Aggressive cytoreduction can prolong survival in patients with unresectable liver metastases(LM)from neuroendocrine neoplasms(NEN),and minimally invasive,liver-directed therapies are gaining increasing interest.Cathet...Aggressive cytoreduction can prolong survival in patients with unresectable liver metastases(LM)from neuroendocrine neoplasms(NEN),and minimally invasive,liver-directed therapies are gaining increasing interest.Catheter-based treatments are used in disseminated disease,whereas ablation techniques are usually indicated when the number of LM is limited.Although radiofrequency ablation(RFA)is by far the most used ablative technique,the goal of this opinion review is to explore the potential role of laser ablation(LA)in the treatment of LM from NEN.LA uses thinner needles than RFA,and this is an advantage when the tumors are in at-risk locations.Moreover,the multi-fiber technique enables the use of one to four laser fibers at once,and each fiber provides an almost spherical thermal lesion of 12-15 mm in diameter.Such a characteristic enables to tailor the size of each thermal lesion to the size of each tumor,sparing the liver parenchyma more than any other liver-directed therapy,and allowing for repeated treatments with low risk of liver failure.A recent retrospective study reporting the largest series of LM treated with LA documents both safety and effectiveness of LA,that can play a useful role in the multimodality approach to LM from NEN.展开更多
AIM： To generate and characcerize the synthetic transoiptional control units for transcriptional targeting of the liver, thereby compensating for the lack of specificity of currently available gene therapeutic vector...AIM： To generate and characcerize the synthetic transoiptional control units for transcriptional targeting of the liver, thereby compensating for the lack of specificity of currently available gene therapeutic vector systems. METHODS： Synthetic transcriptional control unit constructs were generated and analyzed for transcriptional activities in different cell types by FACS quantification, semi-quantitative RT-PCR, and Western blotting. RESULTS： A new bifunctionally-enhanced green fluorescent protein （EGFP）/neor fusion gene cassette was generated, and could flexibly be used both for transcript quantification and for selection of stable cell clones. Then, numerous synthetic transcriptional control units consisting of a minimal promoter linked to “naturally” derived composite enhancer elements from liver-specific expressed genes or binding sites of liver-specific transcription factors were inserted upstream of this reporter cassette. Following liposome-mediated transfection, EGFP reporter protein quantification by FACS analysis identified constructs encoding multimerized composite elements of the apolipoprotein B100 （APOB） promoter or the ornithin transcarbamoylase （OTC） enhancer to exhibit maximum transcriptional activities in liver originating cell lines, but only background levels in non-liver originating cell lines. In contrast, constructs encoding only singular binding sites of liver-specific transcription factors, namely hepatocyte nuclear factor （HNF）, HNF3, HNF4, HNF5, or CAAT/enhancer binding protein （C/EBP） only achieved background levels of EGFP expression. Finally, both semi-quantitative RT-PCR and Western blotting analysis of Hep3B cells demonstrated maximum transcriptional activities for a multimeric 4xAPOB cassette construct, which fully complied with the dataobtained by initial FACS analysis CONCLUSION： Synthetic transcriptional control unit constructs not only exhibit a superb degree of structural compactness, but also provide new means for liver-directed expression of therapeutic genes.展开更多
Background:This article aims to present the single-institution outcomes of patients with Fibrolamellar Carcinoma(FLC)treated with liver-directed therapies(LDT).Methods:In this single-center retrospective study,all pat...Background:This article aims to present the single-institution outcomes of patients with Fibrolamellar Carcinoma(FLC)treated with liver-directed therapies(LDT).Methods:In this single-center retrospective study,all patients diagnosed with FLC who underwent LDT were identified.Between July 2012 and July 2023,six patients were identified.One patient was excluded due to bleeding.Demographic and clinical parameters were recorded.Complications within 30 days of the LDT were evaluated.Radiological treatment responses at 1,6,and 12 months were assessed per mRECIST.Results:A total offive patients,which included three females and two males,were reviewed.Three patients were treated with transarterial hepatic embolization(TAE;n=3),transarterial radioembolization(TARE;n=1),and combined TAE+radiofrequency ablation(n=1).The objective response rate at one month was 80%[CR=2(40%),PR=2(40%),and SD=1(20%)].At 12 months(n=4),two patients demonstrated CR(50%)and two demonstrated PR(50%).Overall survival from LDT atfive years was 50%.There was no 30-day mortality among this group of patients or any adverse event attributable to the LDT.Conclusion:TAE,TARE,and ablation are safe and effective therapeutic options for FLC.Based on this study and previously published case reports,ablation and TARE yielded the most favorable results.展开更多
Metastases of uveal melanoma(UM)spread predominantly to the liver.Due to low response rates to systemic therapies,liver-directed therapies(LDT)are commonly used for tumor control.The impact of LDT on the response to s...Metastases of uveal melanoma(UM)spread predominantly to the liver.Due to low response rates to systemic therapies,liver-directed therapies(LDT)are commonly used for tumor control.The impact of LDT on the response to systemic treatment is unknown.A total of 182 patients with metastatic UM treated with immune checkpoint blockade(ICB)were included in this analysis.Patients were recruited from prospective skin cancer centers and the German national skin cancer registry(ADOReg)of the German Dermatologic Cooperative Oncology Group(DeCOG).Two cohorts were compared:patients with LDT(cohort A,n=78)versus those without LDT(cohort B,n=104).Data were analyzed for response to treatment,progression-free survival(PFS),and overall survival(OS).The median OS was significantly longer in cohort A than in cohort B(20.1 vs.13.8 months;P=0.0016)and a trend towards improved PFS was observed for cohort A(3.0 vs.2.5 months;P=0.054).The objective response rate to any ICB(16.7%vs.3.8%,P=0.0073)and combined ICB(14.1%vs.4.5%,P=0.017)was more favorable in cohort A.Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.展开更多
BACKGROUND The liver represents a common site of distant metastasis in patients with esophageal cancer(EC).Conventional chemotherapy(CMT)presents limited efficacy for EC,and EC patients with liver metastases typically...BACKGROUND The liver represents a common site of distant metastasis in patients with esophageal cancer(EC).Conventional chemotherapy(CMT)presents limited efficacy for EC,and EC patients with liver metastases typically experience a poor prognosis,highlighting an urgent need to explore novel treatment approaches.This study evaluated the overall efficacy and safety of CMT vs CMT combined with immune checkpoint inhibitors(ICIs)in the treatment of EC patients with liver metastases.Furthermore,prognostic factors influencing outcomes in this patient population were identified.AIM To evaluate the efficacy and safety of first-line chemoimmunotherapy for EC patients with liver metastases and to analyze prognostic factors.METHODS This retrospective study included 126 EC patients with liver metastases at Zhejiang Cancer Hospital between 2014 and 2024.Patients receiving CMT were compared with those receiving CMT+ICI.Analyzed variables included clinicopathological features,treatment history,characteristics of metastasis,systemic and local treatments,overall survival(OS),and treatment-related adverse events(TRAEs).Prognostic factors were evaluated using univariate and multivariate Cox proportional-hazards regression models.Finally,efficacy outcomes and TRAE profiles were compared between the two groups.RESULTS A significant difference in median OS was identified between the two groups(10.8 months in the CMT group vs 20.8 months in the CMT+ICI group,P=0.004).The CMT+ICI group also demonstrated a significantly longer median progression-free survival of 11.7 months(P<0.001).Patients receiving combination therapy exhibited significantly improved systemic objective response rate and disease control rate.Multivariate analysis identified key factors significantly influencing OS in EC patients with liver metastases:Karnofsky Performance Status score≥70,receipt of local therapy for liver metastases,and the number of cycles of CMT and immunotherapy received.Furthermore,the incidence of TRAEs did not significantly differ between the CMT+ICI and CMT groups.CONCLUSION For EC patients with liver metastases,the combination of CMT and ICIs demonstrates significantly superior efficacy compared with CMT alone,while maintaining manageable TRAEs.展开更多
Well-differentiated neuroendocrine tumors(NETs)are globally increasing in prevalence and the liver is the most common site of metastasis.Neuroendocrine liver metastases(NELM)are heterogeneous in clinical presentation ...Well-differentiated neuroendocrine tumors(NETs)are globally increasing in prevalence and the liver is the most common site of metastasis.Neuroendocrine liver metastases(NELM)are heterogeneous in clinical presentation and prognosis.Fortunately,recent advances in diagnostic techniques and therapeutic strategies have improved the multidisciplinary management of this challenging condition.When feasible,surgical resection of NELM offers the best long-term outcomes.General indications for hepatic resection include performance status acceptable for major liver surgery,grade 1 or 2 tumors,absence of extrahepatic disease,adequate size and function of future liver remnant,and feasibility of resecting>90%of metastases.Adjunct therapies including concomitant liver ablation are generally safe when used appropriately and may expand the number of patients eligible for surgery.Among patients with synchronous resectable NELM,resection of the primary either in a staged or combined fashion is recommended.For patients who are not surgical candidates,liver-directed therapies such as transarterial embolization,chemoembolization,and radioembolization can provide locoregional control and improve symptoms of carcinoid syndrome.Multiple systemic therapy options also exist for patients with advanced or progressive disease.Ongoing research efforts are needed to identify novel biomarkers that will define the optimal indications for and sequencing of treatments to be delivered in a personalized fashion.展开更多
文摘Aggressive cytoreduction can prolong survival in patients with unresectable liver metastases(LM)from neuroendocrine neoplasms(NEN),and minimally invasive,liver-directed therapies are gaining increasing interest.Catheter-based treatments are used in disseminated disease,whereas ablation techniques are usually indicated when the number of LM is limited.Although radiofrequency ablation(RFA)is by far the most used ablative technique,the goal of this opinion review is to explore the potential role of laser ablation(LA)in the treatment of LM from NEN.LA uses thinner needles than RFA,and this is an advantage when the tumors are in at-risk locations.Moreover,the multi-fiber technique enables the use of one to four laser fibers at once,and each fiber provides an almost spherical thermal lesion of 12-15 mm in diameter.Such a characteristic enables to tailor the size of each thermal lesion to the size of each tumor,sparing the liver parenchyma more than any other liver-directed therapy,and allowing for repeated treatments with low risk of liver failure.A recent retrospective study reporting the largest series of LM treated with LA documents both safety and effectiveness of LA,that can play a useful role in the multimodality approach to LM from NEN.
基金Supported by German Research Foundation (LA 649/11-1)Fortüne-program of the Medical Faculty of the Eberhard-Karls-University Tubingen (F.128101.1) Scholarship from the Pinguin Foundation (Henkel KGaA)
文摘AIM： To generate and characcerize the synthetic transoiptional control units for transcriptional targeting of the liver, thereby compensating for the lack of specificity of currently available gene therapeutic vector systems. METHODS： Synthetic transcriptional control unit constructs were generated and analyzed for transcriptional activities in different cell types by FACS quantification, semi-quantitative RT-PCR, and Western blotting. RESULTS： A new bifunctionally-enhanced green fluorescent protein （EGFP）/neor fusion gene cassette was generated, and could flexibly be used both for transcript quantification and for selection of stable cell clones. Then, numerous synthetic transcriptional control units consisting of a minimal promoter linked to “naturally” derived composite enhancer elements from liver-specific expressed genes or binding sites of liver-specific transcription factors were inserted upstream of this reporter cassette. Following liposome-mediated transfection, EGFP reporter protein quantification by FACS analysis identified constructs encoding multimerized composite elements of the apolipoprotein B100 （APOB） promoter or the ornithin transcarbamoylase （OTC） enhancer to exhibit maximum transcriptional activities in liver originating cell lines, but only background levels in non-liver originating cell lines. In contrast, constructs encoding only singular binding sites of liver-specific transcription factors, namely hepatocyte nuclear factor （HNF）, HNF3, HNF4, HNF5, or CAAT/enhancer binding protein （C/EBP） only achieved background levels of EGFP expression. Finally, both semi-quantitative RT-PCR and Western blotting analysis of Hep3B cells demonstrated maximum transcriptional activities for a multimeric 4xAPOB cassette construct, which fully complied with the dataobtained by initial FACS analysis CONCLUSION： Synthetic transcriptional control unit constructs not only exhibit a superb degree of structural compactness, but also provide new means for liver-directed expression of therapeutic genes.
文摘Background:This article aims to present the single-institution outcomes of patients with Fibrolamellar Carcinoma(FLC)treated with liver-directed therapies(LDT).Methods:In this single-center retrospective study,all patients diagnosed with FLC who underwent LDT were identified.Between July 2012 and July 2023,six patients were identified.One patient was excluded due to bleeding.Demographic and clinical parameters were recorded.Complications within 30 days of the LDT were evaluated.Radiological treatment responses at 1,6,and 12 months were assessed per mRECIST.Results:A total offive patients,which included three females and two males,were reviewed.Three patients were treated with transarterial hepatic embolization(TAE;n=3),transarterial radioembolization(TARE;n=1),and combined TAE+radiofrequency ablation(n=1).The objective response rate at one month was 80%[CR=2(40%),PR=2(40%),and SD=1(20%)].At 12 months(n=4),two patients demonstrated CR(50%)and two demonstrated PR(50%).Overall survival from LDT atfive years was 50%.There was no 30-day mortality among this group of patients or any adverse event attributable to the LDT.Conclusion:TAE,TARE,and ablation are safe and effective therapeutic options for FLC.Based on this study and previously published case reports,ablation and TARE yielded the most favorable results.
文摘Metastases of uveal melanoma(UM)spread predominantly to the liver.Due to low response rates to systemic therapies,liver-directed therapies(LDT)are commonly used for tumor control.The impact of LDT on the response to systemic treatment is unknown.A total of 182 patients with metastatic UM treated with immune checkpoint blockade(ICB)were included in this analysis.Patients were recruited from prospective skin cancer centers and the German national skin cancer registry(ADOReg)of the German Dermatologic Cooperative Oncology Group(DeCOG).Two cohorts were compared:patients with LDT(cohort A,n=78)versus those without LDT(cohort B,n=104).Data were analyzed for response to treatment,progression-free survival(PFS),and overall survival(OS).The median OS was significantly longer in cohort A than in cohort B(20.1 vs.13.8 months;P=0.0016)and a trend towards improved PFS was observed for cohort A(3.0 vs.2.5 months;P=0.054).The objective response rate to any ICB(16.7%vs.3.8%,P=0.0073)and combined ICB(14.1%vs.4.5%,P=0.017)was more favorable in cohort A.Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.
基金Supported by National Natural Science Foundation of China,No.82303672Zhejiang Provincial Health Commission and Zhejiang Provincial Administration of Traditional Chinese Medicine through the Targeted Project for Medical and Health Research,No.2025ZL017and China Primary Health Care Foundation,No.ZLMY20240311001ZJ.
文摘BACKGROUND The liver represents a common site of distant metastasis in patients with esophageal cancer(EC).Conventional chemotherapy(CMT)presents limited efficacy for EC,and EC patients with liver metastases typically experience a poor prognosis,highlighting an urgent need to explore novel treatment approaches.This study evaluated the overall efficacy and safety of CMT vs CMT combined with immune checkpoint inhibitors(ICIs)in the treatment of EC patients with liver metastases.Furthermore,prognostic factors influencing outcomes in this patient population were identified.AIM To evaluate the efficacy and safety of first-line chemoimmunotherapy for EC patients with liver metastases and to analyze prognostic factors.METHODS This retrospective study included 126 EC patients with liver metastases at Zhejiang Cancer Hospital between 2014 and 2024.Patients receiving CMT were compared with those receiving CMT+ICI.Analyzed variables included clinicopathological features,treatment history,characteristics of metastasis,systemic and local treatments,overall survival(OS),and treatment-related adverse events(TRAEs).Prognostic factors were evaluated using univariate and multivariate Cox proportional-hazards regression models.Finally,efficacy outcomes and TRAE profiles were compared between the two groups.RESULTS A significant difference in median OS was identified between the two groups(10.8 months in the CMT group vs 20.8 months in the CMT+ICI group,P=0.004).The CMT+ICI group also demonstrated a significantly longer median progression-free survival of 11.7 months(P<0.001).Patients receiving combination therapy exhibited significantly improved systemic objective response rate and disease control rate.Multivariate analysis identified key factors significantly influencing OS in EC patients with liver metastases:Karnofsky Performance Status score≥70,receipt of local therapy for liver metastases,and the number of cycles of CMT and immunotherapy received.Furthermore,the incidence of TRAEs did not significantly differ between the CMT+ICI and CMT groups.CONCLUSION For EC patients with liver metastases,the combination of CMT and ICIs demonstrates significantly superior efficacy compared with CMT alone,while maintaining manageable TRAEs.
文摘Well-differentiated neuroendocrine tumors(NETs)are globally increasing in prevalence and the liver is the most common site of metastasis.Neuroendocrine liver metastases(NELM)are heterogeneous in clinical presentation and prognosis.Fortunately,recent advances in diagnostic techniques and therapeutic strategies have improved the multidisciplinary management of this challenging condition.When feasible,surgical resection of NELM offers the best long-term outcomes.General indications for hepatic resection include performance status acceptable for major liver surgery,grade 1 or 2 tumors,absence of extrahepatic disease,adequate size and function of future liver remnant,and feasibility of resecting>90%of metastases.Adjunct therapies including concomitant liver ablation are generally safe when used appropriately and may expand the number of patients eligible for surgery.Among patients with synchronous resectable NELM,resection of the primary either in a staged or combined fashion is recommended.For patients who are not surgical candidates,liver-directed therapies such as transarterial embolization,chemoembolization,and radioembolization can provide locoregional control and improve symptoms of carcinoid syndrome.Multiple systemic therapy options also exist for patients with advanced or progressive disease.Ongoing research efforts are needed to identify novel biomarkers that will define the optimal indications for and sequencing of treatments to be delivered in a personalized fashion.
