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BACKGROUND: Diagnostic panels based on multiple biomarkers and clinical characteristics are considered more favorable than individual biomarker to diagnose hepatocellular carcinoma (HCC). Based on age, sex, alpha-fetoprotein (AFP), and protein induced by vitamin K absence II (PIVKA-II) with/without AFP-L3, ASAP and GALAD models are potential diagnostic panels. The diagnostic performances of these two panels were compared relative to HCC detection among patients with various etiologies of chronic liver diseases (CLDs). METHODS: A multicenter case-control study recruited CLDs patients with and without HCC from 14 Chinese hospitals. The etiologies of CLDs included hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). Using area under the receiver operating characteristic curve (AUC) values, the diagnostic performances of ASAP and GALAD models were compared to detect HCC among patients with various etiologies of CLDs. RESULTS: Among 248 HCC patients and 722 CLD controls, the ASAP model demonstrated the highest AUC (0.886) to detect HCC at any stage, outperforming the GALAD model (0.853, P = 0.001), as well as any individual biomarker (0.687-0.799, all P < 0.001). In the subgroup analysis of various CLDs etiologies, the ASAP model outperformed the GALAD model to HCC independent of CLDs etiology. In addition, the ASAP model performed better in detecting early-stage (BCLC stage 0/A) HCC versus the GALAD model. CONCLUSIONS: Despite using one less laboratory variable (AFP-L3), the ASAP model demonstrated better diagnostic performance than the GALAD model to detect all-stage HCC among patients with various etiologies of CLDs-related HCC.
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BACKGROUND: Current surveillance strategies for hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) are insufficient. This study aimed to investigate the diagnostic performance of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and their combinations in HCC underlying NAFLD patients. METHODS: Serologic AFP, AFP-L3, and PIVKA-II levels in NAFLD patients with and without HCC were measured. By receiver operating characteristic (ROC) analyses, the area under the curve (AUC), sensitivity, and specificity were obtained to evaluate the diagnostic accuracy of each biomarker and their combinations. RESULTS: This study was conducted on 139 patients with NAFLD-HCC and 345 NAFLD controls. The elevation of these three biomarkers was observed in patients with NAFLD-HCC compared to those in NAFLD controls (all P < 0.001). When they were analyzed individually, PIVKA-II showed the best performance in diagnosing any-stage HCC with an AUC of 0.869, followed by AFP (0.763; vs. PIVKA-II, P < 0.001) and AFP-L3 (0.689; vs. PIVKA-II, P < 0.001). When they were analyzed in combination, AFP + PIVKA-II yielded the highest AUC (0.906), followed by AFP + PIVKA-II + AFP-L3 (0.904; vs. AFP + PIVKA-II, P = 0.086), PIVKA-II + AFP-L3 (0.881; vs. AFP + PIVKA-II, P < 0.001), and AFP + AFP-L3 (0.759; vs. AFP + PIVKA-II, P < 0.001). Similar findings were obtained in the subgroup with early-stage NAFLD-HCC, as well as the non-cirrhotic subgroup. CONCLUSIONS: These data validated the better diagnostic ability of PIVKA-II than AFP or AFP-L3 alone for diagnosing any-stage HCC among patients with NAFLD, and the combination of AFP + PIVKA-II significantly improved the diagnostic accuracy of NAFLD-HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , alfa-Fetoproteínas/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Neoplasias Hepáticas/diagnóstico , Protrombina/análise , Protrombina/metabolismo , Precursores de Proteínas , Biomarcadores , Vitamina K , Biomarcadores TumoraisRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a recognized sequalae of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. This study aimed to identify long-term survival and prognostic factors after curative resection for HCC among patients with chronic HCV infection. METHODS: From a Chinese multicenter database, the data of consecutive patients with HCV infection undergoing curative liver resection for initial HCC between 2006 and 2015 were retrospectively reviewed. Postoperative 30-day mortality and morbidity, long-term overall survival (OS) and recurrence-free survival (RFS) were evaluated. RESULTS: Among 382 HCC patients with HCV infection, 68 (18%) had concurrent HBV infection and 110 (29%) had portal hypertension. Postoperative 30-day morbidity and mortality rates were 45% and 2.9%, respectively. The 5-year OS and RFS rates were 45% and 34%, respectively. Multivariable Cox-regression analyses identified that concurrent HBV infection, presence of portal hypertension, largest tumor size > 5 cm, and macrovascular and microvascular invasion were independently associated with worse OS and RFS, while postoperative regular anti-HCV therapy was independently associated with better OS. CONCLUSION: Long-term prognosis after HCC resection among patients with HCV infection was worse in those with concurrent HBV infection and concomitant portal hypertension. Postoperative regular anti-HCV therapy was associated with better OS.
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Carcinoma Hepatocelular , Hepatite C Crônica , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirurgia , China/epidemiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , Prognóstico , Estudos RetrospectivosAssuntos
Carcinoma Pulmonar de Células não Pequenas , Diabetes Mellitus Tipo 2 , Neoplasias Pulmonares , Metformina , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Metformina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Imunoterapia/efeitos adversos , Hipoglicemiantes/uso terapêuticoAssuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/etiologia , Duração da Terapia , Neoplasias Hepáticas/etiologia , Antivirais/uso terapêutico , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Vírus da Hepatite BRESUMO
DEAD-box helicase (DDX) family members play differential roles in regulating innate antiviral immune response. However, the physiological roles played by DDX4 in antiviral innate immunity remain unclear. In this study, we unveiled that DDX4 acts as a positive regulatory molecule of Type-I interferon (IFN-I)-mediated antiviral activity. Our findings demonstrate that IFN-I upregulates DDX4 protein levels, and subsequently, overexpression of DDX4 enhances the IFN-I-mediated signaling pathway. This creates a positive feedback loop that amplifies the antiviral response. DDX4 was found to bind with deubiquitinase ubiquitin-specific protease 7 (USP7), leading to the disruption of the interaction between USP7 and suppressor of cytokine signaling 1 (SOCS1) and the subsequent degradation of SOCS1. This process enhances the antiviral function of IFN-I. Our findings provide new insights into the regulatory role of DDX4 in the IFN-I response.IMPORTANCEDDX4, identified as a putative RNA helicase that modulates RNA secondary structure through RNA binding, is primarily acknowledged for its role in regulating mRNA translation within the germline. Nevertheless, the extent of DDX4's involvement in the antiviral innate immune response remains largely unexplored. This study presents evidence of a previously unrecognized positive feedback loop between DDX4 and the antiviral response, suggesting that disruption of this loop may serve as a novel mechanism for viral evasion. Furthermore, our findings elucidate a positive regulatory mechanism by which the DDX4/USP7/SOCS1 axis mediates the antiviral activity of Type-I interferon, which provides new insight into strategies for improving the efficacy of IFN-based antiviral therapy.
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Interferon Tipo I , Peptidase 7 Específica de Ubiquitina/genética , Peptidase 7 Específica de Ubiquitina/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Imunidade Inata , RNARESUMO
Background GALAD score, comprising five clinical parameters, is a predictive model developed for hepatocellular carcinoma (HCC) detection. Since its emergence, its diagnostic ability has been validated in different populations with a wide variation. Therefore, we conducted a meta-analysis to investigate its overall diagnostic performance in differentiating HCC in chronic liver diseases. Methods Eligible studies were searched in the Web of Science, PubMed, Scopus, Ovid, Cochrane Library, and Embase databases by 29 May 2022. Pooled sensitivity, pooled specificity, and area under the receiver operating characteristic curve (AUC) with the corresponding 95% confidence intervals (CI) were estimated. Results Fifteen original studies (comprising 19,021 patients) were included. For detecting any-stage HCC, GALAD score yielded an excellent ability, with pooled sensitivity, specificity, and AUC of 0.82 (95%CI: 0.78-0.85), 0.89 (95%CI: 0.85-0.91), and 0.92 (95%CI: 0.89-0.94), respectively. Notably, further analyses demonstrated a good diagnostic accuracy of GALAD score for identifying Barcelona Clinic Liver Cancer staging (BCLC) 0/A HCC, with a moderate sensitivity (0.73 (95%CI: 0.66-0.79)) and a high specificity (0.87 (95%CI: 0.81-0.91)); by contrast, only 38% of early-stage patients can be identified by alpha-fetoprotein, with an AUC value of 0.70 (95%CI: 0.66-0.74). Following subgroup analyses based on different HCC etiologies, higher sensitivities and AUC values were observed in subgroups with hepatitis C or non-viral liver diseases. For detecting BCLC 0/A HCC in the cirrhotic population, GALAD score had a pooled sensitivity, specificity, and AUC of 0.78 (95%CI: 0.66-0.87), 0.80 (95%CI: 0.72-0.87), and 0.86 (95%CI: 0.83-0.89). Conclusions We highlighted the superior diagnostic accuracy of GALAD score for detecting any-stage HCC with a high sensitivity and specificity, especially for early-stage HCC, with a relatively stable diagnostic performance. The addition of GALAD score into ultrasound surveillance may identify more HCC patients. Our findings imply the robust power of the GALAD score as a HCC screening or diagnostic tool, and it should be further validated by more studies with high quality.
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OBJECTIVES: Hepatocellular carcinoma (HCC) is a common indication for hepatectomy that is often complicated by postoperative complication. The authors sought to investigate the relationship between the open with laparoscopic approach of hepatectomy and incidences of postoperative infectious complications. PATIENTS AND METHODS: Using a multicenter database, HCC patients who underwent laparoscopic hepatectomy (LH) or open hepatectomy (OH) were reviewed and analyzed. Propensity score matching (PSM), inverse probability of treatment weight (IPTW), and multivariate logistic regression analyses were utilized to assess the association of the operative approach with postoperative infectious complications, including incisional surgical site infection (SSI), organ/space SSI, and remote infection (RI). RESULTS: Among 3876 patients, 845 (21.8%) and 3031 (78.2%) patients underwent LH and OH, respectively. The overall incidence of infection was 6.9 versus 14.6% among patients who underwent LH versus OH, respectively ( P <0.001). Of note, the incidences of incisional SSI (1.8 vs. 6.3%, P <0.001), organ/space SSI (1.8 vs. 4.6%, P <0.001), and RI (3.8 vs. 9.8%, P <0.001) were all significantly lower among patients who underwent LH versus OH. After PSM (6.9, 1.8, 1.8, and 3.8% vs. 18.5, 8.4, 5.2, and 12.8%, respectively) and IPTW (9.5, 2.3, 2.1, and 5.5% vs. 14.3, 6.3, 4.5, and 9.8%, respectively), LH remained associated with statistically lower incidences of all types of infectious complications. After adjustment for other confounding factors on multivariate analyses, LH remained independently associated with lower incidences of overall infection, incisional SSI, organ/space SSI, and RI in the overall, PSM, and IPTW cohorts, respectively. CONCLUSION: Compared with open approach, laparoscopic approach was independently associated with lower incidences of postoperative infectious complications following hepatectomy for HCC.
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Carcinoma Hepatocelular , Laparoscopia , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Pontuação de Propensão , Hepatectomia/efeitos adversos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Laparoscopia/efeitos adversos , Tempo de Internação , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Background and Aim: Alpha-fetoprotein (AFP), a lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), is a protein that is induced by vitamin K deficiency or antagonist-II (PIVKA-II) that has been clinically used as a serum biomarker for early detection and diagnosis of hepatocellular carcinoma (HCC). Diagnostic performance of each serum biomarker alone, or their combinations for the detection of hepatitis C virus (HCV)-associated HCC were compared. Methods: Serum AFP, AFP-L3, and PIVKA-II levels were evaluated in patients with HCV-associated HCC, and those with chronic HCV infection without HCC (HCV-controls). The areas under the curve (AUC), sensitivity, and specificity were compared to identify the diagnostic performance of each serum HCC biomarker alone or in combination. Results: Overall, 172 HCV controls and 105 patients with HCV-associated HCC were enrolled. The AFP, AFP-L3, and PIVKA-II levels were significantly increased among patients with HCV-associated HCC when compared with HCV patients without HCC (p < 0.001). When these biomarkers were analyzed individually, PIVKA-II revealed the best predictive performance (AUC: PIVKA-II 0.90 vs. AFP 0.80 vs. AFP-L3 0.69, p < 0.001). In evaluating the combinations of any two biomarkers, the best predictive performance was found in PIVKA-II + AFP (0.93 vs. AFP + AFP-L3 0.78, p = 0.001; and PIVKA-II + AFP-L3 0.89, p < 0.001), which had no difference compared to the predictive performance of the combination of all three serum biomarkers (AFP + AFP-L3 + PIVKA-II 0.93, p = 0.277). Similar results were identified in the subgroups of patients with HCV-induced cirrhosis, and among patients with early-stage HCC defined by BCLC and TNM staging. Conclusions: The addition of the PIVKA-II test to routine AFP test maybe provide a more suitable biomarker approach to detect HCV-induced HCC in patients with HCV infection undergoing HCC surveillance.
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Background: The GALAD and ASAP scores are two well-recognized algorithms to estimate the risk of hepatocellular carcinoma (HCC) based on gender, age, alpha-fetoprotein (AFP), protein induced by vitamin K absence or Antagonist-II (PIVKA-II) and AFP-L3 (included in the GALAD score but not in the ASAP score). The current study sought to compare the diagnostic performance of each score to detect HCC among patients infected with hepatitis C virus (HCV). Methods: A multicenter case-control study was undertaken in which blood samples were collected from HCVinfected patients with and without HCC. Using the area under the receiver operating characteristic curve (AUROC), ASAP and GALAD scores were compared relative to diagnostic performance to detect any stage HCV-HCC and early-stage HCV-HCC. Results: The analytic cohort included 168 HCV-HCC patients and a control group of 193 HCV-infected patients. The ASAP score had a higher AUROC to detect any stage HCV-HCC versus the GALAD score, both in the overall group (0.917 vs. 0.894, P=0.057) and in the cirrhosis subgroup (0.909 vs. 0.889, P=0.132). Similar results were noted relative to the detection of early-stage HCV-HCC, whether defined by BCLC staging (stage 0-A: 0.898 vs. 0.860, P=0.026) or 8th TNM staging (stage I: 0.899 vs. 0.870, P=0.070). In subgroup analysis to detect AFP-negative HCV-HCC, the ASAP score also demonstrated a higher AUROC than the GALAD score to detect any stage HCV-HCC in the AFP-negative subgroup (0.815 vs. 0.764, P=0.063). Conclusions: The ASAP score had better diagnostic performance for early detection of HCV-HCC compared with the GALAD score. The ASAP score may be preferrable to the GALAD score for HCC screening and surveillance among HCV-infected patients.
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BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignancy in the elderly worldwide, but it is also common among younger individuals in areas with endemic hepatitis B virus infection. The differences in long-term oncological prognosis of young versus elderly patients after R0 liver resection for HCC were explored in this study. METHODS: Using a Chinese multicentre database, consecutive patients who underwent R0 liver resection for HCC between 2007 and 2019 were analysed retrospectively. After excluding middle-aged (36-69 years old) patients, overall survival (OS), cancer-specific survival (CSS), and recurrence were compared between young (35 years or younger) and elderly (70 years or older) patients using propensity score matching (PSM). RESULTS: Among 531 enrolled patients, there were 192 (36.2 per cent) and 339 (63.8 per cent) patients categorized as young and elderly respectively. PSM created 140 pairs of matched patients. In the PSM cohort, 5-year OS was comparable for young versus elderly patients (51.7 versus 52.3 per cent, P = 0.533). Young patients, however, had a higher 5-year cumulative recurrence rate (62.1 versus 51.6 per cent, P = 0.011) and a worse 5-year CSS rate (54.0 versus 64.3 per cent, P = 0.034) than elderly patients. On multivariable Cox regression analyses, young patient age remained independently associated with an increased recurrence rate (hazard ratio 1.62, P = 0.016) and a decreased CSS rate (hazard ratio 1.69, P = 0.021) compared with older age. CONCLUSION: Following R0 liver resection for HCC, younger patients were at a higher risk of recurrence, and elderly patients had a better CSS rate. Thus, enhanced surveillance for HCC recurrence should be implemented for young patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Idoso , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Estudos RetrospectivosRESUMO
Novel non-/minimally-invasive and effective approaches are urgently needed to supplement and improve current strategies for diagnosis and management of hepatocellular carcinoma (HCC). Overwhelming evidence from published studies on HCC has documented that multiple molecular biomarkers detected in body fluids and feces can be utilized in early-diagnosis, predicting responses to specific therapies, evaluating prognosis before or after therapy, as well as serving as novel therapeutic targets. Detection and analysis of proteins, metabolites, circulating nucleic acids, circulating tumor cells, and extracellular vesicles in body fluids (e.g., blood and urine) and gut microbiota (e.g., in feces) have excellent capabilities to improve different aspects of management of HCC. Numerous studies have been devoted in identifying more promising candidate biomarkers and therapeutic targets for diagnosis, treatment, and monitoring responses of HCC to conventional therapies, most of which may improve diagnosis and management of HCC in the future. This review aimed to summarize recent advances in utilizing these biomarkers in HCC and discuss their clinical significance.
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Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments. Despite being widely used, alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC. The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins, metabolites, circulating tumor deoxyribonucleic acid, and circulating non-coding ribonucleic acid. Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment, thus prolonging survival outcomes. Currently, multiple clinical trials involving locoregional, systemic therapies, and combinations of these modalities are changing therapeutic strategies for different stage HCC. Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future. This review summarizes the most recent advances in non-invasive early molecular detection, current therapy strategies, and potential immunotherapeutic innovations of HCC.