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BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has shown satisfactory therapeutic efficacy in unresectable hepatocellular carcinoma (HCC) and is regarded as an important conversion treatment. However, limited information is available regarding the optimal timing of HAIC-based conversion hepatectomy. This study aims to determine the optimal timing for HAIC-based conversion surgery in patients with HCC. METHODS: Data from a retrospective cohort of patients who underwent HAIC-based conversion hepatectomy were reviewed. Oncological outcomes, surgical information, and risk factors were comparatively analyzed. RESULTS: In total, 424 patients with HCC who underwent HAIC-based conversion hepatectomy were included and were divided into responder (n=312) and nonresponder (n=112) groups. The overall survival (OS) and recurrence-free survival (RFS) rates of both the whole responder cohort and patients who achieved a response after 4-6 cycles of HAIC were significantly better than those of the nonresponder cohort. Higher OS and RFS were observed in responders than in nonresponders with advanced-stage HCC. Patients in the responder group had a shorter occlusion duration and less intraoperative blood loss than those in the nonresponder group. There were no significant differences in other surgical information or postoperative complications between the two groups. Tumor response, differentiation, postoperative alpha-fetoprotein level, postoperative protein induced by vitamin K absence or antagonist-II level, age, microvascular invasion, pre-HAIC neutrophil-to-lymphocyte ratio, and preoperative systemic inflammatory response index were independent risk factors for poor long-term survival. CONCLUSIONS: Conversion surgery should be considered when tumor response is achieved. Our findings may be useful in guiding surgeons and patients in decision-making regarding HAIC-based conversion hepatectomy.
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BACKGROUND: Hepatic arterial infusionchemotherapy (HAIC) is a promising option for large unresectable hepatocellular carcinoma (HCC). Identifying patients who could benefit from continuous HAIC remains a challenge. We aimed to establish an objective model to guide the decision for retreatment with HAIC. METHODS: Between 2015 and 2020, the data of patients with large unresectable HCC without macrovascular invasion or extrahepatic spread undergoing multiple HAIC cycles from 3 different centers were retrieved. We investigated the basic tumor parameters and the effect of HAIC on liver function and tumor response, and their impact on overall survival (OS). A point score (ARH, Assessment for Retreatment with HAIC) was built by using a stepwise Cox regression model in the training cohort (n = 112) and was validated in an independent validation cohort (n = 71). RESULTS: The high α-fetoprotein before the second cycle of HAIC, an increase in Child-Pugh score, and undesirable radiologic tumor responses remained independent negative prognostic factors and were used to create the ARH score. The prognosis of HCC patients deteriorated significantly with the increase in ARH score. The median OS of patients with ARH score 0-2 points and ≥ 2.5 points were 19.37 months and 11.60 months (P < 0.001). All of these results had been confirmed in the external validation cohort and demonstrated significance across multiple subgroups. CONCLUSIONS: The ARH score makes an excellent prediction of the prognosis of HCC patients who received retreatment of HAIC. Patients with an ARH score ≥ 2.5 prior to the second cycle of HAIC may not profit from further sessions.
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Carcinoma Hepatocelular , Infusiones Intraarteriales , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Arteria Hepática , Retratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Toma de Decisiones Clínicas , Estudios Retrospectivos , Pronóstico , Adulto , alfa-Fetoproteínas/metabolismo , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND: Patients with microvascular invasion (MVI)-positive hepatocellular carcinoma (HCC) have shown promising results with adjuvant hepatic arterial infusion chemotherapy (HAIC) with FOLFOX after curative resection. We aim to develop an imaging-derived biomarker to depict MVI-positive HCC patients more precisely and promote individualized treatment strategies of adjuvant HAIC. MATERIALS AND METHODS: Patients with MVI-positive HCC were identified from five academic centers and utilized for model development (n=470). Validation cohorts were pooled from a previously reported prospective clinical study conducted (control cohort (n=145), adjuvant HAIC cohort (n=143)) (NCT03192618). The primary endpoint was recurrence-free survival (RFS). Imaging features were thoroughly reviewed, and multivariable logistic regression analysis was employed for model development. Transcriptomic sequencing was conducted to identify the associated biological processes. RESULTS: Arterial phase peritumoral enhancement, boundary of the tumor enhancement, tumor necrosis stratification, and boundary of the necrotic area were selected and incorporated into the nomogram for RFS. The imaging-based model successfully stratified patients into two distinct prognostic subgroups in both the training, control, and adjuvant HAIC cohorts (median RFS, 6.00 vs. 66.00 mo, 4.86 vs. 24.30 mo, 11.46 vs. 39.40 mo, all P<0.01). Furthermore, no significant statistical difference was observed between patients at high-risk of adjuvant HAIC and those in the control group (P=0.61). The area under the receiver operating characteristic curve at two years was found to be 0.83, 0.84, and 0.73 for the training, control, and adjuvant HAIC cohorts respectively. Transcriptomic sequencing analyses revealed associations between the radiological features and immune-regulating signal transduction pathways. CONCLUSION: The utilization of this imaging-based model could help to better characterize MVI-positive HCC patients and facilitate the precise subtyping of patients who genuinely benefit from adjuvant HAIC treatment.
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BACKGROUND: The liver function reserve has a significant impact on the therapeutic effects of anti-programmed cell death-1 (PD-1) for hepatocellular carcinoma (HCC). This study aimed to comprehensively evaluate the ability of liver-function-based indicators to predict prognosis and construct a novel prognostic score for HCC patients with anti-PD-1 immunotherapy. METHODS: Between July 2018 and January 2020, patients diagnosed with HCC who received anti-PD-1 treatment were screened for inclusion in the study. The valuable prognostic liver-function-based indicators were selected using Cox proportional hazards regression analysis to build a novel liver-function-indicators-based signature (LFIS). Concordance index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and Kaplan-Meier survival curves were utilized to access the predictive performance of LFIS. RESULTS: A total of 434 HCC patients who received anti-PD-1 treatment were included in the study. The LFIS, based on alkaline phosphatase-to-albumin ratio index, Child-Pugh score, platelet-albumin score, aspartate aminotransferase-to-lymphocyte ratio index, and gamma-glutamyl transpeptidase-to-lymphocyte ratio index, was constructed and identified as an independent risk factor for patient survival. The C-index of LFIS for overall survival (OS) was 0.692, which was higher than the other single liver-function-based indicator. The AUC of LFIS at 6-, 12-, 18-, and 24-month were 0.74, 0.714, 0.747, and 0.865 for OS, respectively. Patients in the higher-risk LFIS group were associated with both worse OS and PFS. An online and easy-to-use calculator was further constructed for better application of the LFIS signature. CONCLUSION: The LFIS score had an excellent prognosis prediction ability superior to every single liver-function-based indicator for anti-PD-1 treatment in HCC patients. It is a reliable, easy-to-use tool to stratify risk for OS and PFS in HCC patients who received anti-PD-1 treatment.
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Carcinoma Hepatocelular , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Pruebas de Función Hepática/métodos , Estudios Retrospectivos , Tasa de Supervivencia , Hígado/patología , Inmunoterapia/métodos , Biomarcadores de Tumor , AdultoRESUMEN
PURPOSE: Limited treatment options exist for unresectable intrahepatic cholangiocarcinoma (ICC), with systemic chemotherapy (SC) serving as the primary approach. This study aimed to assess the effectiveness of first-line hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib and PD-(L)1 inhibitors (HLP) compared to SC combined with PD-(L)1 inhibitors (SCP) or SC alone in treating unresectable ICC. METHODS: Patient with unresectable ICC who underwent first-line treatment with HLP, SCP or SC from January 2016 to December 2022 were retrospectively analyzed. The study evaluated and compared efficacy and safety outcomes across the three treatment groups. RESULTS: The study comprised 42, 49, and 50 patients in the HLP, SCP, and SC groups, respectively. Median progression-free survival (PFS) times were 30.0, 10.2, and 6.5 months for HLP, SCP, and SC groups. While the SC group had a median overall survival (OS) time of 21.8 months, the HLP and SCP groups hadn't reached median OS. The HLP group demonstrated significantly superior PFS (p < 0.001) and OS (p = 0.014) compared to the others. Moreover, the HLP group exhibited the highest objective response rate (ORR) at 50.0% and the highest disease control rate (DCR) at 88.1%, surpassing the SC group (ORR, 6.0%; DCR, 52.0%) and SCP group (ORR, 18.4%; DCR, 73.5%) (p < 0.05). Generally, the HLP group reported fewer grades 3-4 adverse events (AEs) compared with others. CONCLUSION: In contrast to systemic chemotherapy with or without PD-(L)1 inhibitors, the triple combination therapy incorporating HAIC, lenvatinib, and PD-(L)1 inhibitors showcased favorable survival benefits and manageable adverse events for unresectable ICC.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Infusiones Intraarteriales , Compuestos de Fenilurea , Quinolinas , Humanos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Femenino , Masculino , Quinolinas/administración & dosificación , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Anciano de 80 o más Años , Arteria HepáticaRESUMEN
Background: The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Materials and methods: Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). Results: A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7-30.1) and the median PFS was 11.9 months (95% CI, 6.7-17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Conclusion: Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Colangiocarcinoma , Compuestos de Fenilurea , Quinolinas , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Persona de Mediana Edad , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Anciano , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/mortalidad , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/mortalidad , Infusiones Intraarteriales , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Leucovorina/efectos adversos , Adulto , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Resultado del Tratamiento , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/efectos adversos , Arteria Hepática , Estudios RetrospectivosRESUMEN
Background: Microvascular invasion (MVI) is a significant pathological feature in hepatocellular carcinoma (HCC), adjuvant hepatic arterial infusion chemotherapy (a-HAIC) and adjuvant transcatheter arterial chemoembolization (a-TACE), are commonly used for HCC patients with MVI. This study aims to evaluate the efficacies of two adjuvant therapies after surgical treatment for HCC, compare them, and identify the significant factors. Methods: Clinical data from two randomized controlled trials involving HCC patients with MVI after surgical treatment were retrospectively reviewed. Propensity score matching (PSM) analysis was performed to balance baseline differences between patients who received a-HAIC or a-TACE, and control groups who underwent hepatectomy alone. Disease-free survival (DFS) and overall survival (OS) rates were compared. Results: In total of 549 patients were collected from two randomized controlled trials. Using the PSM and Kaplan-Meier method, the median DFS of the a-HAIC, a-TACE, and control groups was 63.2, 21.7, and 11.2 months (P<0.05). The a-HAIC group show significantly better 1-, 3-, and 5-year OS rates compared to the a-TACE and control groups (96.3%, 80.0%, 72.8% vs 84.4%, 57.0%, 29.8% vs 84.5%, 62.8%, 53.4%, P<0.05). But the OS rates of a-TACE and control groups showed no significant difference (P=0.279). Multivariate analysis identified a-HAIC (HR=0.449, P=0.000) and a-TACE (HR=0.633, P=0.007) as independent protective factors. For OS, a-HAIC (HR=0.388, P=0.003) was identified as an independent protective factor, too. Conclusion: Compared to a-TACE and the control group, a-HAIC demonstrated greater benefits in preventing tumor recurrence and improving survival in HCC patients with MVI.
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BACKGROUND: Lenvatinib plus programmed death-1 (PD-1) inhibitors (LEN-P) have been recommended in China for patients with advanced hepatocellular carcinoma (HCC). However, they provide limited survival benefits to patients with extrahepatic metastases. We aimed to investigate whether combining hepatic arterial infusion chemotherapy (HAIC) with LEN-P could improve its efficacy. MATERIALS AND METHODS: This multicenter cohort study included patients with HCC extrahepatic metastases who received HAIC combined with LEN-P (HAIC-LEN-P group, n =127) or LEN-P alone ( n =103) as the primary systemic treatment between January 2019 and December 2022. Baseline data were balanced using a one-to-one propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). RESULTS: After PSM, the HAIC-LEN-P group significantly extended the median overall survival (mOS) and median progression-free survival (mPFS), compared with the LEN-P group (mOS: 27.0 months vs. 9.0 months, P <0.001; mPFS: 8.0 months vs. 3.0 months, P =0.001). After IPTW, the mOS [hazard ratio (HR)=0.384, P <0.001] and mPFS (HR=0.507, P <0.001) were significantly higher in the HAIC-LEN-P group than in the LEN-P group. The HAIC-LEN-P group's objective response rate was twice as high as that of the LEN-P group (PSM cohort: 67.3% vs. 29.1%, P <0.001; IPTW cohort: 66.1% vs. 27.8%, P <0.001). Moreover, the HAIC-LEN-P group exhibited no noticeable increase in the percentages of grade 3 and 4 adverse events compared with the LEN-P group ( P >0.05). CONCLUSION: HAIC can improve the efficacy of LEN-P in patients with HCC extrahepatic metastases and may be an alternative treatment for advanced HCC management.
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Carcinoma Hepatocelular , Infusiones Intraarteriales , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Masculino , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Femenino , Persona de Mediana Edad , Quinolinas/administración & dosificación , Anciano , Compuestos de Fenilurea/administración & dosificación , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , China , Arteria Hepática , Adulto , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Estudios de CohortesRESUMEN
PURPOSE: Vessels encapsulating tumor clusters (VETC) is a novel vascular pattern structurally and functionally distinct from microvascular invasion (MVI) in hepatocellular carcinoma (HCC). This study aims to explore the prognostic value of VETC in patients receiving hepatic arterial infusion chemotherapy (HAIC) for unresectable HCC. METHODS: From January 2016 to December 2017, 145 patients receiving HAIC as the initial treatment for unresectable HCC were enrolled and stratified into two groups according to their VETC status. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were evaluated. RESULTS: The patients were divided into two groups: VETC+ (n = 31, 21.8%) and VETC- (n = 114, 78.2%). The patients in the VETC+ group had worse ORR and DCR than those in the VETC- group (RECIST: ORR: 25.8% vs. 47.4%, P = 0.031; DCR: 56.1% vs. 76.3%, P = 0.007; mRECIST: ORR: 41.0% vs. 52.6%, P = 0.008; DCR: 56.1% vs. 76.3%, P = 0.007). Patients with VETC+ had significantly shorter OS and PFS than those with VETC- (median OS: 10.2 vs. 21.6 months, P < 0.001; median PFS: 3.3 vs. 7.2 months, P < 0.001). Multivariate analysis revealed VETC status as an independent prognostic factor for OS (HR: 2.40; 95% CI: 1.46-3.94; P = 0.001) and PFS (HR: 1.97; 95% CI: 1.20-3.22; P = 0.007). CONCLUSION: VETC status correlates remarkably well with the tumor response and long-term survival in patients undergoing HAIC. It may be a promising efficacy predictor and help identify patients who will benefit from HAIC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Resultado del Tratamiento , Infusiones Intraarteriales , PronósticoRESUMEN
BACKGROUND: Lack of opportunity for radical surgery and postoperative tumor recurrence are challenges for surgeons and hepatocellular carcinoma (HCC) patients. This study aimed to develop nomograms to predict recurrence risk and recurrence-free survival (RFS) probability after conversion hepatectomy for patients previously receiving transarterial interventional therapy. METHODS: In total, 261 HCC patients who underwent conversion liver resection and previously received transarterial interventional therapy were retrospectively enrolled. Nomograms to predict recurrence risk and RFS were developed, with discriminative ability and calibration evaluated by C-statistics, calibration plots, and the Area under the Receiver Operator Characteristic (AUROC) curves. RESULTS: Univariate/multivariable logistic regression and Cox regression analyses were used to identify predictive factors for recurrence risk and RFS, respectively. The following factors were selected as predictive of recurrence: age, tumor number, microvascular invasion (MVI) grade, preoperative alpha-fetoprotein (AFP), preoperative carbohydrate antigen 19-9 (CA19-9), and Eastern Cooperative Oncology Group performance score (ECOG PS). Similarly, age, tumor number, postoperative AFP, postoperative protein induced by vitamin K absence or antagonist-II (PIVKA-II), and ECOG PS were incorporated for the prediction of RFS. The discriminative ability and calibration of the nomograms revealed good predictive ability. Calibration plots showed good agreement between the nomogram predictions of recurrence and RFS and the actual observations. CONCLUSIONS: A pair of reliable nomograms was developed to predict recurrence and RFS in HCC patients after conversion resection who previously received transarterial interventional therapy. These predictive models can be used as guidance for clinicians to help with treatment strategies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirugía , Hepatectomía , Nomogramas , alfa-Fetoproteínas , Estudios Retrospectivos , Neoplasias Hepáticas/cirugíaRESUMEN
BACKGROUND: The treatment efficacy of transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) for huge single hepatocellular carcinoma (HCC) has not been fully documented. The aim of this study was to compare TACE and HAIC for patients with solitary nodular HCCs greater than or equal to 10 cm without vascular invasion and metastasis. METHODS: From July 2015 to June 2020, a total of 147 patients with single nodular HCC greater than or equal to 10 cm without vascular invasion and metastasis receiving TACE ( n =77) or HAIC ( n =70) were retrospectively enrolled. The tumor response, overall survival (OS), and progression-free survival (PFS) were investigated and compared. The treatment outcome of two transarterial interventional therapies was explored. RESULTS: The objective response rate and PFS were higher in patients who received HAIC than in those who received TACE (44.3 vs. 10.4% and 8.9 vs. 4.2 months, respectively; P =0.001 and P =0.030), whereas the disease control rate and OS were not significantly different (92.9 vs. 84.4% and 21.3 vs. 26.6 months, respectively; P =0.798 and P =0.749). The decreased levels of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in patients treated with HAIC were significantly higher than those treated with TACE ( P =0.038 and P <0.001). Multivariable analysis showed that the aspartate aminotransferase/platelet ratio index was associated with OS, whereas albumin-bilirubin grade and PIVKA-II were associated with PFS. CONCLUSIONS: HAIC has better potential than TACE to control local tumors for huge single HCC without vascular invasion and metastasis and thus may be the preferred conversion therapy for these tumors.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Infusiones Intraarteriales , Resultado del TratamientoRESUMEN
Background: Hepatocellular carcinoma (HCC) is one of the most malignant cancers and has a poor prognosis. The immune microenvironment is closely related to the drug sensitivity of a tumor. Necroptosis was reported to be a key factor for HCC. The prognostic value of necroptosis-related genes and their association with the tumor immune microenvironment are still unknown. Methods: Necroptosis-related genes that could comprise a signature for predicting the prognosis of HCC cases were identified using univariate analysis and least absolute shrinkage and selection operator Cox regression analysis. The association between this prognosis prediction signature and HCC immune microenvironment was analyzed. The immunological activities and drug sensitivities were compared between different risk score groups identified using the prognosis prediction signature. The expression levels of the five genes comprising the signature were validated using RT-qPCR. Results: A prognosis prediction signature consisting of five necroptosis-related genes was constructed and validated. Its risk score was = (0.1634 × PGAM5 expression) + (0.0134 × CXCL1 expression) - (0.1007 × ALDH2 expression) + (0.2351 × EZH2 expression) - (0.0564 × NDRG2 expression). The signature was found to be significantly associated with the infiltration of B cells, CD4+ T cells, neutrophils, macrophages, and myeloid dendritic cells into the HCC immune microenvironment. The number of infiltrating immune cells and the expression levels of immune checkpoints in the immune microenvironment of high-risk score patients were higher. Sorafenib and immune checkpoint blockade were determined to be ideally suited for treating high-risk score patients and low-risk score patients, respectively. Finally, RT-qPCR results confirmed that the expression levels of EZH2, NDRG2, and ALDH2 were significantly down-regulated in HuH7 and HepG2 cells compared to those in LO2 cells. Conclusion: The necroptosis-related gene signature developed herein can classify patients with HCC according to prognosis risk well and is associated with infiltration of immune cells into the tumor immune microenvironment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Necroptosis , Pronóstico , Biología Computacional , Microambiente Tumoral/genética , Proteínas Supresoras de Tumor , Aldehído Deshidrogenasa MitocondrialRESUMEN
BACKGROUND: The level of Creactive protein (CRP) and alphafetoprotein (AFP) in immunotherapy (CRAFITY) score was associated with the prognosis of hepatocellular carcinoma (HCC) patients treated with immunotherapy. Based on the CRAFITY score, this study aimed to investigate the efficacy and safety of locoregional-immunotherapy for treating HCC patients. METHODS: HCC patients who received locoregional-immunotherapy were consecutively recruited at Sun Yat-sen University Cancer Center in 2019. CRAFITY 0 score was defined as the AFP level below 100 ng/ml and a CRP level of less than 1 mg/dl, CRAFITY 1 score was defined as the AFP level of at least 100 ng/ml or the CRP level of at least 1 mg/dl, and CRAFITY 2 score was defined as both the AFP level over 100 ng/ml and the CRP level of more than 1 mg/dl. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The second outcomes were tumor response rate and treatment-related adverse events (AEs). RESULTS: The median PFS for HCC patients with the CRAFITY 0 score was not estimable. The PFS was 11.0 months [95% confidence interval (CI) 7.2-14.9] and 6.0 months (95% CI 4.2-7.8) for patients with CRAFITY 1 and 2 scores, respectively, with a significant difference between the two groups (p < 0.001). HCC patients with CRAFITY 0, 1, and 2 scores had 3 years OS rates of 63.8%, 60.8%, and 32.1%, respectively, with statistical differences among the three groups (p < 0.001). Patients with the CRAFITY 2 score were more likely to experience fever than those with other scores (p < 0.05). A greater CRAFITY score was correlated with a higher incidence of grade 3 and above liver injury (p < 0.01). CONCLUSIONS: The CRAFITY score is a superior predictor of prognosis and treatment-related AEs in HCC patients treated with locoregional-immunotherapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , alfa-Fetoproteínas , Neoplasias Hepáticas/patología , Pronóstico , Inmunoterapia/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: This study aimed to establish and validate nomograms to predict the probability of recurrence and recurrence-free survival (RFS) in patients with hepatocellular carcinoma (HCC) after conversion hepatectomy based on hepatic arterial infusion chemotherapy (HAIC). METHODS: Nomograms were constructed using data from a retrospective study of 214 consecutive patients treated with HAIC-based conversion liver resection between January 2016 and July 2020. Nomograms predicting the probability of tumor recurrence and RFS were established based on predictors selected by multivariate regression analysis. Predictive accuracy and discriminative ability of the nomogram were examined. Bootstrap method was used for internal validation. External validation was performed using cohorts ( n =128) from three other centers. RESULTS: Recurrence rates in the primary and external validation cohorts were 63.6 and 45.3%, respectively. Nomograms incorporating clinicopathological features of tumor recurrence and RFS were generated. Concordance index (C-index) scores of the nomograms for predicting recurrence probability and RFS were 0.822 (95% CI, 0.703-0.858) and 0.769 (95% CI, 0.731-0.814) in the primary cohort, and 0.802 (95% CI, 0.726-0.878) and 0.777 (95% CI, 0.719-0.835) in the external validation cohort, respectively. Calibration curves indicated good agreement between the nomograms and actual observations. Moreover, the nomograms outperformed the commonly used staging systems. Patients with low risk, stratified by the median nomogram scores had better RFS (low risk vs. high risk, 36.5 vs. 5.2 months, P <0.001). The external validation cohort supported these findings. CONCLUSIONS: The presented nomograms showed favorable accuracy for predicting recurrence probability and RFS in HCC patients treated with HAIC-based conversion hepatectomy. Identifying risk factors and estimating tumor recurrence may help clinicians in the decision-making process regarding adjuvant therapies for patients with HCC, which eventually achieves better oncological outcomes.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Nomogramas , Estudios Retrospectivos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Hepatectomía/métodos , Factores de RiesgoAsunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombosis de la Vena , Humanos , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Sorafenib/uso terapéutico , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Vena Porta/patología , Trombosis de la Vena/complicaciones , Trombosis de la Vena/tratamiento farmacológico , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica , Antineoplásicos/uso terapéuticoRESUMEN
Image-guided local thermal ablation (LTA) plays an important role in the treatment of hepatocellular carcinoma (HCC), especially in patients with HCC who are not suitable for hepatectomy. Radiofrequency ablation (RFA) and microwave ablation (MWA) are the most widely used LTA clinically. Radiofrequency ablation can achieve the best result; that is, a similar therapeutic effect as hepatectomy if the tumor ≤3 cm, while MWA can effectively ablate tumors ≤5 cm. Local thermal ablation has an advantage over liver resection in terms of minimally invasive surgery and can achieve a comparable prognosis and efficacy to liver resection. For borderline liver function, selecting LTA as the first-line therapy may bring more benefits to patients with cirrhosis background. In addition, a combination of multiple therapies for HCC is a good choice, such as LTA combined with transcatheter arterial chemoembolization (TACE), which can achieve a better prognosis than single therapy for larger tumors. For patients who are awaiting liver transplantation, LTA is a good choice. The main problem of LTA needed to be solved is to prevent the local tumor recurrence after ablation in patients with HCC.
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Carcinoma Hepatocelular , Ablación por Catéter , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Terapia Combinada , Pronóstico , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Resultado del Tratamiento , Fluorouracilo/efectos adversos , Infusiones Intraarteriales , Adyuvantes Inmunológicos/uso terapéuticoRESUMEN
Purpose:Sorafenib is recommended for patients with hepatocellular carcinoma refractory to transarterial chemoembolization but with unsatisfactory overall survival and tumor response rate. Previously published studies showed hepatic arterial infusion chemotherapy of oxaliplatin, fluorouracil, and leucovorin was an effective and safe treatment. The aims of this study were to compare the clinical efficacy and safety of oxaliplatin, fluorouracil, and leucovorin-based hepatic arterial infusion chemotherapy with sorafenib in patients with hepatocellular carcinoma refractory to transarterial chemoembolization. Methods: This was a retrospective subgroup analysis of 2 prospective clinical trials, including 114 patients with hepatocellular carcinoma who were confirmed to be transarterial chemoembolization refractoriness. Of these, 55 patients received hepatic arterial infusion chemotherapy of fluorouracil, and leucovorin (FOLFOX-HAIC group, oxaliplatin 85 or 130â mg/m2, leucovorin 400â mg/m2, fluorouracil bolus 400â mg/m2, and 2400â mg/m2 for 23 or 46â h, every 3 weeks), and 59 patients were treated with sorafenib (sorafenib group, 400â mg sorafenib twice daily). Overall survival, progression-free survival, objective response rate, and treatment-related adverse events were compared between the 2 groups. Results: The FOLFOX-HAIC group showed a longer overall survival (17.1 months [95% confidence interval 13.4-20.8] vs 9.1 months [95% confidence interval 7.5-10.6]; hazard ratio 0.35 [95% confidence interval 0.23-0.53]; P < .001), a higher objective response rate (RECIST: 18 [32.7%] vs 1 [1.7%], P < .001), and a longer progression-free survival (7.6 months [95% confidence interval 5.6-9.6] vs 3.9 months [95% confidence interval 2.3-5.4]; hazard ratio 0.49 [95% confidence interval 0.33-0.72]; P < .001) than the sorafenib group. The safety results suggested that both oxaliplatin, fluorouracil, and leucovorin-based hepatic arterial infusion chemotherapy and sorafenib had acceptable treatment-related toxic effects. No significant difference was observed in the overall occurrence of any grade, grade 3/4, or serious adverse events between the 2 groups. Conclusions: Oxaliplatin, fluorouracil, and leucovorin-based hepatic arterial infusion chemotherapy might be a better choice than sorafenib for patients with hepatocellular carcinoma refractory to transarterial chemoembolization.