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Immune checkpoint inhibitors, widely used in the treatment of malignancies, can improve the prognosis of patients, while it also can induce various immune-related adverse events, and type 1 diabetes induced by anti-programmed cell death protein-1 is a rare but severe complication. Here we reported a case of type 1 diabetes induced by anti-PD-1 which was to treat intrahepatic cholangiocarcinoma. The case was a 61-year-old female who developed diabetes and ketoacidosis symptoms at the 16th week after anti-PD-1 therapy. Her blood glucose was 30.32 mmol/L, HBA1c was 8.10%, and C-peptide was <0.10 ng/ml. The patient was diagnosed as fulminant type 1 diabetes mellitus complicated with ketoacidosis induced by anti-PD-1, and was treated with massive fluid rehydration, intravenous infusion of insulin and correction of acid-base electrolyte disorder. Hepatectomy was performed after stabilization, and the patient was treated with long-term insulin. Through the case report and literature review, this study aims to improve oncologists' understanding of anti-PD-1 induced type 1 diabetes, so as to make early diagnosis and treatment of the complications and ensure medical safety.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Diabetes Mellitus Tipo 1 , Insulinas , Cetosis , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos , Muerte Celular , Colangiocarcinoma/complicaciones , Colangiocarcinoma/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/diagnóstico , Femenino , Humanos , Insulinas/efectos adversos , Cetosis/complicaciones , Persona de Mediana EdadRESUMEN
Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1ß derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1ß blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy. SIGNIFICANCE: Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Hepáticas/terapia , Macrófagos/metabolismo , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Serina , Treonina , Microambiente Tumoral , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
According to the EPOC study, chemotherapy could improve 5-year disease-free survival of stage IV colon cancer patients by 8.1%. However, more molecular biomarkers are required to identify patients who need neoadjuvant chemotherapy. DENND2D expression was evaluated by immunohistochemistry in 181 stage IV colon cancer patients. The prognosis was better for patients with DENND2D expression than patients without DENND2D expression (5-year overall survival [OS]: 42% vs. 12%, p = 0.038; 5-year disease-free survival: 20% vs. 10%, p = 0.001). Subgroup analysis of the DENND2D-negative group showed that patients treated with neoadjuvant chemotherapy achieved longer OS than patients without neoadjuvant chemotherapy (RR = 0.179; 95% CI = 0.054-0.598; p = 0.003). DENND2D suppressed CRC proliferation in vitro and in vivo. Downregulation of DENND2D also promoted metastasis to distant organs in vivo. Mechanistically, DENND2D suppressed the MAPK pathway in CRC. Colon cancer patients who were DENND2D negative always showed a worse prognosis and were more likely to benefit from neoadjuvant chemotherapy. DENND2D may be a new prognostic factor and a predictor of the need for neoadjuvant chemotherapy in stage IV colon cancer.
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Neoplasias del Colon , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Supervivencia sin Enfermedad , Humanos , Inmunohistoquímica , Estadificación de Neoplasias , Estudios RetrospectivosRESUMEN
BACKGROUND: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line choices regarding the treatment of chronic hepatits B. The impact of the two antiviral agents on prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative liver resection remains to be explored. We aimed to assess the effect of antiviral therapy with ETV or TDF after curative resection on the prognosis of patients with HBV-related HCC. METHODS: A total of 1173 consecutive patients who were treated with ETV or TDF after curative liver resection for HCC were enrolled in the study. HCC recurrence, overall survival, postoperative liver function reserve, and early virologic (VR) and biochemical responses (BR) of patients were compared between the ETV and TDF groups by propensity score matching (PSM) from the date of liver resection for HCC. RESULTS: No difference was observed with recurrence-free survival between TDF and ETV in the PSM cohort (hazard ratio [HR], 0.91; 95% confidence interval [CI] 0.70-1.17; P = 0.45). No difference was observed with early VR and BR between TDF and ETV in the PSM cohort. Compared with ETV, TDF therapy was associated with significantly better protection of liver function and higher overall survival rates in the PSM cohort (HR, 0.37; 95% CI 0.20-0.71; P = 0.002). After PSM, 69 (40.8%) patients in the ETV group and 63 (57.3%) patients in the TDF group had single tumor recurrence, while the TDF group had significantly more patients with single tumor recurrence in the PSM cohort (P = 0.007). CONCLUSIONS: For patients who underwent curative resection for HBV-related HCC, TDF treatment had a significantly better overall survival and better protection of liver function, but no difference in the incidences of HCC recurrence than ETV treatment.
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Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/patología , Guanina/análogos & derivados , Virus de la Hepatitis B , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/etiología , Pronóstico , Estudios Retrospectivos , Tenofovir/uso terapéutico , Resultado del TratamientoRESUMEN
The population of patients with huge hepatocellular carcinoma (H-HCC diameter > 10.0 cm) is an odd group that is not well adjudicated in the current staging systems, whose prognosis after curative resection varies. We aimed to develop novel models to predict the long-term outcomes of patients with H-HCC without portal vein tumor thrombus after hepatectomy. There were 1076 H-HCC patients enrolled who underwent curative liver resection in five institutions in China. In total, 670 patients were recruited from our center and randomly divided into the training cohort (n = 502) and internal validation (n = 168) cohorts. Additionally, 406 patients selected from other four centers as the external validation cohort. Novel models were constructed based on independent preoperative and postoperative predictors of postsurgical recurrence (PSR) and postsurgical mortality (PSM) determined in multivariable cox regression analysis. The predictive accuracy and discriminative ability of the model were measured using Harrell's concordance index (C index) and calibration curve and compared with five conventional HCC staging systems. PSR model and PSM model were constructed based on tumor number, microscopic vascular invasion, tumor differentiation, preoperative alpha-fetoprotein level, albumin-bilirubin grade, liver segment invasion, neutrophil-to-lymphocyte ratio or platelet-to-neutrophil ratio, and surgical margin or intraoperative blood transfusion. The C-indexes were 0.84 (95% CI, 0.78-0.90) and 0.85 (95% CI, 0.78-0.91) for the PSR and PSM models, respectively, which were substantially higher than those of the five conventional HCC staging systems (0.63-0.75 for PSR; 0.66-0.77 for PSM). The two novel models achieved more accurate prognostic predictions of PSR and PSM for H-HCC patients after curative liver resection.
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Carcinoma Hepatocelular/patología , Hepatectomía/mortalidad , Neoplasias Hepáticas/patología , Modelos Estadísticos , Recurrencia Local de Neoplasia/patología , Nomogramas , Carcinoma Hepatocelular/cirugía , China , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
AIM: Adherence to dietary recommendations has been linked to a reduced risk of developing hepatocellular carcinoma (HCC) and dying of chronic liver disease. However, its role in the prognosis of HCC is still unclear. We prospectively investigated the association of two dietary quality indices, the Chinese Healthy Eating Index (CHEI) and the Healthy Eating Index-2015 (HEI-2015), with all-cause and HCC-specific mortality in a large prospective cohort of HCC survivors. METHODS: We included 887 patients with newly diagnosed, previously untreated HCC enrolled in the Guangdong Liver Cancer Cohort (GLCC) between September 2013 and April 2017 in the analysis. CHEI and HEI-2015 scores were calculated based on the dietary intake in the year before diagnosis of HCC. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for each index. RESULTS: During a median follow-up of 797 days, 389 deaths were identified, including 347 from HCC. Higher CHEI scores, reflecting favorable adherence to the 2016 Dietary Guidelines for Chinese, were associated with a lower risk of all-cause mortality (T3 vs. T1 : HR = 0.75, 95% CI: 0.58-0.98) and HCC-specific mortality (T3 vs. T1 : HR = 0.74, 95% CI: 0.56-0.98). Non-significant, inverse associations of HEI-2015 score with all-cause mortality (T3 vs. T1 : HR = 0.86, 95% CI: 0.67-1.11) and HCC-specific mortality (T3 vs. T1 : HR = 0.93, 95% CI: 0.71-1.21) were suggested. CONCLUSIONS: Our findings suggest that better adherence to the 2016 Dietary Guidelines for Chinese may reduce the risk of all-cause and HCC-specific mortality in patients with HCC.
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BACKGROUND: Hepatocellular carcinoma (HCC) is a major health problem and a primary cause of cancer-related death worldwide. Although great advances have achieved recently by large-scale high-throughput analysis, the precise molecular mechanism underlying HCC progression remains to be clearly elucidated. We investigated the relationship between Tescalcin (TESC), a candidate oncogene, and clinicopathological features of HCC patients and explored the role of TECS in HCC development. METHODS: To identify new genes involved in HCC development, we analyzed The Cancer Genome Atlas liver cancer database, and TESC was selected for further investigation. HCC tissue microarray analysis for TESC and its association with clinicopathological features were performed to investigate its clinical significance. TESC was knocked down by using short-hairpin RNAs. Cell proliferation was analyzed by WST-1 assay and cell counting. Cell apoptosis was tested by fluorescence-activated cell sorting. A subcutaneous xenograft tumor model in nude mice was established to determine the in vivo function of TESC. Affymetrix microarray was used to identify its molecular mechanism. RESULTS: TESC was significantly increased in HCC tissues compared with the adjacent normal liver tissues. High expression of TESC was detected in 61 of 172 HCC patients by tissue microarray. Large tumor (> 5 cm) and elevated total bilirubin were associated with high TESC expression (both P < 0.050). In multivariate analysis, TESC was identified as an independent prognostic factor for short overall survival of HCC patients. TESC knockdown impaired HCC cell growth in vitro and in vivo. TESC knockdown significantly increased cell apoptosis in HCC cell lines. Furthermore, Affymetrix microarray analysis revealed that TESC knockdown inhibited tumor proliferation-related pathways while activated cell death-related pathways. CONCLUSION: TESC was identified as an independent prognostic factor for short overall survival of HCC patients, and was critical for HCC cell proliferation and survival.
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Proteínas de Unión al Calcio/genética , Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Animales , Apoptosis , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Proliferación Celular , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , PronósticoRESUMEN
Skin toxicity, especially hand-foot syndrome (HFS), is one of the most common sorafenib-induced adverse events (AEs) in hepatocellular carcinoma (HCC) patients, leading to treatment interruption and failure. Mucocutaneous inflammation may cause HFS; therefore, we investigated whether celecoxib can alleviate HFS, improve patients' quality of life and increase survival when administered in conjunction with active therapy. Our randomized, open-label study prospectively enrolled 116 advanced HCC patients receiving sorafenib as targeted therapy from July 2015 to July 2016. All patients were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib with or without celecoxib. Sorafenib-related AEs were recorded, Survival was compared between the two groups. Compared to the Sorafenib group, the SoraCele group had lower incidence rates of ≥ grade 2 and grade 3 HFS (63.8% vs 29.3%, P < 0.001; 19.0% vs 3.4%, P = 0.008, respectively), hair loss, rash and abdominal pain. Kaplan-Meier analysis revealed a lower risk of ≥ grade 2 HFS (HR, 0.384; P = 0.002) and a lower dose reduction/interruption rate (46.6% to 15.5%, P < 0.001) in the SoraCele group. Cox proportional hazards regression analysis demonstrated that celecoxib was the only independent predictive factor of developing ≥ grade 2 HFS (HR, 0.414; P = 0.004). Longer progression-free survival (PFS) was also observed in the SoraCele group (P = 0.039), although overall survival was not prolonged (P = 0.305). These results suggest that sorafenib + Celecoxib administration alleviated sorafenib-related skin toxicity. Longer PFS was achieved in clinical practice, although overall survival was not prolonged (ClinicalTrials.gov: NCT02961998).
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Hepatocellular carcinoma (HCC) metastasis is largely responsible for HCC-associated recurrence and mortality. We aimed to identify metastasis-related long non-coding RNAs (lncRNAs) to understand the molecular mechanism of HCC metastasis. We first identified that miR-1258 was downregulated in HCC tissues both in The Cancer Genome Atlas (TCGA) and Sun Yat-sen University Cancer Center (SYSUCC) dataset. MiR-1258 expression negatively correlated with recurrence-free survival and overall survival of HCC patients. MiR-1258 overexpression inhibited migration and invasion of HCC cells both in vitro and in vivo, whereas miR-1258 downregulation promoted cell metastasis. Luciferase assays verified direct binding of miR-1258 to Smad2 and Smad3, thereby attenuating TGF-ß/Smad signaling. We further established that lncRNA LINC01278 was a negative regulator of miR-1258. In vivo and in vitro assays demonstrated that LINC01278-mediated HCC metastasis was dependent on miR-1258 expression. Furthermore, miR-1258 downregulation in turn increased LINC01278 expression. We also observed that TCF-4 could bind to the LINC01278 promoter site. In addition, LINC01278 downregulation decreased migration and invasion of HCC cells induced by ß-catenin and TGF-ß1 both in vitro and in vivo. We uncovered a novel mechanism for ß-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 feedback loop activation in HCC metastasis, and the study indicated that LINC01278 could serve as a therapeutic target for HCC metastasis.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Metástasis de la Neoplasia/patología , ARN Largo no Codificante/genética , Vía de Señalización Wnt/fisiología , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Humanos , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Trasplante de Neoplasias , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Transcripción 4/genética , Factor de Transcripción 4/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Trasplante Heterólogo , Proteína Wnt1/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND: Excessive intraoperative hemorrhage is a critical factor of poor prognoses after hepatectomy. Low central venous pressure during parenchymal transection is recognized to effectively reduce intraoperative hemorrhage in open procedures. However, the role of controlled low central venous pressure in laparoscopic hepatectomy is still controversial. METHODS: In the present randomized clinical trial, we set up a standard boundary of low central venous pressure according to our Pilot Study, then enrolled patients scheduled for elective laparoscopic hepatectomy and allocated them randomly to a group undergoing central venous pressure reduction by anesthesiologic interventions or a control group. The primary efficacy endpoint was total intraoperative blood loss and perioperative adverse events. Analyses were performed following the intention-to-treat principle, and patients and surgeons were blinded (ClinicalTrials.gov, Number: NCT03422913). RESULTS: Between January 2017 and October 2018, 146 out of 469 patients were randomized and eligible for inclusion in the final analyses. Based on the retrospective training cohort, we set a central venous pressure of 5 cm H2O as a cutoff value (standard low central venous pressure). Compared with patients in the control group, those in the controlled low central venous pressure group had a significantly lower central venous pressure during resection (4.83 ± 3.41 cm H2O vs 9.26 ± 3.38 cm H2O; P < .001) and significantly reduced total intraoperative blood loss (188.00 ± 162.00 mL vs 346.00 ± 336.00 mL; P < .001). The perioperative adverse events were comparable in both study groups (P = .313). CONCLUSION: The safety and efficacy of controlled low central venous pressure were demonstrated in complex laparoscopic hepatectomy for the first time by our study, and this technique is recommended to be applied routinely in laparoscopic hepatectomy.
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Pérdida de Sangre Quirúrgica/prevención & control , Presión Venosa Central , Hepatectomía , Laparoscopía , Vasoconstrictores/uso terapéutico , Adulto , Aspartato Aminotransferasas/sangre , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Método Doble Ciego , Procedimientos Quirúrgicos Electivos , Femenino , Hemoglobinas/análisis , Hemorragia/prevención & control , Humanos , Cuidados Intraoperatorios , Complicaciones Intraoperatorias/prevención & control , Masculino , Persona de Mediana Edad , Posicionamiento del PacienteRESUMEN
BACKGROUND AND AIMS: Free and bioavailable 25-hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival. APPROACH AND RESULTS: We included 1,031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum-free 25OHD levels were measured using a two-step enzyme-linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer-specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C-reactive protein, Barcelona Clinic Liver Cancer stage, and cancer treatment. The multivariable-adjusted HRs in the highest versus lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend = 0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend = 0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS. CONCLUSIONS: Higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population-based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis.
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Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Vitamina D/análogos & derivados , Adulto , Anciano , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Vitamina D/sangreRESUMEN
BACKGROUND: Both radiofrequency ablation (RFA) and laparoscopic hepatectomy (LH) are minimally invasive approach for hepatocellular carcinoma (HCC) at early stage. This study aimed to compare the efficacy of RFA and LH for treating HCC with a large cohort. METHODS: From March 2014 to July 2016, 477 patients who underwent RFA (nâ¯=â¯314) or LH (nâ¯=â¯163) for HCC tumors meeting the criteria were included. Overall survival (OS) and recurrence-free survival (RFS) were compared. Propensity score matching (PSM) was performed to balance for the factors that may affect the choice of treatment. RESULTS: Collectively, the 1-, 2- and 3-year OS rates were significantly greater after LH than RFA, as well the corresponding RFS rates, before and after PSM by 2:1. However, the RFA group had fewer major complications (P=0.004), shorter postoperative stays (P=0.023) and lower hospital charges (P<0.001) than the LH group. In the subgroup analysis, RFA demonstrated comparable RFS in treating less than 3â¯cm tumor (P=0.22) located in noncentral bisection (SII, SIII, SVI, SVII) and tumor between 3â¯cm and 5â¯cmâ¯(P=0.07) located in central bisections (SIV, SV, SVIII). The female, HBV infection, and RFA are factors of worse OS, and the latter two factors also indicated higher RFS. CONCLUSIONS: Though, LH possessed superior intrahepatic control rate than RFA in most condition of tumor smaller than 5â¯cm, the RFA could be an optimal approach achieved comparable outcomes in patients with centrally located HCC, with fewer major complications, shorter postoperative stays and lower hospital charges.
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Carcinoma Hepatocelular/cirugía , Ablación por Catéter/métodos , Hepatectomía/métodos , Laparoscopía/métodos , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Cirugía Asistida por Computador , Resultado del Tratamiento , Ultrasonografía , Adulto JovenRESUMEN
BACKGROUND: Brucea javanica oil emulsion (BJOE) is a traditional Chinese medicine with recognized antitumor effects in various cancers, but the effects and mechanisms of action of BJOE against cervical cancer need to be further studied. Herein, we investigated the effects of BJOE on the human papillomavirus (HPV)16-expressing human cervical cancer line SiHa and explored the possible underlying mechanisms. METHODS: Cell viability and apoptosis of SiHa cells treated with BJOE were assessed by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and annexin V-fluorescein isothiocyanate (annexin V-FITC)/propidium iodide (PI) staining assays, respectively. Quantitative reverse transcription-polymerase chain reaction and Western blot analyses were performed to assess the expression levels of the E6 oncogene and key signaling molecules involved in apoptosis. A subcutaneous xenograft nude mouse model bearing SiHa cells was established and treated with BJOE through intraperitoneal injection. Tumor growth was monitored, and immunohistochemical analysis was performed. RESULTS: BJOE exhibited substantial cytotoxic effects in SiHa cells and significantly suppressed tumor growth in SiHa cell xenografts. BJOE inhibited E6 expression and induced apoptosis in vitro in a dose-dependent manner. BJOE-induced apoptosis was characterized by activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). Moreover, BJOE induced phosphorylation of extracellular-signal regulated kinase (ERK) and inhibited the expression of nuclear factor-kappa B (NF-κB). CONCLUSIONS: BJOE exerts a strong tumor-suppressive effect in SiHa cells in vitro and in vivo, likely caused by E6 inhibition and apoptosis induction achieved through the ERK/mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, supporting potential use of BJOE in cervical cancer treatment.
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BACKGROUND: Accumulating studies suggest that targeting epigenetic modifications could improve the efficacy of tumor immunotherapy; however, the mechanisms underlying this phenomenon remain largely unknown. Here, we investigated the ability of the epigenetic modifier, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), to regulate the expression of immune checkpoint inhibitor, programmed death-1 ligand 1 (PD-L1) in hepatocellular carcinoma (HCC). METHODS: Immunohistochemistry and multiplex immunofluorescence staining were performed to analyze the expression and correlation of EZH2 and PD-L1 in HCC tissues. Immunoblotting, quantitative real-time PCR, flow cytometry, chromatin immunoprecipitation, and dual-luciferase reporter gene assays were performed to evaluate the regulatory roles of EZH2 on PD-L1 expression. RESULTS: In vitro cell experiments revealed that EZH2 negatively regulated the PD-L1 expression of hepatoma cell lines in IFNγ-dependent manner. Mechanistic studies demonstrated that EZH2 could suppress PD-L1 expression by upregulating the H3K27me3 levels on the promoters of CD274 (encoding PD-L1) and interferon regulatory factor 1 (IRF1), an essential transcription factor for PD-L1 expression, without affecting the activation of the IFNγ-signal transducer and activator of transcription 1 (STAT1) pathway. Clinical samples from HCC patients with immune-activated microenvironments showed negative correlations between EZH2 and PD-L1 expression in hepatoma cells. Multivariate Cox analysis demonstrated that the combination of EZH2 and PD-L1 was an independent prognostic factor for both OS and RFS for patients with HCC. CONCLUSIONS: The epigenetic modificator EZH2 can suppress the expression of immune checkpoint inhibitor PD-L1 by directly upregulating the promoter H3K27me3 levels of CD274 and IRF1 in hepatoma cells, and might serve as a potential therapeutic target for combination of immunotherapy for immune-activated HCC.
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Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Factor 1 Regulador del Interferón/genética , Histona Demetilasas con Dominio de Jumonji/genética , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Interferón gamma/inmunología , Neoplasias Hepáticas/genética , Masculino , Persona de Mediana Edad , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: Patients with hepatocellular carcinoma (HCC) undergoing surgical resection still have a high 5-year recurrence rate (~ 60%). With the development of laparoscopic hepatectomy (LH), few studies have compared the efficacy between LH and traditional surgical approach on HCC. The objective of this study was to establish a nomogram to evaluate the risk of recurrence in HCC patients who underwent LH. METHODS: The clinical data of 432 patients, pathologically diagnosed with HCC, underwent LH as initial treatment and had surgical margin > 1 cm were collected. The significance of their clinicopathological features to recurrence-free survival (RFS) was assessed, based on which a nomogram was constructed using a training cohort (n = 324) and was internally validated using a temporal validation cohort (n = 108). RESULTS: Hepatitis B surface antigen (hazard ratio [HR], 1.838; P = 0.044), tumor number (HR, 1.774; P = 0.003), tumor thrombus (HR, 2.356; P = 0.003), cancer cell differentiation (HR, 0.745; P = 0.080), and microvascular tumor invasion (HR, 1.673; P =0.007) were found to be independent risk factors for RFS in the training cohort, and were used for constructing the nomogram. The C-index for RFS prediction in the training cohort using the nomogram was 0.786, which was higher than that of the 8th edition of the American Joint Committee on Cancer TNM classification (C-index, 0.698) and the Barcelona Clinic Liver Cancer staging system (C-index, 0.632). A high consistency between the nomogram prediction and actual observation was also demonstrated by a calibration curve. An improved predictive benefit in RFS and higher threshold probability of the nomogram were determined by receiver operating characteristic curve analysis, which was also confirmed in the validation cohort compared to other systems. CONCLUSIONS: We constructed and validated a nomogram able to quantify the risk of recurrence after initial LH for HCC patients, which can be clinically implemented in assisting the planification of individual postoperative surveillance protocols.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia , Adulto , Femenino , Hepatectomía , Humanos , Estimación de Kaplan-Meier , Laparoscopía , Masculino , Persona de Mediana Edad , NomogramasRESUMEN
(1) Background: To investigate the clinical outcomes between radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) for residual hepatocellular carcinoma (RHCC). (2) Methods: 139 patients were diagnosed with the RHCC after post-operative checkup, among whom 39 and 33 patients underwent RFA or SBRT as salvage treatments, respectively. We applied the propensity score matching (PSM) to adjust for imbalances in treatment assignment. Local disease progression, progression-free survival (PFS), overall survival (OS), and treatment-related side effects were the study endpoints. (3) Results: Before PSM, the SBRT group demonstrated significantly lower local disease progression rate (6/33 vs. 23/39; p = 0.002), better PFS (the 1- and 3-year PFS were 63.3% and 49.3% vs. 41.5% and 22.3%, respectively, p = 0.036), and comparable OS (the 1- and 3-year OS were 85.4% and 71.1% vs. 97.3% and 57.6%, respectively, p = 0.680). After PSM of 23 matched cases, the SBRT group demonstrated significantly lower local disease progression rate, better PFS and comparable OS. Centrally located tumor predicted the worse OS. No acute grade 3+ toxicity was observed in both groups. (4) Conclusion: SBRT might be the preferred treatment for RHCC, especially for patients with larger tumors or tumors abutting major vessels, rather than repeated RFA.
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BACKGROUND: Radical surgery for Bismuth type III/IV hilar cholangiocellular carcinoma, which was usually considered unresectable, seems to improve prognosis by increasing the surgical curability rate. However, the dilemma of multiple billiary stumps and high postoperative complication rate caused by hepato-enteric anastomosis has been the main impediment. Thus, we practiced and introduce a new technique called "basin-shaped" hepaticojejunostomy to improve the treatment. METHODS: Thirty-two cases with Bismuth type III/IV hilar cholangiocarcinoma admitted to our department from Aug. 2013 to Dec. 2015 and who underwent hilar resection and resection segment 4(or plus resection segment 1) were reconstructed by "basin-shaped" hepaticojejunostomy. The clinical data were collected and analyzed. RESULTS: All patients underwent successful R0 high hilar resection following basin-shaped hepaticojejunostomy and were discharged from the hospital without severe postoperative complications. The average operation time for hepato-enteric anastomosis was 42.1 ± 8.5 min. The postoperative bile leakage rate was 3.1% (1/32), and the biliary infection rate was 6.2% (2/32). Within a median follow-up of 25.6 months, none of the patients developed local recurrence around the hepato-enteric anastomosis. CONCLUSIONS: For patients with Bismuth type III/IV hilar cholangiocellular carcinoma who underwent resection segment 4(or plus resection segment 1), basin-shaped hepaticojejunostomy was a safe, simple and valid method for bile duct reconstruction, with a relatively low incidence of postoperative complications.
Asunto(s)
Neoplasias de los Conductos Biliares/cirugía , Hepatectomía/métodos , Yeyunostomía/métodos , Yeyuno/cirugía , Tumor de Klatskin/cirugía , Hígado/cirugía , Anastomosis Quirúrgica/métodos , Neoplasias de los Conductos Biliares/patología , Femenino , Humanos , Tumor de Klatskin/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
Existing data on folate status and hepatocellular carcinoma (HCC) prognosis are scarce. We prospectively examined whether serum folate concentrations at diagnosis were associated with liver cancer-specific survival (LCSS) and overall survival (OS) among 982 patients with newly diagnosed, previously untreated HCC, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study between September 2013 and February 2017. Serum folate concentrations were measured using chemiluminescent microparticle immunoassay. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95 % CI by sex-specific quartile of serum folate. Compared with patients in the third quartile of serum folate, patients in the lowest quartile had significantly inferior LCSS (HR = 1·48; 95 % CI 1·05, 2·09) and OS (HR = 1·43; 95 % CI 1·03, 1·99) after adjustment for non-clinical and clinical prognostic factors. The associations were not significantly modified by sex, age at diagnosis, alcohol drinking status and Barcelona Clinic Liver Cancer (BCLC) stage. However, there were statistically significant interactions on both multiplicative and additive scale between serum folate and C-reactive protein (CRP) levels or smoking status and the associations of lower serum folate with worse LCSS and OS were only evident among patients with CRP > 3·0 mg/l or current smokers. An inverse association with LCSS were also observed among patients with liver damage score ≥3. These results suggest that lower serum folate concentrations at diagnosis are independently associated with worse HCC survival, most prominently among patients with systemic inflammation and current smokers. A future trial of folate supplementation seems to be promising in HCC patients with lower folate status.
Asunto(s)
Carcinoma Hepatocelular/mortalidad , Ácido Fólico/sangre , Neoplasias Hepáticas/mortalidad , Adulto , Anciano , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/sangre , China , Femenino , Humanos , Neoplasias Hepáticas/sangre , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios ProspectivosRESUMEN
Sorafenib is the most recommended first-line systemic therapy for advanced hepatocellular carcinoma (HCC). Yet there is no clinically applied biomarker for predicting sorafenib response. We have demonstrated that a vascular pattern, named VETC (Vessels that Encapsulate Tumor Clusters), facilitates the release of whole tumor clusters into the bloodstream; VETC-mediated metastasis relies on vascular pattern, but not on migration and invasion of cancer cells. In this study, we aimed to explore whether vascular pattern could predict sorafenib benefit. Two cohorts of patients were recruited from four academic hospitals. The survival benefit of sorafenib treatment for patients with or without the VETC pattern (VETC+ /VETC- ) was investigated. Kaplan-Meier analyses revealed that sorafenib treatment significantly reduced death risk and prolonged overall survival (OS; in cohort 1/2, P = 0.004/0.005; hazard ratio [HR] = 0.567/0.408) and postrecurrence survival (PRS; in cohort 1/2, P = 0.001/0.002; HR = 0.506/0.384) in VETC+ patients. However, sorafenib therapy was not beneficial for VETC- patients (OS in cohort 1/2, P = 0.204/0.549; HR = 0.761/1.221; PRS in cohort 1/2, P = 0.121/0.644; HR = 0.728/1.161). Univariate and multivariate analyses confirmed that sorafenib treatment significantly improved OS/PRS in VETC+ , but not VETC- , patients. Further mechanistic investigations showed that VETC+ and VETC- HCCs displayed similar levels of light chain 3 (LC3) and phosphorylated extracellular signal-regulated kinase (ERK) in tumor tissues (pERK) or endothelial cells (EC-pERK), and greater sorafenib benefit was consistently observed in VETC+ HCC patients than VETC- irrespective of levels of pERK/EC-pERK/LC3, suggesting that the different sorafenib benefit between VETC+ and VETC- HCCs may not result from activation of Raf/mitogen-activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2)/ERK signaling or induction of autophagy. Conclusion: Sorafenib is effective in prolonging the survival of VETC+ , but not VETC- , patients. VETC pattern may act as a predictor of sorafenib benefit for HCC.