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BACKGROUNDS: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. METHODS: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. RESULTS: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, Pâ <â .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, Pâ <â .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, Pâ =â .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, Pâ =â 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, Pâ <â .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, Pâ <â .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, Pâ <â .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, Pâ <â .05). CONCLUSION: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.
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BACKGROUND: The effect of age, sex, and eastern cooperative oncology group performance status (ECOG PS) on the efficacy and safety of immune checkpoint inhibitor (ICI) therapy among hepatocellular carcinoma (HCC) patients remains elusive. Thus, a meta-analysis was conducted to evaluate whether such effects exist. RESEARCH DESIGN AND METHODS: Eligible studies in PubMed, Embase, and Cochrane Library databases were retrieved. RESULTS: One-hundred-and-eleven studies involving 14,768 HCC patients were included. The findings indicated that the ECOG PS didn't have a significant effect on the ORR and PFS in ICI-treated HCC patients (higher ECOG PS vs. lower ECOG PS: ORR: OR = 0.78, 95%CI = 0.55-1.10; PFS: HR = 1.15, 95%CI = 0.97-1.35), while those patients with a higher ECOG PS may have a worse OS (HR = 1.52, 95% CI = 1.26-1.84). There is no significant evidence of the effect of age (older vs. younger) or sex (males vs. females) on the efficacy of ICI therapy in HCC. CONCLUSION: ICI therapy in HCC should not be restricted strictly to certain patients in age or sex categories, while HCC patients with higher ECOG PS may require closer medication or follow-up strategy during ICI therapy. PROSPERO REGISTRATION: CRD42024518407.
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Carcinoma Hepatocelular , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/farmacología , Factores de Edad , Factores Sexuales , Masculino , Femenino , Supervivencia sin ProgresiónRESUMEN
BACKGROUND AND AIM: The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS: We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. RESULTS: Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031). CONCLUSIONS: For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.
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Carcinoma Hepatocelular , Antígenos del Núcleo de la Hepatitis B , Hepatitis B Crónica , Neoplasias Hepáticas , Recurrencia Local de Neoplasia , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/virología , Humanos , Hepatitis B Crónica/complicaciones , Antígenos del Núcleo de la Hepatitis B/sangre , Antígenos del Núcleo de la Hepatitis B/inmunología , Factores de Riesgo , Valor Predictivo de las Pruebas , Antígenos e de la Hepatitis B/sangre , Masculino , Femenino , Biomarcadores de Tumor/sangreRESUMEN
INTRODUCTION: The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing globally. We aimed to assess the performance of alpha-fetoprotein (AFP), AFP-L3, des-gamma-carboxy prothrombin (DCP), and GALAD score in detecting NAFLD-related HCC. METHODS: We searched the relevant literature in PubMed, Embase and Cochrane. Conventional and network meta-analyses were performed for sensitivity, specificity, Youden index (YI), and the area under the summary receiver operator characteristic curve (AUC). RESULTS: Fifteen studies involving 2031 NAFLD participants were included in this meta-analysis. When detecting early-stage NAFLD-related HCC, GALAD score and DCP process excellent performance. The sensitivity and AUC of DCP (0.60, 0.74, respectively) were higher than AFP (0.34, 0.59, respectively). The network meta-analysis showed that DCP and GALAD score had similar performance. In detecting all-stage NAFLD-related HCC, GALAD score (sensitivity = 0.87; YI = 0.77) performed better than AFP (sensitivity = 0.56; YI = 0.50), AFP-L3 (sensitivity = 0.39; YI = 0.36) and DCP (sensitivity = 0.73; YI = 0.62). Network meta-analysis obtained consistent results with conventional meta-analysis. CONCLUSIONS: Due to the lower cost-effectiveness, DCP was more suitable for detecting early NAFLD-related HCC. AFP could be used in detecting all-stage NAFLD-related HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiología , alfa-Fetoproteínas/análisis , Metaanálisis en Red , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiología , Precursores de Proteínas , Protrombina , Biomarcadores , Biomarcadores de TumorRESUMEN
BACKGROUND AND AIM: The presence of microvascular invasion (MVI) will impair the surgical outcome of hepatocellular carcinoma (HCC). Adipose and muscle tissues have been confirmed to be associated with the prognosis of HCC. We aimed to develop and validate a nomogram based on adipose and muscle related-variables for preoperative prediction of MVI in HCC. METHODS: One hundred fifty-eight HCC patients from institution A (training cohort) and 53 HCC patients from institution B (validation cohort) were included, all of whom underwent preoperative CT scan and curative resection with confirmed pathological diagnoses. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied to data dimensionality reduction and screening. Nomogram was constructed based on the independent variables, and evaluated by external validation, calibration curve, receiver operating characteristic (ROC) curve and decision curve analysis (DCA). RESULTS: Histopathologically identified MVI was found in 101 of 211 patients (47.9%). The preoperative imaging and clinical variables associated with MVI were visceral adipose tissue (VAT) density, intramuscular adipose tissue index (IMATI), skeletal muscle (SM) area, age, tumor size and cirrhosis. Incorporating these 6 factors, the nomogram achieved good concordance index of 0.79 (95%CI: 0.72-0.86) and 0.75 (95%CI: 0.62-0.89) in training and validation cohorts, respectively. In addition, calibration curve exhibited good consistency between predicted and actual MVI probabilities. ROC curve and DCA of the nomogram showed superior performance than that of models only depended on clinical or imaging variables. Based on the nomogram score, patients were divided into high (> 273.8) and low (< = 273.8) risk of MVI presence groups. For patients with high MVI risk, wide-margin resection or anatomical resection could significantly improve the 2-year recurrence free survival. CONCLUSION: By combining 6 preoperative independently predictive factors of MVI, a nomogram was constructed. This model provides an optimal preoperative estimation of MVI risk in HCC patients, and may help to stratify high-risk individuals and optimize clinical decision making.
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Depression and cancer are both prevalent diseases worldwide. Numerous cancer patients experience psychological illnesses, especially depression, following a malignancy's dismal prognosis. Although some research has suggested that caffeine may be protective against depressive symptoms, it is still unclear how caffeine and cancer patients are related. Thus, we hypothesized that moderate daily caffeine intake may reduce the risk of depression in both the cancer and noncancer populations. Data were extracted and combined from the National Health and Nutrition Examination Survey from 2007 to 2016. After controlling for potential confounding factors, interaction effects analysis was used to clarify the interaction between caffeine and cancer on depressive symptoms. Linear regression analysis and restricted cubic splines were used to further analyze the relationship between caffeine and depression in cancer and noncancer populations. A total of 24,145 participants were included in the analysis. In the noncancer population, the quartile 3 group of caffeine intake showed a negative association between caffeine intake and Patient Health Questionnaire-9 (PHQ-9) scores (ß = -0.23, 95% confidence interval, -0.45 to -0.01; P = .041). No association between caffeine intake and PHQ-9 scores was observed in the cancer population. In both cancer and noncancer populations, restricted cubic splines indicated a nonlinear trend between caffeine and PHQ-9 scores, with the lowest PHQ-9 scores when caffeine intake was 119.52 mg. In the noncancer population, moderate daily caffeine intake (quartile 3 group; range, 119.5-236.5 mg) was associated with reduced depressive symptoms, whereas in the cancer population, no association was found between caffeine intake and depression.
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Depresión , Neoplasias , Humanos , Encuestas Nutricionales , Depresión/epidemiología , Cafeína , Modelos LinealesRESUMEN
BACKGROUND: The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to play a vital role in the occurrence and development of various tumors. However, the underlying mechanism of MALAT1 in hepatocellular carcinoma (HCC) has not been thoroughly elucidated. METHODS: The expression levels of MALAT1 in HCC tissues and different cell lines were detected by qRT-PCR. Antisense oligonucleotides (ASO)-MALAT1 transfected cells were used to explore the biological effects of MALAT1 in HCC cells by cell counting kit 8 (CCK-8), colony formation, transwell, wound healing, and flow cytometry analysis. Western blotting was performed to measure AMPK and apoptosis-related protein levels. Dual-luciferase reporter assay was performed to verify the relationship between MALAT1 and its specific targets. RESULTS: We found that MALAT1 was upregulated in HCC, and MALAT1 knockdown in HCC cells inhibited cell proliferation, migration, and invasion and inhibited apoptosis in vitro. Further studies demonstrated that MALAT1 positively regulated the expression of transcription factor II Brelated factor 2 (BRF2), which was associated with tumor recurrence, large tumor size, and poor prognosis in HCC. Mechanistically, MALAT1 was found to act as a competitive endogenous RNA to sponge has-miR-1-3p, which upregulated BRF2 expression. Knockdown of BRF2 inhibited the progression of HCC by activating the LKB1/AMPK signaling pathway. Overexpression of BRF2 reversed the inhibitory effect of MALAT1 knockdown on HCC cell viability. Moreover, ASO targeting MALAT1 inhibited the growth of xenograft tumors. CONCLUSIONS: Our results demonstrate a novel MALAT1/miR-1-3p/BRF2/LKB1/AMPK regulatory axis in HCC, which may provide new molecular therapeutic targets for HCC in the future.
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As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Lipoproteína Lipasa/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
OBJECTIVE: Obesity has increasingly become a prominent public health problem. Although some studies have shown that obesity is associated with the risk for primary liver cancer (PLC)-related mortality, the regional and sex differences are not clear. The aim of this meta-analysis was to further elucidate the influence of obesity on PLC prognosis from multiple aspects. METHODS: This study used a systematic literature search on PubMed, Embase, Cochrane Library, Web of Science, Sinomed, and CNKI for eligible studies evaluating the effects of obesity on the prognosis of PLC. Data on PLC-related mortality, all-cause mortality, or recurrence should be available to obtain, and studies providing regional, or sex specificity are of concern. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to assess the pooled risk. RESULTS: Obesity is strongly associated with an increased risk for PLC-related mortality. A significant regional difference was observed (North America: HR, 1.57; 95% CI, 1.06-2.34; Europe: HR, 1.53; 95% CI, 1.08-2.16; Asia: HR, 1.05; 95% CI, 0.92-1.19; Oceania: HR, 1.13; 95% CI, 0.76-1.67). A stronger association between excess body mass index (BMI) and an increased risk for PLC-related mortality was demonstrated in men compared with women (men: HR, 1.87; 95% CI, 1.25-2.77; women: HR, 1.22; 95% CI, 1.00-1.47). No association was observed in the analysis between obesity and all-cause mortality and recurrence risk in PLC (all-cause mortality: HR, 1.01; 95% CI, 0.96-1.06; recurrence risk: HR, 1.00; 95% CI, 0.88-1.15). CONCLUSION: This study demonstrated a stronger association between obesity and PLC-related mortality in North America and Europe and among men.
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Neoplasias Hepáticas , Caracteres Sexuales , Femenino , Humanos , Masculino , Obesidad/complicaciones , Índice de Masa Corporal , Pronóstico , Neoplasias Hepáticas/complicacionesRESUMEN
Liver metastasis is a frequent phenomenon in advanced tumor disease. Immune checkpoint inhibitors (ICIs) are a new class of therapeutics that can improve the prognosis of cancer patients. The purpose of this study is to elucidate the relationship between liver metastasis and survival outcomes of patients receiving ICIs treatment. We searched four main databases, including PubMed, EMBASE, Cochrane Library, and Web of Science. Overall survival (OS) and progression-free survival (PFS) were the survival outcomes of our concern. Hazard ratio (HR) with 95% confidence interval (CI) were used to evaluate the relationship between liver metastasis and OS/ PFS. Finally, 163 articles were included in the study. The pooled results showed that patients with liver metastasis receiving ICIs treatment had worse OS (HR=1.82, 95%CI:1.59-2.08) and PFS (HR=1.68, 95%CI:1.49-1.89) than patients without liver metastasis. The effect of liver metastasis on ICIs efficacy differed in different tumor types, and patients with urinary system tumors (renal cell carcinoma OS: HR=2.47, 95%CI:1.76-3.45; urothelial carcinoma OS: HR=2.37, 95%CI:2.03-2.76) had the worst prognosis, followed by patients with melanoma (OS: HR=2.04, 95%CI:1.68-2.49) or non-small cell lung cancer (OS: HR=1.81, 95%CI:1.72-1.91). ICIs efficacy in digestive system tumors (colorectal cancer OS: HR=1.35, 95%CI:1.07-1.71; gastric cancer/ esophagogastric cancer OS: HR=1.17, 95%CI:0.90-1.52) was less affected, and peritoneal metastasis and the number of metastases have a greater clinical significance than liver metastasis based on univariate data. For cancer patients receiving ICIs treatment, the occurrence of liver metastasis is associated with poor prognosis. Different cancer types and metastatic sites may hold a different prognostic effect on the efficacy of ICIs treatment in cancer patients.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Transicionales , Neoplasias Esofágicas , Neoplasias Renales , Neoplasias Hepáticas , Neoplasias Pulmonares , Neoplasias Gástricas , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive. Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells' pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes' expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation. Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-â ¡ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines. Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.
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BACKGROUND AND AIMS: Adiposity is associated with an increased risk of primary liver cancer (PLC). As the most commonly used indicator of adiposity, the body mass index (BMI) has been questioned for its limitations in reflecting visceral fat. This study aimed to investigate the role of different anthropometric indicators in identifying the risk of PLC by accounting for potential non-linear associations. METHODS: Systematic searches were conducted in the PubMed, Embase, Cochrane Library, Sinomed, Web of Science, and CNKI databases. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to assess the pooled risk. The dose-response relationship was assessed using a restricted cubic spline model. RESULTS: Sixty-nine studies involving more than 30 million participants were included in the final analysis. Regardless of the indicator used, adiposity was strongly associated with an increased risk of PLC. When comparing the HRs per 1-standard deviation increment across indicators of adiposity, the association was strongest for waist-to-height ratio (WHtR) (HR = 1.39), followed by waist-to-hip ratio (WHR) (HR = 1.22), BMI (HR = 1.13), waist circumference (WC) (HR = 1.12), and hip circumference (HC) (HR = 1.12). A strong non-linear association was observed between each anthropometric parameter and the risk of PLC, regardless of whether the original or decentralised value was used. The positive association between WC and PLC risk remained substantial after adjusting for BMI. The incidence of PLC was higher with central adiposity (52.89 per 100,000 person-years, 95% CI = 50.33-55.44) than general adiposity (39.01 per 100,000 person-years, 95% CI = 37.26-40.75). CONCLUSION: Central adiposity seems to contribute more to the development of PLC than general adiposity. A larger WC, independent of BMI, was strongly associated with the risk of PLC and might be a more promising predictive indicator than BMI.
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Adiposidad , Neoplasias Hepáticas , Humanos , Factores de Riesgo , Obesidad/epidemiología , Circunferencia de la Cintura , Índice de Masa Corporal , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/complicacionesRESUMEN
BACKGROUND AND AIMS: The impacts of macrovascular invasion (MVI) or extrahepatic spread (EHS) on the efficacy and safety of immune checkpoint inhibitors (ICIs) among hepatocellular carcinoma (HCC) patients remain unclear. Thus, we conducted a systematic review and meta-analysis to clarify whether ICI therapy is a feasible treatment option for HCC with MVI or EHS. METHODS: Eligible studies published before September 14, 2022, were retrieved. In this meta-analysis, the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of adverse events (AEs) were outcomes of interest. RESULTS: Fifty-four studies involving 6187 individuals were included. The findings indicated that the presence of EHS in ICI-treated HCC patients may indicate an inferior ORR (OR 0.77, 95% CI 0.63-0.96), but may not significantly affect the PFS (multivariate analyses: HR 1.27, 95% CI 0.70-2.31) and OS (multivariate analyses: HR 1.23, 95% CI 0.70-2.16). Additionally, the presence of MVI in ICI-treated HCC patients may not have significant prognostic impact on ORR (OR 0.84, 95% CI 0.64-1.10), but may indicate inferior PFS (multivariate analyses: HR 1.75, 95% CI 1.07-2.84) and OS (multivariate analyses: HR 2.03, 95% CI 1.31-3.14). The presence of EHS or MVI in ICI-treated HCC patients may not significantly impact the occurrence of any serious immune-related adverse events (irAEs) (grades ≥ 3) (EHS: OR 0.44, 95% CI 0.12-1.56; MVI: OR 0.68, 95% CI 0.24-1.88). CONCLUSION: The presence of MVI or EHS in ICI-treated HCC patients may not significantly impact the occurrence of serious irAEs. However, the presence of MVI (but not EHS) in ICI-treated HCC patients may be a significant negative prognostic factor. Therefore, ICI-treated HCC patients with MVI warrant more attention.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Hepáticas/patología , PronósticoRESUMEN
The introduction of immune checkpoint inhibitors (ICIs) has reshaped the therapy of hepatocellular carcinoma (HCC). ICIs are a novel therapy with frequent adverse events (AEs), including treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). However, no comprehensive overview of the toxicity spectrum of ICIs in HCC patients has been provided. Electronic databases were searched to identify eligible studies. A meta-analysis of the incidence rate of AEs in HCC patients treated with ICIs was performed. Lastly, the prognostic value of irAEs in HCC patients treated with ICIs was verified. Forty-seven studies with 6472 participations met the inclusion criteria. The pooled all-grade trAEs incidence rate was 83.4% (95% confidence interval [95% CI] 77.0-89.1%), ≥ grade 3 trAEs incidence rate was 33.0% (95% CI 26.9-39.5%), all-grade irAEs incidence rate was 34% (95% CI 22-47%), and ≥ grade 3 irAEs incidence rate was 9% (95% CI 5-14%). Aspartate aminotransferase (AST) increase (38%, 95% CI 35-40%) is the most common trAEs. Fatigue (14%, 95% CI 7-23%) is the most common irAEs. The pooled results also showed that 18.8% (95% CI 13.2-25.2%) of patients required systemic steroid therapy due to AEs, while 6.6% (95% CI 4.6-9.0%) of patients withdrew from treatment due to AEs. Additionally, patients experiencing irAEs may have a better progression-free survival (PFS) (multivariate analysis: hazard ratio [HR] = 0.41, 95% CI 0.27-0.61, I2 = 36.3%) but not overall survival (OS) (multivariate analysis: HR = 0.54, 95% CI 0.22-1.36, I2 = 83.2%) than those with no irAEs. Our study presents a systemic assessment of the AEs profile in HCC patients receiving ICIs, providing important reference for clinicians on toxicity profile. Besides, patients with irAEs may have a better PFS. More large-scale and prospective studies are needed to confirm our conclusions.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Aspartato AminotransferasasRESUMEN
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, having a significantly poor prognosis and no sufficiently efficient treatments. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided new therapeutic approaches for HCC patients. Nevertheless, most patients with HCC do not benefit from immunotherapy. Exosomes are biologically active lipid bilayer nano-sized vesicles ranging in size from 30 to 150 nm and can be secreted by almost any cell. In the HCC tumor microenvironment (TME), numerous cells are involved in tumor progression, and exosomes-derived from tumor cells and immune cells-exhibit unique composition profiles and act as intercellular communicators by transporting various substances. Showing the dual characteristics of tumor promotion and suppression, exosomes exert multiple functions in shaping tumor immune responses in the crosstalk between tumor cells and surrounding immune cells, mediating immunotherapy resistance by affecting the PD-1/PD-L1 axis or the anti-tumor function of immune cells in the TME. Targeting exosomes or the application of exosomes as therapies is involved in many aspects of HCC immunotherapies (e.g., ICIs, tumor vaccines, and adoptive cell therapy) and may substantially enhance their efficacy. In this review, we discuss the impact of exosomes on the HCC TME and comprehensively summarize the role of exosomes in immunotherapy resistance and therapeutic application. We also discuss the potential of exosomes as biomarkers for predicting the efficacy of immunotherapy to help clinicians in identifying HCC patients who are amenable to immunotherapies.
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Ionic liquids (ILs) are used in lignocellulosic biomass (LCB) pretreatment because of their ability to disrupt the extensive hydrogen-bonding network in cellulose and hemicellulose, and thereby decrease LCB recalcitrance to subsequent enzymatic degradation. However, this approach necessitates the development of cellulases and hemicellulases that can tolerate â¼20% (w/v) IL, an amount that either co-precipitates with the sugar polymers after the initial pretreatment or is typically used in single-pot biomass deconstructions. By investigating the secretomes from 4 marine-derived fungal endophytes, we identified a ß-xylosidase derived from Trichoderma harzianum as the most promising in terms of tolerating 1-ethyl-3-methylimidazolium-dimethyl phosphate (EMIM-DMP), an IL. When tested with p-nitrophenyl-ß-d-xyloside, this extracellular xylosidase retained â¼50% activity even in 1.2 mol·L-1 (20% w/v) EMIM-DMP after incubation for 48 h. When tested on the natural substrate xylobiose, there was â¼85% of the initial activity in 1.2 mol·L-1 EMIM-DMP after incubation for 9 h and â¼80% after incubation for 48 h. Despite previous findings associating thermostability and IL tolerance, our findings related to the mesophilic T. harzianum ß-xylosidase(s) emphasize the need to include the marine habitat in the bioprospecting dragnet for identification of new IL-tolerant LCB-degrading enzymes.
Asunto(s)
Endófitos/enzimología , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Líquidos Iónicos/farmacología , Compuestos Organofosforados/farmacología , Trichoderma/enzimología , Xilosidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Imidazoles/química , Líquidos Iónicos/química , Compuestos Organofosforados/química , Cloruro de Sodio/químicaRESUMEN
Chronic heart failure is often characterized by the elevated amounts of reactive oxygen species such as hydrogen peroxide (H2O2) in the heart. Thus, it is of importance that selective release of therapeutic drugs occurs at the heart failure site to maximize therapeutic effects. In this work, functional mesoporous silica nanoparticles (MSNPs) were developed for detection of H2O2, selective drug release and controlled treatment toward heart failure. The H2O2-sensitive probe was attached to the surface of the MSNPs, and a therapeutic drug of heart failure, captopril, was loaded within the pores of the MSNPs and retained by the binding of α-cyclodextrin to the probe. H2O2 present in tissue could react with the probe and enable the dissociation of α-cyclodextrin present on the nanoparticle surface, so that captopril could be successfully released along with "turn-on" of the probe fluorescence. In vivo experiments using the KillerRed heart failure transgenic zebrafish model demonstrated that this therapeutic system is physiologically responsive. Captopril-loaded MSNPs showed high therapeutic efficacy, improving the heartbeat rate and cardiac output in zebrafish experiencing acute KillerRed-induced heart failure.
Asunto(s)
Captopril/administración & dosificación , Sistemas de Liberación de Medicamentos , Insuficiencia Cardíaca/tratamiento farmacológico , Peróxido de Hidrógeno/análisis , Nanopartículas , Dióxido de Silicio , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Liberación de Fármacos , Porosidad , Pez Cebra , alfa-CiclodextrinasRESUMEN
Responsive nanomaterials have emerged as promising candidates as drug delivery vehicles in order to address biomedical diseases such as cancer. In this work, polymer-based responsive nanoparticles prepared by a supramolecular approach are loaded with doxorubicin (DOX) for the cancer therapy. The nanoparticles contain disulfide bonds within the polymer network, allowing the release of the DOX payload in a reducing environment within the endoplasm of cancer cells. In addition, the loaded drug can also be released under acidic environment. In vitro anticancer studies using redox and pH dual responsive nanoparticles show excellent performance in inducing cell death and apoptosis. Zebrafish larvae treated with DOX-loaded nanoparticles exhibit an improved viability as compared with the cases treated with free DOX by the end of a 3 d treatment. Confocal imaging is utilized to provide the daily assessment of tumor size on zebrafish larva models treated with DOX-loaded nanoparticles, presenting sustainable reduction of tumor. This work demonstrates the development of functional nanoparticles with dual responsive properties for both in vitro and in vivo drug delivery in the cancer therapy.