Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis.

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, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .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, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .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, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .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.

Role of hepatitis B core-related antigen in predicting the occurrence and recurrence of hepatocellular carcinoma in patients with chronic hepatitis B: A systemic review and meta-analysis.

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.

Efficacy and safety of immune checkpoint inhibitors for hepatocellular carcinoma patients with macrovascular invasion or extrahepatic spread: a systematic review and meta-analysis of 54 studies with 6187 hepatocellular carcinoma patients.

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.

MALAT1/ mir-1-3p mediated BRF2 expression promotes HCC progression via inhibiting the LKB1/AMPK signaling pathway.

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.

TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB-EGF Expression and Proteolytic Cleavage.

BACKGROUND AND AIMS: Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB-EGF to promote angiogenesis and HCC progression. APPROACH AND RESULTS: A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB-EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia-inducible factor 1 α signaling pathway. In addition, HB-EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3-kinase/Akt signaling pathway. The level of HB-EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence-free survival, which suggests that HB-EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB-EGF inhibitor cross-reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression. CONCLUSIONS: HB-EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB-EGF inhibitor cross-reacting material 197 with sorafenib might be used for individualized treatment of HCC.

Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: A systematic review with meta-analysis.

BACKGROUND AND AIM: The role of hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF-1α and HIF-2α overexpression with the prognosis and clinicopathological features of HCC. METHODS: A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. RESULTS: Twenty-two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF-1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53-2.00)] and DFS [HR = 1.64 (95% CI: 1.34-2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36-2.48)], tumor size [OR = 1.36 (95% CI: 1.12-1.66)], and tumor number [1.74 (95% CI: 1.34-2.25)]. In contrast, HIF-2α overexpression was not associated with the prognosis and clinicopathological features of HCC. CONCLUSION: Our data provided compelling evidence of a worse prognosis of HCC in HIF-1α overexpression patients but not HIF-2α overexpression ones.

Correction to: Hepatic metastatic paraganglioma 12 years after retroperitoneal paraganglioma resection: a case report.

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Hepatic metastatic paraganglioma 12 years after retroperitoneal paraganglioma resection: a case report.

BACKGROUND: Paragangliomas, also known as chemodectomas, are rare tumors arise from chemoreceptor tissue, and most commonly locate at the bifurcation of the common carotid, the jugular foramen, aortic arch, and retroperitoneum. Paragangliomas generally are considered to be benign tumors, and rarely produce local or distant metastases. Metastasis to liver is extremely rare. CASE PRESENTATION: We report the case of a 39-year-old woman, who had undergone resection of a retroperitoneal paraganglioma at her local hospital for 12 years. She was referred to our hospital for further evaluation of a hepatic mass, which was misdignosed as hepatocellular carcinoma (HCC) and was treated by transarterial chemoembolization (TACE) in the local hospital 6 years ago. At admission, CT scan revealed a huge hypervascular mass with many feeding arteries, almost the same size as 5 years ago. Ultrasound-guided biopsy of the liver tumor was performed and immunohistochemical examination confirmed the diagnosis of hepatic metastatic paraganglioma. Though liver metastasis failed to achieve complete response or partial response to TACE treatment, it remained stable without progression during the 7-year follow-up. CONCLUSION: Paragangliomas are slow growing tumors and metastasis may develop decades after resection of the primary lesion. Long-term follow-up is necessary, and curative or palliative treatment should be considered to control symptoms, improve life quality, reduce complications and prolong survival.

Neoadjuvant immunotherapy based on PD-1/L1 inhibitors for gastrointestinal tumors: a review of the rationale and clinical advances.

The landscape of current tumor treatment has been revolutionized by the advent of immunotherapy based on PD-1/PD-L1 inhibitors. Leveraging its capacity to mobilize systemic antitumor immunity, which is primarily mediated by T cells, there is growing exploration and expansion of its potential value in various stages of clinical tumor treatment. Neoadjuvant immunotherapy induces a robust immune response against tumors prior to surgery, effectively facilitating tumor volume reduction, early eradication or suppression of tumor cell activity, and control of potential metastatic spread, to improve curative surgical resection rates, and prevent tumor recurrence. This review delineates the theoretical basis of neoadjuvant immunotherapy from preclinical research evidence, discusses specific challenges in clinical application, and provides a comprehensive overview of clinical research progress in neoadjuvant immunotherapy for gastrointestinal tumors. These findings suggest that neoadjuvant immunotherapy has the potential to ameliorate immunosuppressive states and enhance cytotoxic T cell function while preserving lymphatic drainage in the preoperative period. However, further investigations are needed on specific treatment regimens, suitable patient populations, and measurable endpoints. Despite numerous studies demonstrating the promising efficacy and manageable adverse events of neoadjuvant immunotherapy in gastrointestinal tumors, the availability of high-quality randomized controlled trials is limited, which highlights the necessity for further research.

The effect of age, sex, and eastern cooperative oncology group performance status on the efficacy and safety of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

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.

Caffeine intake is associated with less severe depressive symptoms in noncancer populations: an analysis based on NHANES 2007-2016.

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.

Efficacy and security of tumor vaccines for hepatocellular carcinoma: a systemic review and meta-analysis of the last 2 decades.

BACKGROUND: Tumor vaccines for hepatocellular carcinoma (HCC) is an area of intense interest. Tremendous clinical trials have been conducted globally, but the efficacy and security of tumor vaccines are elusive. The aim of our study was to evaluate the efficacy and security of tumor vaccines. METHODS: All relevant studies were identified in PubMed, EMBASE, Web of science and Cochrane Library databases. Objective response rate (ORR), median overall survival (OS), or median progression-free survival (PFS) and 95% CI were meta-analyzed based on the random-effects model. The individual-level data of OS, PFS were pooled by conducting survival analysis. All observed adverse events were collected. RESULTS: 31 studies containing 35 eligible cohorts with 932 HCC patients were included. The pooled ORR were 7% (95% CI 3-14%), while ORR of dendritic cell (DC) vaccine (19%, 95% CI 11-29%) were highly significant than ORR of peptide vaccine (1%, 95% CI 0-5%). The pooled median OS and PFS were 13.67 months (95% CI 8.20-22.80) and 6.19 months (95% CI 2.97-12.91), respectively. The pooled median OS (DC vaccine: median OS = 21.77 months, 95% CI 18.33-25.86; Peptide vaccine: median OS = 10.08 months, 95% CI 5.23-19.44) and PFS (DC vaccine: median PFS = 11.01 months, 95% CI 5.25-23.09; Peptide vaccine: median PFS = 1.97 months, 95% CI 1.53-2.54) of DC vaccine were also longer than that of peptide vaccine. HBV-related HCC may acquire more benefits from tumor vaccines than HCV-related HCC. In almost all studies, the observed toxicities were moderate even tiny. CONCLUSIONS: Tumor vaccines for HCC, especially DC vaccine, are safe and worth exploring. More high-quality prospective studies are warranted.

Hepatitis B virus reactivation in patients undergoing immune checkpoint inhibition: systematic review with meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been explored as first-line treatment in various types of previously untreatable malignancies, while limited evidence is available on the management of hepatitis B virus (HBV) in patients undergoing immunotherapy. We systematically reviewed data concerning challenges of hepatic adverse events including HBV reactivation and hepatitis in patients with chronic HBV infection undergoing immunotherapy. METHODS: A systematic search was conducted in Medline, web of science, Embase and Cochrane library up to May 31, 2022. Studies reporting the safety profile of ICIs in patients with HBV infection were eligible. Meta-analyses were conducted to generate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 13 studies including 2561 patients were included for meta-analysis. The overall incidence rates of HBV reactivation in patients with chronic HBV infection and past HBV infection were 1.0% (95% CI 0-3%) and 0% (95% CI 0-0%), respectively. Among patients with chronic HBV infection, the incidence rates of HBV reactivation were 1.0% (95% CI 0-2%) and 10.0% (95% CI 4-18%) for patients with and without antiviral prophylaxis, respectively. Patients with chronic HBV infection were at a higher risk of HBV reactivation compared with those with past HBV infection [OR = 8.69, 95% CI (2.16-34.99)]. Antiviral prophylaxis significantly reduced the risk of HBV reactivation [OR = 0.12, 95% CI (0.02-0.67)] and HBV-associated hepatitis [OR = 0.05, 95% CI (0.01-0.28)] in patients with chronic HBV infection. CONCLUSIONS: Prophylactic antiviral therapy should be administered to patients with chronic HBV infection undergoing anticancer immunotherapy. Patients with past HBV infection are at lower risk of HBV reactivation compared with those with chronic HBV infection, they could be initiated with antiviral prophylaxis or monitored with the intent of on-demand antiviral therapy.

Evaluating liver function and the impact of immune checkpoint inhibitors in the prognosis of hepatocellular carcinoma patients: A systemic review and meta-analysis.

BACKGROUND: Most patients with hepatocellular carcinoma (HCC) have underlying cirrhosis and a compromised liver function. Immune checkpoint inhibitors (ICIs) have emerged as an important approach for HCC treatment. The purpose of our study was to explore the prognostic significance of liver function in HCC patients receiving ICIs. METHODS: Hazard ratios (HR) with 95% confidence intervals (CI) were used to evaluate the relationship between liver function and overall survival (OS)/progression-free survival (PFS). RESULTS: 41 articles with 4483 patients with HCC were included. The pooled results revealed that either Child-Pugh score (OS:HR = 2.01,95 %CI:1.69-2.38; PFS:HR = 1.39,95 %CI:1.15-1.68) or albumin-bilirubin (ALBI) score (OS:HR = 2.04,95 %CI:1.55-2.69; PFS:HR = 1.42,95 %CI:1.21-1.67) can predict the patient prognosis. The Child-Pugh score has some degree of subjectivity, and the ALBI score can better stratify patients. Therefore, the ALBI score was used to evaluate patients' liver function and determine treatment options. Further subgroup analysis found that the results of prospective studies were statistically significant only for the ALBI score with regards to OS (HR = 1.69,95 %CI:1.26-2.26). Meanwhile, the effect of liver function on the efficacy of ICIs in the large-sample studies was not as obvious as that in small-sample studies. Moreover, the incidence of adverse events did not significantly increase in patients with impaired liver function. CONCLUSION: Poor liver function is associated with a poor prognosis in patients with HCC receiving ICIs. The ALBI score is simpler and reliable for patient stratification than the Child-Pugh score. Although the survival time of patients with impaired liver function may be relatively short, ICIs still have great potential for therapeutic applications.

Systemic therapy with or without locoregional therapy for advanced hepatocellular carcinoma: A systematic review and network meta-analysis.

We aim to identify the optimal treatment option of systemic therapy with or without locoregional therapy for advanced hepatocellular carcinoma (HCC). Outcomes of interest include overall survival (OS), progression-free survival (PFS), objective response rate (ORR), grade 3-4 treatment-related adverse events (TRAEs), and incidence of treatment discontinuation due to AEs. The surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the interventions. 23 randomized-controlled trials including 14,303 patients with advanced HCC were included. Lenvatinib plus transcatheter arterial chemoembolization (TACE) ranked best regarding OS benefit (SUCRA: 0.99). Immuno-oncology (IO)-multikinase inhibitor (MKI)/vascular endothelial growth factor (VEGF) inhibitor combinations had a higher probability of providing better OS than IO-IO combinations. IO monotherapies demonstrated superior safety profile while combination therapies caused more toxicity in general. We conclude that combination therapies achieve remarkable efficacy in patients with advanced HCC and clinical decision making requires a careful balance of efficacy versus risk.

Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity.

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.

Regional and sex differences in the mortality risk associated with primary liver cancer in obesity: A systematic review and meta-analysis.

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.

Adverse events of immune checkpoint inhibitors in hepatocellular carcinoma: a systemic review and meta-analysis.

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.

Anthropometric indicators of adiposity and risk of primary liver cancer: A systematic review and dose-response meta-analysis.

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.

The somatic mutational landscape and role of the ARID1A gene in hepatocellular carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Clarification of the somatic mutational landscape of important genes could reveal new therapeutic targets and facilitate individualized therapeutic approaches for HCC patients. The mutation and expression changes in the ARID1A gene in HCC remain controversial. Methods: First, cBioPortal was used to visualize genetic alterations and DNA copy number alterations (CNAs) in ARID1A. The relationships between ARID1A mutation status and HCC patient clinicopathological features and overall survival (OS) were also determined. Then, a meta-analysis was performed to evaluate the effect of ARID1A mutation or expression on the prognosis of HCC patients. Finally, the role of ARID1A in HCC progression was verified by in vitro experiments. Results: ARID1A mutation was detected in 9.35% (33/353) of sequenced HCC cases, and ARID1A mutation decreased ARID1A mRNA expression. Patients with ARID1A alterations presented worse OS than those without ARID1A alterations. Meta-analysis and human HCC tissue microarray (TMA) analysis revealed that HCC patients with low ARID1A expression had worse OS and relapse-free survival (RFS), and low ARID1A expression was negatively correlated with tumour size. Then, ARID1A gain-of-function and loss-of-function experiments demonstrated the tumour suppressor role of ARID1A in HCC in vitro. In terms of the mechanism, we found that ARID1A could inhibit HCC progression by regulating retinoblastoma-like 1 (RBL1) expression via the JNK/FOXO3 pathway. Conclusions: ARID1A can be considered a potential prognostic biomarker and candidate therapeutic target for HCC.