RESUMEN
Alpha-foetoprotein (AFP) is taken as a diagnostic tumor marker for the screening and diagnosis of cancer. Nucleic acid-based isothermal amplification strategies are emerging as a potential technology in early screening and clinical diagnosis of AFP. The leakages between hairpins dramatically increase the background and reduce the sensitivity. Thus, it is necessary to develop some strategies to reduce the leakage for isothermal amplification strategies. A DNAzyme-locked leakless enzyme-free amplification system was developed for AFP detection in liver cancer and breast cancer. AFP could open the apt-hairpin and initiate the catalytic hairpin assembly (CHA) reaction to produce a Y-shaped duplex. Two tails of a Y-shaped duplex cleaved the two kinds of leakless hairpins. Then, the third tail of the Y-shaped duplex catalyzed the second CHA between the cleaved leakless hairpins to recover the fluorescent intensity. The limit of detection reached 5 fg/mL by the two levels of signal amplifications. Importantly, the leakless hairpin design effectively reduced leakage between hairpins and weakened the background. In addition, it also showed a great promising potential for AFP detection in early screening and clinical diagnosis.
Asunto(s)
Neoplasias de la Mama , ADN Catalítico , Límite de Detección , Neoplasias Hepáticas , Técnicas de Amplificación de Ácido Nucleico , alfa-Fetoproteínas , ADN Catalítico/química , ADN Catalítico/metabolismo , alfa-Fetoproteínas/análisis , Humanos , Técnicas de Amplificación de Ácido Nucleico/métodos , Neoplasias de la Mama/diagnóstico , Neoplasias Hepáticas/diagnóstico , Femenino , Biomarcadores de Tumor/sangre , Técnicas Biosensibles/métodosRESUMEN
Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. Results: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Impact and implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.
RESUMEN
BACKGROUND: The combination of atezolizumab and bevacizumab (AtezoBev) is the current first-line treatment for patients with hepatocellular carcinoma (HCC). Our aim was to evaluate the prognostic role of alpha-foetoprotein (AFP) early response and its combination with albumin-bilirubin (ALBI) in these patients. METHODS: Patients with HCC under AtezoBev with AFP > 20 ng/ml were included in three centres. The optimal threshold of AFP variation after 3 weeks of treatment was identified for overall survival (OS) and radiological response (RR) using RECIST 1.1 and mRECIST and its ability to predict progression-free survival (PFS) and OS was tested using univariate and multivariate analysis in derivation and validation cohorts. RESULTS: Seventy-five patients with AFP values >20 ng/ml were included. Fifty-eight patients were male with a median age of 63.5 years; 73% had cirrhosis and HCC stage was classified as BCLC B (18.7%) or C (81.3%). In the derivation cohort (n = 38), a decline in AFP ≥ 20% at 3 weeks (AFP early response) was associated with RR using mRECIST criteria (OR: 13.09 95% CI: 1.44-19.34 p = .02), PFS (HR: 0.42; 95% CI: 0.19-0.93, p = .03) and OS (HR: 0.35; 95% CI: 0.15-0.83, p = .01). AFP early response was confirmed as predictor of RR (p = .02 for mRECIST) and OS (p = .03) in the validation cohort (n= 37). In the whole cohort, the combination of ALBI and AFP early response was significantly associated with OS (p = .046) and PFS (p = .012) with a poor prognosis in patients belonging to the ALBI2-AFP non-responders class. CONCLUSION: AFP early response at 3 weeks predicts oncological outcomes in HCC patients treated with AtezoBev and combination with ALBI grade refines prognostic discrimination.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Neoplasias Hepáticas/patología , alfa-Fetoproteínas/análisis , Bevacizumab , Bilirrubina , Albúminas , Estudios RetrospectivosRESUMEN
Background & Aims: Patients with hepatocellular carcinoma (HCC) are selected for liver transplantation (LT) based on pre-LT imaging ± alpha-foetoprotein (AFP) level, but discrepancies between pre-LT tumour assessment and explant are frequent. Our aim was to design an explant-based recurrence risk reassessment score to refine prediction of recurrence after LT and provide a framework to guide post-LT management. Methods: Adult patients who underwent transplantation between 2000 and 2018 for HCC in 47 centres were included. A prediction model for recurrence was developed using competing-risk regression analysis in a European training cohort (TC; n = 1,359) and tested in a Latin American validation cohort (VC; n=1,085). Results: In the TC, 76.4% of patients with HCC met the Milan criteria, and 89.9% had an AFP score of ≤2 points. The recurrence risk reassessment (R3)-AFP model was designed based on variables independently associated with recurrence in the TC (with associated weights): ≥4 nodules (sub-distribution of hazard ratio [SHR] = 1.88, 1 point), size of largest nodule (3-6 cm: SHR = 1.83, 1 point; >6 cm: SHR = 5.82, 5 points), presence of microvascular invasion (MVI; SHR = 2.69, 2 points), nuclear grade >II (SHR = 1.20, 1 point), and last pre-LT AFP value (101-1,000 ng/ml: SHR = 1.57, 1 point; >1,000 ng/ml: SHR = 2.83, 2 points). Wolber's c-index was 0.76 (95% CI 0.72-0.80), significantly superior to an R3 model without AFP (0.75; 95% CI 0.72-0.79; p = 0.01). Four 5-year recurrence risk categories were identified: very low (score = 0; 5.5%), low (1-2 points; 15.1%), high (3-6 points; 39.1%), and very high (>6 points; 73.9%). The R3-AFP score performed well in the VC (Wolber's c-index of 0.78; 95% CI 0.73-0.83). Conclusions: The R3 score including the last pre-LT AFP value (R3-AFP score) provides a user-friendly, standardised framework to design post-LT surveillance strategies, protocols, or adjuvant therapy trials for HCC not limited to the Milan criteria. Clinical Trials Registration: NCT03775863. Lay summary: Considering discrepancies between pre-LT tumour assessment and explant are frequent, reassessing the risk of recurrence after LT is critical to further refine the management of patients with HCC. In a large and international cohort of patients who underwent transplantation for HCC, we designed and validated the R3-AFP model based on variables independently associated with recurrence post-LT (number of nodules, size of largest nodule, presence of MVI, nuclear grade, and last pre-LT AFP value). The R3-AFP model including last available pre-LT AFP value outperformed the original R3 model only based on explant features. The final R3-AFP scoring system provides a robust framework to design post-LT surveillance strategies, protocols, or adjuvant therapy trials, irrespective of criteria used to select patients with HCC for LT.
RESUMEN
BACKGROUND: Chaperonin-containing tailless complex polypeptide 1 subunit 6A (CCT6A) plays roles in cancer progression, but its clinical implication in hepatocellular carcinoma (HCC) management needs further exploration. This study aimed to explore the correlation of CCT6A with clinical characteristics, liver function indexes, tumor markers and prognosis in HCC patients. METHODS: 240 HCC patients were retrospectively enrolled. 240 pairs of cancer and adjacent specimens were used to evaluate CCT6A protein expression by immunohistochemistry assay; among which 184 pairs were used to assess CCT6A mRNA expression by reverse transcription-quantitative polymerase chain reaction. RESULTS: Both CCT6A protein expression and CCT6A mRNA expression were higher in HCC tumor tissue than in adjacent tissue (P < 0.001). The receiver operating characteristic (ROC) curve showed that CCT6A had certain potential in discriminating tumor tissues from adjacent tissues. In addition, CCT6A protein expression was positively correlated with multifocal tumor nodule (P = 0.001), ≥ 5.0 cm tumor size (P = 0.028), BCLC stage (P = 0.002) and abnormal AFP (P = 0.021). Besides, CCT6A mRNA expression was associated with multifocal tumor nodule (P = 0.025), ≥ 5.0 cm tumor size (P = 0.018), higher BCLC stage (P = 0.036), abnormal CA199 (P = 0.027) and abnormal AFP (P = 0.008). However, no correlation was found in CCT6A with liver function indexes (all P ≥ 0.05). Moreover, CCT6A protein and mRNA high expressions were both correlated with poor accumulating overall survival (OS) (P = 0.004, P = 0.002, respectively). Furthermore, CCT6A protein high expression (vs. low) independently predicted shorter OS (P = 0.027). CONCLUSIONS: CCT6A serves as a possible biomarker reflecting tumor features and prognostication in HCC patients.
Asunto(s)
Carcinoma Hepatocelular , Chaperonina con TCP-1 , Neoplasias Hepáticas , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Chaperonina con TCP-1/genética , Chaperonina con TCP-1/metabolismo , Humanos , Neoplasias Hepáticas/patología , Pronóstico , ARN Mensajero , Estudios Retrospectivos , alfa-FetoproteínasRESUMEN
BACKGROUND & AIMS: Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and 'all-comers'. METHODS: This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000-2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. RESULTS: From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8-55.8) and 38.2% (CI 25.4-52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p <0.0001]) and not significantly higher for the UCSF-DS group (SHR 1.60 [p = 0.32]), compared with patients remaining within Milan. The all-comers presented more frequent features of aggressive HCC and higher tumour burden at explant. Among the UCSF-DS group, an AFP value of ≤20 ng/ml at listing was associated with lower recurrence (SHR 2.01 [p = 0.006]) and better survival. However, recurrence was still significantly high irrespective of AFP ≤20 ng/ml in all-comers. CONCLUSIONS: Patients within the UCSF-DS protocol at listing have similar post-transplant outcomes compared with those within Milan when successfully downstaged. Meanwhile, all-comers have a higher recurrence and inferior survival irrespective of response to LRT. Additionally, in the UCSF-DS group, an ALP of ≤20 ng/ml might be a novel tool to optimise selection of candidates for LT. CLINICAL TRIAL NUMBER: This study was registered as part of an open public registry (NCT03775863). LAY SUMMARY: Patients with more extended HCC (within the UCSF-DS protocol) successfully downstaged to the conventional Milan criteria do not have a higher recurrence rate after LT compared with the group remaining in the Milan criteria from listing to transplantation. Moreover, in the UCSF-DS patient group, an ALP value equal to or below 20 ng/ml at listing might be a novel tool to further optimise selection of candidates for LT.
RESUMEN
BACKGROUND & AIMS: There are conflicting data regarding the epidemiology of hepatocellular carcinoma (HCC) arising in the context of non-alcoholic and metabolic-associated fatty liver disease (NAFLD and MAFLD). We aimed to examine the changing contribution of NAFLD and MAFLD, stratified by sex, in a well-defined geographical area and highly characterised HCC population between 1990 and 2014. METHODS: We identified all patients with HCC resident in the canton of Geneva, Switzerland, diagnosed between 1990 and 2014 from the prospective Geneva Cancer Registry and assessed aetiology-specific age-standardised incidence. NAFLD-HCC was diagnosed when other causes of liver disease were excluded in cases with type 2 diabetes, metabolic syndrome, or obesity. Criteria for MAFLD included one or more of the following criteria: overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. RESULTS: A total of 76/920 (8.3%) of patients were diagnosed with NAFLD-HCC in the canton of Geneva between 1990 and 2014. Between the time periods 1990-1994 and 2010-2014, there was a significant increase in HCC incidence in women (standardised incidence ratio [SIR] 1.83, 95% CI 1.08-3.13, p = 0.026) but not in men (SIR 1.10, 95% CI 0.85-1.43, p = 0.468). In the same timeframe, the proportion of NAFLD-HCC increased more in women (0-29%, p = 0.037) than in men (2-12%, p = 0.010) while the proportion of MAFLD increased from 21% to 68% in both sexes and from 7% to 67% in women (p <0.001). From 2000-2004 to 2010-2014, the SIR of NAFLD-HCC increased to 1.92 (95% CI 0.77-5.08) for men and 12.7 (95% CI 1.63-545) in women, whereas it decreased or remained stable for other major aetiologies of HCC. CONCLUSIONS: In a populational cohort spanning 25 years, the burden of NAFLD and MAFLD associated HCCs increased significantly, driving an increase in HCC incidence, particularly in women. LAY SUMMARY: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, increasingly arising in patients with liver disease caused by metabolic syndrome, termed non-alcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). We assessed all patients with HCC between 1990 and 2014 in the canton of Geneva (western Switzerland) and found an increase in all HCC cases in this timeframe, particularly in women. In addition, we found that HCC caused by NAFLD or MAFLD significantly increased over the years, particularly in women, possibly driving the increase in overall HCC cases.
RESUMEN
BACKGROUND & AIMS: Zinc finger and BTB domain containing 20 (ZBTB20) has been implicated as a potential oncogene in liver cancer. However, knockout studies have shown it to be a transcriptional repressor of the alpha-foetoprotein (Afp) gene in adult liver, and reduced levels of ZBTB20 allow for upregulation of AFP with increased tumour severity in certain cases of hepatocellular carcinoma (HCC). As there are many discrepancies in the literature regarding its role in liver tumourigenesis, the aim of this study was to elucidate the role of ZBTB20 in HCC tumourigenesis. METHODS: A reverse genetic study using the Sleeping Beauty (SB) transposon system in mice was performed to elucidate the role of ZBTB20 in HCC tumourigenesis. In vitro ZBTB20 gain- and loss-of-function experiments were used to assess the relationship amongst ZBTB20, peroxisome proliferator activated receptor gamma (PPARG) and catenin beta 1 (CTNNB1). RESULTS: Transgenic overexpression of ZBTB20 in hepatocytes and in the context of transformation related protein (T r p53) inactivation induced hepatic hypertrophy, activation of WNT/CTNNB1 signalling, and development of liver tumours. In vitro overexpression and knockout experiments using CRISPR/Cas9 demonstrated the important role for ZBTB20 in downregulating PPARG, resulting in activation of the WNT/CTNNB1 signalling pathway and its downstream effectors in HCC tumourigenesis. CONCLUSIONS: These findings demonstrate a novel interaction between ZBTB20 and PPARG, which leads to activation of the WNT/CTNNB1 signalling pathway in HCC tumourigenesis. LAY SUMMARY: ZBTB20 has been implicated as a potential oncogene in liver cancer. Herein, we uncover its important role in liver cancer development. We show that it interacts with PPARG to upregulate the WNT/CTNNB1 signalling pathway, leading to tumourigenesis.
RESUMEN
BACKGROUND AND STUDY AIMS: Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide. Talin-1 was previously proposed as a potential novel biomarker for HCC diagnosis but with limited and inconsistent data. We aimed to study the possible role of talin-1 in diagnosis and prognostic stratification of patients with hepatocellular carcinoma. PATIENTS AND METHODS: Ninety-six patients were recruited and classified into three groups; 1) cirrhosis group: 40 patients with liver cirrhosis, 2) HCC group: 40 patients with HCC, 3) control group: 16 healthy volunteers with matched age and sex. Serum talin-1 level was detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: The highest levels of talin-1 were observed among the HCC group followed by cirrhosis then control groups (p = 0.000). In the HCC group, a significant correlation was found between talin-1 and each of multifocal HCC (p = 0.013), portal vein invasion (p = 0.022) and presence of ascites (p = 0.001), while no significant correlation was detected with tumour foci size (p = 0.605). For HCC detection, talin-1 had AUC = 0.858, 100% sensitivity and 65% specificity, while AFP had AUC = 1.000, 100% sensitivity and specificity. CONCLUSION: Talin-1 is a potential marker for diagnosis and prognostic assessment of HCC. Further studies are needed to investigate the ultimate diagnostic and prognostic utility of serum talin-1.
Asunto(s)
Carcinoma Hepatocelular , Cirrosis Hepática/sangre , Neoplasias Hepáticas , Talina/sangre , alfa-Fetoproteínas/análisis , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/patología , Femenino , Humanos , Cirrosis Hepática/diagnóstico , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo/métodos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Recent studies indicate that a group of patients with cirrhosis receiving a liver transplantation for hepatocellular cancer (HCC) beyond the Milan Criteria (MC) can achieve a similar outcome compared to patients within these criteria. This study aims to investigate the value of the Asan critera (AC), up-to-7 criteria (UT7), French alpha-foetoprotein (AFP) model and Metroticket 2.0 (MT2.0) model compared to the MC. METHODS: 526 patients transplanted for non-metastatic HCC were analyzed. Patient groups within and beyond MC and extended criteria were determined according to radiological assessment and AFP value at listing. RESULTS: Overall survival (OS) and recurrence (RR) rates were similar between patients within MC and all extended criteria. Five-year OS within MC was 71.3% compared to 70.9% for AC, 71.4% for UT7, 69.7% for AFP-model and 71.0% for MT2.0 criteria. Five-year RR within MC was 12.3% compared to 13.5% for AC, 13.0% for UT7, 14.3% for AFP-model and 13.2% for MT2.0 criteria. Patients beyond MC but within the extended criteria had tendency towards higher recurrence. CONCLUSIONS: All validated extended criteria (AC, UT7, AFP-model and MT2.0) could be proposed as alternatives to the MC with similar outcome. Prospective data are awaited to assess recurrence beyond MC.
Asunto(s)
Carcinoma Hepatocelular/cirugía , Cirrosis Hepática/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/métodos , Selección de Paciente , Anciano , Bélgica , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Supervivencia sin Enfermedad , Femenino , Hepatitis B Crónica/complicaciones , Hepatitis C Crónica/complicaciones , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/metabolismo , Hepatopatías Alcohólicas/complicaciones , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Estudios Retrospectivos , Tasa de Supervivencia , alfa-Fetoproteínas/metabolismoRESUMEN
BACKGROUND: Post-treatment decline in serum alpha-foetoprotein (AFP) levels has been shown to predict the treatment efficacy of antiangiogenic therapy for advanced hepatocellular carcinoma (HCC). We explored whether a decline in AFP levels was also associated with treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with advanced HCC. METHODS: We reviewed all patients who received ICI therapy for advanced HCC. AFP response was evaluated in patients with the pretreatment AFP level of >20 ng/mL. We defined early AFP response as a >20% decline in serum AFP levels within the first 4 weeks of treatment initiation relative to pretreatment levels. We then studied whether early AFP response was associated with treatment outcomes. RESULTS: Sixty patients were enrolled in this study; 43 of them were evaluable for early AFP response. The objective response rate of early AFP responders was significantly higher than that of early AFP nonresponders (73% vs. 14%, P < .001). Early AFP responders, compared with early AFP nonresponders, exhibited significantly longer overall survival (OS) (median, 28.0 vs 11.2 months, P = .048) and progression-free survival (PFS) (median, 15.2 vs 2.7 months, P = .002). After adjusting for other clinicopathological variables and treatments, early AFP response remained an independent predictor for longer OS (hazard ratio [HR] = 0.089, 95% confidence interval [CI] = 0.018-0.441; P = .003) and PFS (HR = 0.128, 95% CI = 0.041-0.399; P < .001). CONCLUSION: Early AFP response was associated with higher treatment efficacy of ICIs for advanced HCC. Additional validation studies are nonetheless warranted.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Inmunológicos/orina , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , alfa-Fetoproteínas/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Taiwán , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: In Caucasian patients with compensated cirrhosis caused by hepatitis B virus (HBV), the risk of hepatocellular carcinoma (HCC) developing persist despite long-term nucleos(t)ide analogs (NUC) treatment. In the surveillance of this population with persistently normal transaminases because of NUCs, the added value of serum alpha-foetoprotein (AFP) monitoring is poorly defined. METHODS: Two hundred and fifty-eight Caucasian HCC-free patients with HBV-compensated cirrhosis who started tenofovir or entecavir while having normal serum AFP levels (≤7 ng/mL) at baseline or within the first year of treatment underwent HCC surveillance by semiannual ultrasound evaluation and serum AFP determination. RESULTS: During 96 (18-120) months of antiviral therapy, 3947 AFP values were collected, median AFP level was 2 ng/mL. Thirty-five patients developed an HCC at an overall 8-year crude cumulative incidence of 14% (annual incidence of 2%). HCC incidence increased in parallel with increasing AFP thresholds: 24%, 36%, 64% and 92% for AFP levels after exceeding 2, 4, 6 and 7 ng/mL for the first-time. Of the 12 patients who experienced an AFP rise > 7 ng/mL, 11 developed an HCC and one had liver metastases of lung cancer. Overall, an AFP > 7 ng/mL had 99.6% specificity, 31.4% sensitivity, 91.7% PPV, 90.2% NPV, LR+ 70.1 and LR- 0.69 for HCC; this excellent specificity was maintained up to 18 months before HCC detection. CONCLUSIONS: In Caucasian patients with HBV-compensated cirrhosis on long-term NUC, an increase in AFP over 7 ng/mL shows excellent specificity, heralding HCC development within 1 year.
Asunto(s)
Carcinoma Hepatocelular/epidemiología , Hepatitis B Crónica/tratamiento farmacológico , Cirrosis Hepática/sangre , Neoplasias Hepáticas/epidemiología , alfa-Fetoproteínas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/uso terapéutico , Biomarcadores/sangre , Carcinoma Hepatocelular/virología , Femenino , Guanina/análogos & derivados , Hepatitis B Crónica/complicaciones , Humanos , Italia/epidemiología , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/virología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Tenofovir , Adulto JovenRESUMEN
Background & objectives: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. The objective of this study was to find out the differential expression of apolipoproteins (ApoAI and ApoAIV) in HCC and cases of liver cirrhosis and chronic hepatitis (controls) without HCC and to compare ApoAI and ApoAIV expression with alpha-foetoprotein (AFP), the conventional marker in HCC. Methods: Fifty patients with HCC and 50 controls comprising patients with liver cirrhosis (n=25) and chronic hepatitis (n=25) without HCC were included in this study. Total proteins were precipitated using acetone precipitation method followed by albumin and IgG depletion of precipitated protein using depletion kit. Proteins were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The expression changes of ApoAI and ApoAIV were confirmed by western blotting using specific primary and secondary polyclonal antibodies followed by densitometric protein semi-quantitative estimation. ApoAI, ApoAIV and AFP were measured in the plasma samples by ELISA method. Results: Semi-quantitative densitometric image analysis of the western blot images and the comparison between HCC patients with those without HCC (control) revealed differential expression of ApoAI and ApoAIV. Levels of ApoAI were significantly higher in patients with HCC compared to controls without HCC (0.279±0.216 vs 0.171±0.091 and 0.199±0.014; P <0.001). Levels of ApoAIV were significantly lower in patients of HCC compared to controls without HCC (0.119±0.061 vs 0.208±0.07 and 0.171±0.16; P <0.01). ELISA assays of apolipoproteins (ApoAI and ApoAIV) revealed similar results of expression of ApoAI and ApoAIV as detected in western blotting densitometric image analysis. Interpretation & conclusions: Increased expression of ApoAI and decreased expression of ApoAIV in HCC patients compared to controls without HCC revealed the abnormalities in HCC. These molecules need to be studied further for their use as potential biomarkers in the future diagnostic tools along with other conventional biomarkers for screening of HCC cases. It needs further analysis in higher number of patient population.
Asunto(s)
Apolipoproteína A-I/metabolismo , Apolipoproteínas A/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Apolipoproteínas , Biomarcadores de Tumor , Estudios de Casos y Controles , Humanos , India , Cirrosis Hepática/metabolismoRESUMEN
BACKGROUND & AIMS: This study investigates the long-term incidences and predictors of developing hepatocellular carcinoma (HCC), cirrhotic events and mortality in cirrhotic patients receiving entecavir (ETV) therapy. METHODS: We enrolled 481 nucleos(t)ide analogue-naïve chronic hepatitis B (CHB) patients who had compensated cirrhosis upon entry and had received ETV monotherapy for >12 months. RESULTS: The 8-year cumulative incidences of developing HCC, cirrhotic events and liver-related mortality were 26.5%, 8.62% and 10.03% respectively. Multivariate analysis revealed that diabetic mellitus (DM), higher fibrosis-4 (FIB-4) and alpha-foetoprotein (AFP) levels at 12 months of treatment, and FIB-4 increase from baseline to 12 months were independent factors of HCC. FIB-4 and AFP levels at 12 months of treatment were also independent factors of cirrhotic events and mortality. FIB-4 cut-off values of 3, 3 and 5 as well as AFP cut-offs of 5, 5, and 9 ng/mL at 12 months of treatment were optimal for predicting HCC, cirrhotic events and mortality during therapy respectively. The FIB-4 and AFP levels at 12 months of treatment were assessed for the combined risk of developing clinical outcomes. The 8-year incidences of HCC, cirrhotic events and liver-related mortality in the subgroups with low FIB-4 and AFP levels were only 5.95%, 1.03% and 2.43% respectively. DM was an independent predictor of HCC and mortality. CONCLUSION: The combination of FIB-4 and AFP levels at 12 months of treatment is a useful marker for predicting the development of HCC, cirrhotic events and mortality in compensated cirrhotic patients with CHB who are receiving ETV therapy.
Asunto(s)
Biomarcadores/sangre , Carcinoma Hepatocelular/epidemiología , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Cirrosis Hepática/mortalidad , Neoplasias Hepáticas/epidemiología , Adulto , Anciano , Alanina Transaminasa/sangre , Antivirales/uso terapéutico , Aspartato Aminotransferasas/sangre , Carcinoma Hepatocelular/virología , China/epidemiología , Femenino , Guanina/uso terapéutico , Hepatitis B Crónica/complicaciones , Humanos , Incidencia , Cirrosis Hepática/sangre , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recuento de Plaquetas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Taiwán/epidemiología , alfa-Fetoproteínas/metabolismoRESUMEN
Given the interest of many people and families directly or indirectly affected by hereditary tyrosinemia (HT1), I have tried to give my view on the history of the disease from 1965 to 2015 (Fig. 1.1).
Asunto(s)
Herencia/genética , Tirosinemias/epidemiología , Tirosinemias/genética , Animales , Canadá/epidemiología , HumanosRESUMEN
BACKGROUND & AIM: Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction. This work aimed at analyzing characteristics and factors associated with development of hepatocellular carcinoma (HCC) in patients with primary BCS. METHODS: A total of 348 Egyptian BCS patients were included. They were presented to the Budd-Chiari Study Group of Ain Shams University Hospital. BCS was confirmed using abdominal Doppler US. Abdominal magnetic resonance imaging (MRI), MR venography and/or multislice computed tomography (CT) were performed to confirm all diagnoses and to assess vascular anatomy. Hepatic focal lesions detected during the study period (2005-2011) were evaluated using serum alpha foetoprotein (AFP) level, imaging features and histopathological examination. RESULTS: Diagnosis of HCC was confirmed in 15/348 patients (4.3%). Imaging studies showed that 60% had multiple hepatic focal lesions ranging from 2 to 6.3 cm in size. The median level of serum AFP in BCS with HCC was 300 ng/mL vs 11 ng/mL in those without HCC (P<.001). A cut-off level >24.5 ng/mL for serum AFP showed sensitivity 80%, specificity 97.9%, positive predictive value 93.18% and negative predictive value 99.1% for detection of HCC in BCS patients. Male gender, older age, cigarette smoking, serum AFP (>24.5 ng/mL) and shrunken liver by ultrasonography were independent factors associated with HCC development. CONCLUSION: Male gender, older age and cigarette smoking are independent risk factors for development of HCC in BCS. Serum AFP is a good screening test in BCS.
Asunto(s)
Síndrome de Budd-Chiari/sangre , Síndrome de Budd-Chiari/complicaciones , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Adulto , Carcinoma Hepatocelular/diagnóstico , Egipto/epidemiología , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico , Modelos Logísticos , Imagen por Resonancia Magnética , Masculino , Análisis Multivariante , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Fumar/efectos adversos , Tomografía Computarizada por Rayos X , Ultrasonografía Doppler , Adulto Joven , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND & AIMS: We investigated the significance of 18 F-fluoro-2-deoxyglucose positron emission tomography (18 F-FDG PET) parameters and alpha-foetoprotein (AFP) levels in patients with locally advanced hepatocellular carcinoma (LA-HCC). METHODS: We retrospectively analysed data of 228 patients with LA-HCC who underwent pretreatment 18 F-FDG PET between January 2003 and December 2013. All patients were treated using liver-directed therapy involving radiotherapy. The maximum standardized uptake values (SUVs) and tumour-to-extratumoural liver SUV ratios were calculated, and pretreatment AFP values were obtained. RESULTS: Patients were divided into high and low maximum SUV (SUVmax) groups according to a SUV cut-off of 4.825 determined via receiver-operating characteristic analysis. High AFP level (>550 ng/mL) and high SUVmax were significant predictors of overall and progression-free survival. Better treatment responses and longer median progression-free and overall survival were observed in the low SUVmax group, compared to the high SUVmax group. Similar results were obtained for SUV ratio-based (cut-off value: 2.355) and AFP-based analyses (cut-off value: 550 ng/mL). Three risk groups were identified using the double biomarkers of SUVmax and AFP value as strong prognosticators predictive of survival outcomes. This risk stratification was identified as a prognosticator of survival outcomes, even after subgroup analyses. Furthermore, in high risk group, significantly high extrahepatic failure was shown while in low risk group, significantly low intrahepatic failure. CONCLUSIONS: Clinical significance of double biomarkers, SUV and AFP, could be translated into risk stratification for LA-HCC. It could be a valuable tool for survival outcome prediction.
Asunto(s)
Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico por imagen , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico por imagen , alfa-Fetoproteínas/análisis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Radiofármacos , República de Corea/epidemiología , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Adulto JovenRESUMEN
Alpha-foetoprotein (AFP), one of the first protein tumour markers discovered, is widely used today in clinical practice. Its application for the screening and diagnosis of hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour, is a matter of extensive debate. In addition to the studies focused on the role of the AFP in the diagnosis of HCC, in recent years AFP has been used to guide the therapeutic choice in HCC and monitor the treatment. Here, we summarize the latest studies that show the interest of AFP quantification in determining the suitability of liver transplantation or to follow-up on patients receiving the targeted treatment sorafenib. We also highlight the recent studies showing the active role of AFP in tumour progression, and the new modes of regulation of this tumour marker. Among these is the regulation of AFP through tumour proteostasis and the Unfolded Protein Response (UPR). We discuss the implications of this new knowledge in the therapeutic context, in terms of interpreting serum levels of AFP, and the new perspectives offered by AFP for the study of tumour proteostasis.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , alfa-Fetoproteínas/metabolismo , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , alfa-Fetoproteínas/análisisRESUMEN
BACKGROUND & AIMS: The aim of this study was to re-evaluate the diagnostic performance of alpha-foetoprotein (AFP) as a surveillance test for hepatocellular carcinoma (HCC) in patients with hepatitis B virus-related chronic liver disease who were treated with entecavir (ETV). METHODS: Between January 2007 and August 2012, we analysed 373 treatment-naïve patients with HBV-related chronic hepatitis (n = 229) or cirrhosis (n = 144) who were candidates for surveillance test, and were treated with ETV (0.5 mg/day) for longer than 12 months. To minimize the effect of AFP elevation caused by hepatitis activity, serum AFP levels were measured 12 months after the initiation of ETV treatment. RESULTS: Hepatocellular carcinoma developed in 28 patients (7.5%) during a median follow-up period of 48.0 months (IQR = 40.5-57.3 months). The area under the receiver operating characteristic curve for AFP was 0.71 (95% CI = 0.59-0.84). The optimal AFP cut-off value was 13 ng/ml, leading to a sensitivity of 50.0%, specificity of 98.8%, positive predictive value of 77.8% and negative predictive value of 96.1%. In multivariate Cox analysis, an older age, the presence of cirrhosis and AFP levels of ≥20 ng/ml at 12 months after treatment were found to be significantly associated with an increased incidence of HCC. CONCLUSIONS: The role of serum AFP as a surveillance test should be re-evaluated in patients with HBV-related chronic liver diseases who were treated with antiviral therapy.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Guanina/análogos & derivados , Hepatitis B/complicaciones , Hepatitis B/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico , alfa-Fetoproteínas/análisis , Adulto , Área Bajo la Curva , Carcinoma Hepatocelular/etiología , Femenino , Guanina/uso terapéutico , Humanos , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Curva ROC , Sensibilidad y EspecificidadRESUMEN
BACKGROUND & AIMS: In this study, we investigated the clinical usefulness of AFP and PIVKA-II in subdividing prognostic groups in patients with locally advanced HCC treated locally. METHODS: Patients who had undergone local treatment for locally advanced HCC between 2001 and 2006 were enrolled. Response to treatment was defined as a reduction in AFP or PIVKA-II by more than 50% from baseline levels at 1 month after the treatment completion. Patients were divided according to their AFP and PIVKA-II response: A↓P↓ [AFP response (+) and PIVKA-II response (+)]; A↓P↑ [AFP response (+) and PIVKA-II response (-)]; A↑P↓ [AFP response (-) and PIVKA-II response (+)]; A↑P↑ [AFP response (-) and PIVKA-II response (-)]. Clinical characteristics and prognosis were compared between groups. RESULTS: Patients were subdivided into four groups by the change in the level of the biomarkers AFP and PIVKA-II, and the survival outcomes of each group were distinct. Among patients with an AFP response, further subdivision by PIVKA-II response revealed that those in the A↓P↓ group had a longer median progression-free survival (PFS) and overall survival (OS) compared with those in the A↓P↑ group (PFS: 16.2 vs. 5.1 months, P = 0.009; OS: 26.3 vs. 7.3 months, P = 0.017). Combination of AFP and PIVKA-II response showed a predictive power for PFS and OS comparable to radiological criteria and better than AFP response alone. CONCLUSIONS: In patients with locally advanced HCC, the use of a combination of two biomarkers, AFP and PIVKA-II, appears useful in predicting treatment outcomes through the subdivision of prognostic groups.