also conducted.RESULTS A total of twelve studies involving 1174 patients met the inclusion criteria.Significant heterogeneity was observed for both OS(I^(2)=72.6%,P<0.001)and PFS(I^(2)=83.7%,P<0.001).The combined treatment of sorafenib with TACE significantly improved OS[hazard ratio(HR)=0.60,95%confidence interval(CI):0.44-0.76]and PFS(HR=0.54,95%CI:0.38-0.69).Sensitivity analysis confirmed the robustness of these findings.Funnel plots and Egger's test indicated no significant publication bias.CONCLUSION Sorafenib combined with TACE significantly enhances both OS and PFS in patients with advanced HCC compared to monotherapy.This combination therapy represents a promising approach to improving clinical outcomes in advanced liver cancer.展开更多
BACKGROUND Cirrhotic patients with super-giant hepatocellular carcinoma(HCC)and portal vein invasion generally have a poor prognosis.This paper presents a patient with super-giant HCC and portal vein invasion,who unde...BACKGROUND Cirrhotic patients with super-giant hepatocellular carcinoma(HCC)and portal vein invasion generally have a poor prognosis.This paper presents a patient with super-giant HCC and portal vein invasion,who underwent hepatectomy followed by a combination of sorafenib and camrelizumab,resulting in complete remission(CR)for 5 years.CASE SUMMARY A 40-year-old male with compensated hepatitis B-related cirrhosis was diagnosed with HCC,Barcelona Clinic Liver Cancer stage C.Enhanced computed tomography imaging revealed a 152 mm×171 mm tumor in the right liver,invading the portal vein and hepatic vein.Liver function was normal.The patient successfully underwent hepatectomy on July 18,2019.However,by December 2019,HCC recurrence with lung metastases and portal vein invasion were detected.He started treatment with sorafenib(200 mg twice daily)and camrelizumab(200 mg every 3 weeks).By May 12,2020,the patient was confirmed to have CR.Camrelizumab was adjusted to 200 mg every 12 weeks from June 16,2021,with the last infusion on March 29,2024.Although no further tumor recurrence was observed,he experienced two episodes of gastrointestinal bleeding due to esophagogastric varices,which were managed with endoscopic therapy.To date,the patient has remained in CR for 5 years.CONCLUSION The combination of hepatectomy with sorafenib and camrelizumab can achieve durable CR in patients with supergiant HCC and portal vein invasion.Further research is necessary to address these challenges and improve patient outcomes.展开更多
Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic ...Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic stem cell transplantation(allo-HSCT)demonstrated improved survival outcomes,however,some still experienced relapse during the maintenance.This study aimed to explore risk factors which might be indicators for poor survival after allo-HSCT in this population.Methods:We consecutively enrolled FLT3-ITD AML patients undergoing transplantation at three centers.By integrating genetic profiles with clinical information,we assessed their impact on transplant outcomes.Results:A total of 196 patient were eligible in the analysis,among whom 14%harbored myelodysplasia-related(MR)mutations,including ASXL1,BCOR,EZH2,RUNX1,SF3B1,SRSF2,STAG2,U2AF1,and ZRSR2.Co-mutant MR was independently associated with poorer overall survival(OS)[hazard ratio(HR):2.4,95%confidence interval(95%CI):1.1-5.3,P=0.030].DNMT3A co-mutations strongly predicted adverse survival and relapse[OS:HR:2.1,95%CI:1.0-4.3,P=0.045;relapse-free survival(RFS):HR:2.2,95%CI:1.1-4.1,P=0.017;cumulative incidence of relapse(CIR):HR:2.3,95%CI:1.1-4.8,P=0.030].Compared to patients with negative measurable residual disease(MRD)complete remission(CR),no significant differences were observed in CR patients with positive MRD,while those without CR exhibited significantly inferior outcomes(P=0.003).Conclusions:Patients with myelodysplasia-related gene mutations(MRmut)and/or DNMT3A mutations experienced inferior outcomes after transplantation,requiring further exploration.Furthermore,similar prognoses among CR patients highlighted the need for monitoring specific molecular residual lesions.展开更多
Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To ad...Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To address these challenges,IL-2-So-Lipo,a novel liposomal formulation combining IL-2 with sorafenib derivative,was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth.Sorafenib derivatives could target at melanoma-specific receptors,further enhancing liposomal specificity at the tumor site.Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies,as well as their combination.In a B16F10 melanoma model,IL-2-So-Lipo was found to significantly inhibit tumor progression(tumor volume of 108.01±62.99 mm^(3))compared to the control group(tumor volume of 1,397.13±75.55 mm^(3)),improving the therapeutic efficacy.This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes.Additionally,liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency,promoting tumor cell apoptosis and suppressing angiogenesis.Mechanistically,IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype.Furthermore,IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway,exerting a significant role in mediating tumor resistance to sorafenib.These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers.Moreover,the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy,offering a synergistic approach to improve therapeutic outcomes for solid tumors.展开更多
Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficac...Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo.Methods:After observing epithelial-mesenchymal transformation(EMT)changes in HepG2 and HepG2/Sorafenib cells,we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC.Subsequently,specific inhibitors of c-Jun N-terminal kinase(JNK,SP600125)and extracellular signal-regulated kinase(ERK,PD98059)were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor(EGFR)/JNK/ERK signaling pathway in vitro and in vivo.Biological behavior changes were assessed through cell counting kit-8(CCK-8),colony formation,transwell,and immunofluorescence tests.Simultaneously,Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway.Results:The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells,and sorafenib-resistant HCC was characterized by EMT changes.Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells,with minimal impact on HepG2 cells.Additionally,apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells.Furthermore,there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups.Notably,SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC.Conclusion:Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.展开更多
Sorafenib is a novel antitumor drug,which is poorly absorbed in the gastrointestinal tract due to its low solubility in water.To improve the bioavailability of sorafenib,a self-microemulsifying drug delivery system(SM...Sorafenib is a novel antitumor drug,which is poorly absorbed in the gastrointestinal tract due to its low solubility in water.To improve the bioavailability of sorafenib,a self-microemulsifying drug delivery system(SMEDDS) formulation of sorafenib was prepared and its relative bioavailability in rats was evaluated.The blank SMEDDS was prepared from a mixture of ethyl oleate(oil phase,20%,w/w),Cremophol EL(surfactant,48%,w/w),PEG-400(co-surfactant,16%,w/w) and ethanol (co-surfactant,16%,w/w).Sorafenib was subsequently dissolved in the blank SMEDDS to obtain a sorafenib SMEDDS formulation with a final sorafenib concentration at 20 mg/mL.The particle size of the emulsified sorafenib SMEDDS was about 20-25 nm. Compared with sorafenib suspension,the prepared SMEDDS formulation exhibited no effect on the T_(max),but significantly increased the AUC,C_(max) and MRT and decreased the drug clearance.Most importantly,the oral bioavailability based on AUC_(0-72h) increased about 25 times after formulating sorafenib in SMEDDS.We concluded that SMEDDS could be a promising vesicle for the oral delivery of the poorly soluble antitumor drug sorafenib.展开更多
Objective:Sorafenib resistance has been a major factor limiting its clinical use as a targeted drug in liver cancer.The present study aimed to investigate whether cryptotanshinone can enhance the sensitivity of liver ...Objective:Sorafenib resistance has been a major factor limiting its clinical use as a targeted drug in liver cancer.The present study aimed to investigate whether cryptotanshinone can enhance the sensitivity of liver cancer and reduce the resistance to sorafenib.Methods:Sorafenib-resistant cells were established based on HepG2 and Huh7 cell lines.And the anti-tumor effect of sorafenib combined with cryptotanshinone on the sorafenib-resistant cells was verified by MTT,colony formation,transwell assays and tumor growth xenograft model.Moreover,the effects of the combined treatment on the expression of phosphorylated(p)-STAT3,as well as epithelial mesenchymal transition(EMT)and apoptosis related proteins of cells were evaluated by western blot analysis.Results:It was identified that cryptotanshinone inhibited the viability of both HepG2 and Huh7 cells in a dose-and time-dependent manner,and decreased p-STAT3 expression rather than total STAT3 expression at a concentration of 40μmol/L.In the sorafenib-resistant cells,sorafenib in combination with cryptotanshinone markedly inhibited cell viability,invasion and migration compared with sorafenib alone.In contrast,increased p-STAT3 level by colivelin led to the inhibition of the synergistic effect of cryptotanshinone and sorafenib not only on cell viability,but also on EMT and apoptosis,suggesting that cryptotanshinone and sorafenib may act by downregulating STAT3 signaling.Further,the inhibition of carcinogenicity effect was also verified in xenografted tumor models.Conclusion:The present results indicated that cryptotanshinone could synergize with sorafenib to inhibit the proliferative,invasive,and migratory abilities of sorafenib-resistant cells by downregulating STAT3 signaling.展开更多
文摘BACKGROUND Sorafenib has been the conventional treatment for advanced hepatocellular carcinoma(HCC)since 2008.While radiological complete responses are extremely rare,improved supportive care and multidisciplinary approaches in clinical practice may explain the recent increase in case reports and retrospective series documenting such responses.CASE SUMMARY This case series describes 3 patients with advanced HCC who achieved durable complete responses using first-line sorafenib therapy,even in the presence of portal vein thrombosis or extrahepatic spread,and highlights the potential for sustained remission in selected patients.Dermatologic toxicity and non-viral etiology may correlate with favorable outcomes;however,reliable predictive biomarkers for sorafenib response are lacking.CONCLUSION Future research into the etiology and molecular differences in HCC is necessary to develop more personalized therapy options.
基金Supported by Instituto de Salud Carlos III(ISCiii),No.PI19/01266 and No.PI22/00857Consejería de Salud y Familias(Junta de Andalucía),No.PI-0216-2020 and No.PIP-0215-2020Biomedical Research Network Center for Liver and Digestive Diseases(CIBERehd)founded by the ISCIII and co-financed by European Regional Development Fund“A way to achieve Europe”ERDF.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is the most common subtype of primary liver cancer with varied incidence and epidemiology worldwide.Sorafenib is still a recommended treatment for a large proportion of patients with advanced HCC.Different patterns of treatment responsiveness have been identified in differentiated hepatoblastoma HepG2 cells and metastatic HCC SNU449 cells.AIM To define the long non-codingRNA-microRNA-mRNA(lncRNA-miRNA-mRNA)predicted signatures related to selected hallmarks of cancer(apoptosis,autophagy,cell stress,cell dedifferentiation and invasiveness)in RNAseq studies using Sorafenib-treated HepG2 and SNU449 cells.Various available software analyses allowed us to establish the lncRNA-miRNA-mRNA regulatory axes following treatment in HepG2 and SNU449 cells.METHODS HepG2 and SNU449 cells were treated with Sorafenib(10μmol/L)for 24 hours.Total RNA,including small and long RNA,was extracted with a commercial miRNeasy kit.RNAseq was carried out for the identification of changes in lncRNA-miRNA-mRNA regulatory axes.RESULTS MALAT,THAP9-AS1 and SNGH17 appeared to coordinately regulate miR-374b-3p and miR-769-5p that led to upregulation of SMAD7,TIRARP,TFAP4 and FAXDC2 in HepG2 cells.SNHG12,EPB41 L4A-AS1,LINC01578,SNHG12 and GAS5 interacted with let-7b-3p,miR-195-5p and VEGFA in SNU449 cells.The axes MALAT1/hsamir-374b-3p/SMAD7 and MALAT1/hsa-mir-769-5p/TFAP4 were of high relevance for Sorafenib response in HepG2 cells,whereas PVT1/hsa-miR-195-5p/VEGFA was responsible for the differential response of SNU449 cells to Sorafenib treatment.CONCLUSION Critical lncRNAs acting as sponges of miRNA were identified that regulated mRNA expression,whose proteins mainly increased the antitumor effectiveness of the treatment(SMAD7,TIRARP,TFAP4,FAXDC2 and ADRB2).However,the broad regulatory axis leading to increased VEGFA expression may be related to the side effect of Sorafenib in SNU449 cells.
基金the financial support by National Natural Science Foundation of China(No.82171997)the Guangdong Basic and Applied Basic Research Fund Foundation(No.2023B1515120073)+2 种基金the Science and Technology Planning Project of Guangdong Province(No.2023B1212060013)Guangzhou Science and Technology Bureau(No.2023A03J0708)Shenzhen Science and Technology Program(Nos.JCYJ20230807111120043,JCYJ20220818102014028)。
文摘Sorafenib(Sora)not only has an inhibitory effect on angiogenesis via indirectly inhibiting tumor growth through antiangiogenesis,but also can inactivate the glutathione peroxidase 4(GPX4)to induce ferroptosis.Nonetheless,the therapeutic efficacy is hampered by a plethora of factors,including low bioavailability and tumor microenvironment(TME).Of particular note is the hypoxic and reductive TME,which acts as a significant impediment and poses formidable challenges to attain the most optimal treatment outcomes.Herein,we developed a novel therapeutic platform based on Sora-loaded mesoporous ferromanganese nanoparticles(PMFNs@Sora).PMFNs mimics both catalase and GPX activities.The self-sustained catalase activity enables continuous decomposition of hydrogen peroxide to generate oxygen,which alleviates hypoxia microenvironment.The GPX activity simultaneously amplifies the therapeutic efficacy of Sora.The as-synthesized PMFNs@Sora demonstrates significantly enhanced antitumor effect in vitro through apoptosis-ferroptosis,revealed by Western blot.Furthermore,PMFNs@Sora also showed effective tumor growth inhibition in vivo.This multifunctional nanoplatform offers a promising strategy for modulating the TME and enhancing cancer treatment in clinical application.
基金Supported by the Shenzhen High-Level Hospital Construction Fund,the Sanming Project of Medicine in Shenzhen,No.SZSM202011010Intramural Research Projects of Shenzhen Hospital,Cancer Hospital,Chinese Academy of Medical Sciences,No.SZ2020MS010the Scientific Research Program Fund of Hunan Provincial Health Commission,No.202204014693.
文摘BACKGROUND Lenvatinib and sorafenib are tyrosine kinase inhibitors that are effective in the treatment of unresectable hepatocellular carcinoma(uHCC).The efficacy of which of them is better suited to combine transarterial chemoembolization(TACE)for the treatment of uHCC is ripe.RESULTS A total of six studies involving 547 patients were included,248 in the TACE-lenvatinib group and 299 in the TACE-sorafenib group.Meta-analysis results showed that TACE-lenvatinib was more effective than TACE-sorafenib in complete response[relative risk(RR)=1.81,95%confidence interval(CI):1.11-2.96,P=0.02],partial response(RR=1.38,95%CI:1.12-1.70,P=0.002),objective response rate(RR=1.47,95%CI:1.24-1.74,P<0.0001)and disease control rate(RR=1.22,95%CI:1.00-1.49,P=0.05).TACE-lenvatinib was significantly lower than TACE-sorafenib in progressive disease rate(RR=0.54,95%CI:0.39-0.74,P=0.002).No significant difference was found in stable disease rate(RR=0.89,95%CI:0.60-1.33,P=0.58)between the two groups.TACE-lenvatinib was significantly more effective than TACE-sorafenib in overall survival(hazard ratio=2.00,95%CI:1.59-2.50,P<0.05)and progression free survival(hazard ratio=2.04,95%CI:1.49-2.86,P<0.05).As regards adverse events,TACE-lenvatinib was better in reducing the incidence of hypertension than TACE-sorafenib,while no significant difference was found in overall adverse events,abdominal pain,fever,fatigue,nausea and vomiting,decreased appetite,liver dysfunction,hand-foot skin reaction,diarrhea,thrombocytopenia,and rash between the two groups.CONCLUSION In patients with uHCC,TACE-lenvatinib induced a better tumor response rate and survival outcome than TACE-sorafenib,while TACE-lenvatinib resulted in a higher incidence of hypertension than TACE-sorafenib.However,these conclusions are derived from currently available medical evidence,and further confirmation by more rigorously designed randomized controlled studies is still needed.
基金Supported by Sichuan Science and Technology Program,No.2022YFS0625。
文摘BACKGROUND The combination of sorafenib with transarterial chemoembolization(TACE)is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma(HCC).AIM To evaluate the efficacy of this combined treatment strategy in enhancing overall survival(OS)and progression-free survival(PFS)compared to monotherapies.METHODS A systematic review was conducted following the PRISMA guidelines.A comprehensive search was performed across PubMed,EMBASE,Web of Science,and the Cochrane Library up to May 8,2024.Studies were included if they compared sorafenib plus TACE to sorafenib alone or TACE alone in adults with advanced HCC.Primary outcomes were OS,PFS,response rates,and safety profiles.Data extraction and quality assessment were independently performed by two reviewers.Heterogeneity was assessed using the I^(2)statistic,and a random-effects model was applied for pooling data.Sensitivity analysis and publication bias assessment were also conducted.RESULTS A total of twelve studies involving 1174 patients met the inclusion criteria.Significant heterogeneity was observed for both OS(I^(2)=72.6%,P<0.001)and PFS(I^(2)=83.7%,P<0.001).The combined treatment of sorafenib with TACE significantly improved OS[hazard ratio(HR)=0.60,95%confidence interval(CI):0.44-0.76]and PFS(HR=0.54,95%CI:0.38-0.69).Sensitivity analysis confirmed the robustness of these findings.Funnel plots and Egger's test indicated no significant publication bias.CONCLUSION Sorafenib combined with TACE significantly enhances both OS and PFS in patients with advanced HCC compared to monotherapy.This combination therapy represents a promising approach to improving clinical outcomes in advanced liver cancer.
文摘BACKGROUND Cirrhotic patients with super-giant hepatocellular carcinoma(HCC)and portal vein invasion generally have a poor prognosis.This paper presents a patient with super-giant HCC and portal vein invasion,who underwent hepatectomy followed by a combination of sorafenib and camrelizumab,resulting in complete remission(CR)for 5 years.CASE SUMMARY A 40-year-old male with compensated hepatitis B-related cirrhosis was diagnosed with HCC,Barcelona Clinic Liver Cancer stage C.Enhanced computed tomography imaging revealed a 152 mm×171 mm tumor in the right liver,invading the portal vein and hepatic vein.Liver function was normal.The patient successfully underwent hepatectomy on July 18,2019.However,by December 2019,HCC recurrence with lung metastases and portal vein invasion were detected.He started treatment with sorafenib(200 mg twice daily)and camrelizumab(200 mg every 3 weeks).By May 12,2020,the patient was confirmed to have CR.Camrelizumab was adjusted to 200 mg every 12 weeks from June 16,2021,with the last infusion on March 29,2024.Although no further tumor recurrence was observed,he experienced two episodes of gastrointestinal bleeding due to esophagogastric varices,which were managed with endoscopic therapy.To date,the patient has remained in CR for 5 years.CONCLUSION The combination of hepatectomy with sorafenib and camrelizumab can achieve durable CR in patients with supergiant HCC and portal vein invasion.Further research is necessary to address these challenges and improve patient outcomes.
基金supported by grants from the National Key Research and Development Program of China(No.2022YFA1103500)the National Natural Science Foundation of China(No.82170210)。
文摘Objective:Acute myeloid leukemia(AML)patients with internal tandem duplications in the FMS-like tyrosine kinase 3 receptor gene(FLT3-ITD)receiving tyrosine kinase inhibitors maintenance after allogeneic hematopoietic stem cell transplantation(allo-HSCT)demonstrated improved survival outcomes,however,some still experienced relapse during the maintenance.This study aimed to explore risk factors which might be indicators for poor survival after allo-HSCT in this population.Methods:We consecutively enrolled FLT3-ITD AML patients undergoing transplantation at three centers.By integrating genetic profiles with clinical information,we assessed their impact on transplant outcomes.Results:A total of 196 patient were eligible in the analysis,among whom 14%harbored myelodysplasia-related(MR)mutations,including ASXL1,BCOR,EZH2,RUNX1,SF3B1,SRSF2,STAG2,U2AF1,and ZRSR2.Co-mutant MR was independently associated with poorer overall survival(OS)[hazard ratio(HR):2.4,95%confidence interval(95%CI):1.1-5.3,P=0.030].DNMT3A co-mutations strongly predicted adverse survival and relapse[OS:HR:2.1,95%CI:1.0-4.3,P=0.045;relapse-free survival(RFS):HR:2.2,95%CI:1.1-4.1,P=0.017;cumulative incidence of relapse(CIR):HR:2.3,95%CI:1.1-4.8,P=0.030].Compared to patients with negative measurable residual disease(MRD)complete remission(CR),no significant differences were observed in CR patients with positive MRD,while those without CR exhibited significantly inferior outcomes(P=0.003).Conclusions:Patients with myelodysplasia-related gene mutations(MRmut)and/or DNMT3A mutations experienced inferior outcomes after transplantation,requiring further exploration.Furthermore,similar prognoses among CR patients highlighted the need for monitoring specific molecular residual lesions.
基金supported by the Macao Science and Technology Development Fund (FDCT 0148/2022/A3 and 0019/2024/RIA1)the National Natural Science Foundation of China (No. 81572979)
文摘Immunotherapy with interleukin-2(IL-2)in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise.To address these challenges,IL-2-So-Lipo,a novel liposomal formulation combining IL-2 with sorafenib derivative,was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth.Sorafenib derivatives could target at melanoma-specific receptors,further enhancing liposomal specificity at the tumor site.Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies,as well as their combination.In a B16F10 melanoma model,IL-2-So-Lipo was found to significantly inhibit tumor progression(tumor volume of 108.01±62.99 mm^(3))compared to the control group(tumor volume of 1,397.13±75.55 mm^(3)),improving the therapeutic efficacy.This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes.Additionally,liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency,promoting tumor cell apoptosis and suppressing angiogenesis.Mechanistically,IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype.Furthermore,IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway,exerting a significant role in mediating tumor resistance to sorafenib.These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers.Moreover,the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy,offering a synergistic approach to improve therapeutic outcomes for solid tumors.
基金supported by Natural Science Foundation of Shandong Province,No.ZR2021QH186National Natural Science Foundation of China,No.81870205+3 种基金Foundation Research Project of Qinghai Province,2021-ZJ-719National Natural Science Foundation of China,No.82000579Qinghai Provincial Health System Key Project No.2021-wjzd-06Foundation Research Project of Qinghai Province,2023-ZJ-786.
文摘Objectives:Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma(HCC)patients.However,the underlying mechanism remains ambiguous.The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo.Methods:After observing epithelial-mesenchymal transformation(EMT)changes in HepG2 and HepG2/Sorafenib cells,we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC.Subsequently,specific inhibitors of c-Jun N-terminal kinase(JNK,SP600125)and extracellular signal-regulated kinase(ERK,PD98059)were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor(EGFR)/JNK/ERK signaling pathway in vitro and in vivo.Biological behavior changes were assessed through cell counting kit-8(CCK-8),colony formation,transwell,and immunofluorescence tests.Simultaneously,Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway.Results:The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells,and sorafenib-resistant HCC was characterized by EMT changes.Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells,with minimal impact on HepG2 cells.Additionally,apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells.Furthermore,there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups.Notably,SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC.Conclusion:Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.
基金The 973 Project(Grant No.2009CB930300)Scientific and Technological Major Special Project -"Significant Creation of New Drugs"(Grant No.2009ZX09310-001).
文摘Sorafenib is a novel antitumor drug,which is poorly absorbed in the gastrointestinal tract due to its low solubility in water.To improve the bioavailability of sorafenib,a self-microemulsifying drug delivery system(SMEDDS) formulation of sorafenib was prepared and its relative bioavailability in rats was evaluated.The blank SMEDDS was prepared from a mixture of ethyl oleate(oil phase,20%,w/w),Cremophol EL(surfactant,48%,w/w),PEG-400(co-surfactant,16%,w/w) and ethanol (co-surfactant,16%,w/w).Sorafenib was subsequently dissolved in the blank SMEDDS to obtain a sorafenib SMEDDS formulation with a final sorafenib concentration at 20 mg/mL.The particle size of the emulsified sorafenib SMEDDS was about 20-25 nm. Compared with sorafenib suspension,the prepared SMEDDS formulation exhibited no effect on the T_(max),but significantly increased the AUC,C_(max) and MRT and decreased the drug clearance.Most importantly,the oral bioavailability based on AUC_(0-72h) increased about 25 times after formulating sorafenib in SMEDDS.We concluded that SMEDDS could be a promising vesicle for the oral delivery of the poorly soluble antitumor drug sorafenib.
文摘Objective:Sorafenib resistance has been a major factor limiting its clinical use as a targeted drug in liver cancer.The present study aimed to investigate whether cryptotanshinone can enhance the sensitivity of liver cancer and reduce the resistance to sorafenib.Methods:Sorafenib-resistant cells were established based on HepG2 and Huh7 cell lines.And the anti-tumor effect of sorafenib combined with cryptotanshinone on the sorafenib-resistant cells was verified by MTT,colony formation,transwell assays and tumor growth xenograft model.Moreover,the effects of the combined treatment on the expression of phosphorylated(p)-STAT3,as well as epithelial mesenchymal transition(EMT)and apoptosis related proteins of cells were evaluated by western blot analysis.Results:It was identified that cryptotanshinone inhibited the viability of both HepG2 and Huh7 cells in a dose-and time-dependent manner,and decreased p-STAT3 expression rather than total STAT3 expression at a concentration of 40μmol/L.In the sorafenib-resistant cells,sorafenib in combination with cryptotanshinone markedly inhibited cell viability,invasion and migration compared with sorafenib alone.In contrast,increased p-STAT3 level by colivelin led to the inhibition of the synergistic effect of cryptotanshinone and sorafenib not only on cell viability,but also on EMT and apoptosis,suggesting that cryptotanshinone and sorafenib may act by downregulating STAT3 signaling.Further,the inhibition of carcinogenicity effect was also verified in xenografted tumor models.Conclusion:The present results indicated that cryptotanshinone could synergize with sorafenib to inhibit the proliferative,invasive,and migratory abilities of sorafenib-resistant cells by downregulating STAT3 signaling.
