Pub Date : 2024-09-07DOI: 10.1016/j.jhepr.2024.101212
<div><h3>Background & Aims</h3><div>Transforming growth factor β (TGF-β) plays an oncogenic role in advanced cancer by promoting cell proliferation, metastasis and immunosuppression. <em>PMEPA1</em> (prostate transmembrane protein androgen induced 1) has been shown to promote TGF-β oncogenic effects in other tumour types. Thus, we aimed to explore the role of <em>PMEPA1</em> in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>We analysed 1,097 tumours from patients with HCC, including discovery (n = 228) and validation (n = 361) cohorts with genomic and clinicopathological data. <em>PMEPA1</em> levels were assessed by qPCR (n = 228), gene expression data (n = 869) and at the single-cell level (n = 54). Genetically engineered mouse models overexpressing <em>MYC+PMEPA1</em> compared to <em>MYC</em> were generated and molecular analyses were performed on the HCCs obtained.</div></div><div><h3>Results</h3><div><em>PMEPA1</em> was overexpressed in 18% of HCC samples (fold-change >2; n = 201/1,097), a feature associated with TGF-β signalling activation (<em>p <</em>0.05) and absence of gene body hypomethylation (<em>p <</em>0.01). HCCs showing both TGF-β signalling and high <em>PMEPA1</em> levels (12% of cases) were linked to immune exhaustion, late TGF-β activation, aggressiveness and higher recurrence rates after resection, in contrast to HCCs with only TGF-β signalling (8%) or <em>PMEPA1</em> overexpression (9%). Single-cell RNA sequencing analysis identified <em>PMEPA1</em> expression in HCC and stromal cells. <em>PMEPA1</em>-expressing tumoural cells were predicted to interact with CD4<sup>+</sup> regulatory T cells and CD4<sup>+</sup> CXCL13<sup>+</sup> and CD8<sup>+</sup> exhausted T cells. <em>In vivo</em>, overexpression of <em>MYC</em>+<em>PMEPA1</em> led to HCC development in ∼60% of mice and a decreased survival compared to mice overexpressing <em>MYC</em> alone (<em>p =</em> 0.014). <em>MYC</em>+<em>PMEPA1</em> tumours were enriched in TGF-β signalling, paralleling our human data.</div></div><div><h3>Conclusions</h3><div>In human HCC, <em>PMEPA1</em> upregulation is linked to TGF-β activation, immune exhaustion, and an aggressive phenotype. Overexpression of <em>PMEPA1+MYC</em> led to tumoural development <em>in vivo</em>, demonstrating the oncogenic role of <em>PMEPA1</em> in HCC for the first time.</div></div><div><h3>Impact and implications:</h3><div><em>PMEPA1</em> can enhance the tumour-promoting effects of TGF-β in cancer. In this study, we demonstrate that <em>PMEPA1</em> is highly expressed in ∼18% of patients with hepatocellular carcinoma (HCC), a feature associated with poor prognosis, TGF-β activation and exhaustion of immune cells. Similarly, in mouse models, <em>PMEPA1</em> overexpression promotes HCC development, which demonstrates its oncogenic role. The identification of <em>PMEPA1</em> as oncogenic driver in HCC and its role in immune exhaustion and poor clinical outcomes enhances our under
{"title":"Oncogenic role of PMEPA1 and its association with immune exhaustion and TGF-β activation in HCC","authors":"","doi":"10.1016/j.jhepr.2024.101212","DOIUrl":"10.1016/j.jhepr.2024.101212","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Transforming growth factor β (TGF-β) plays an oncogenic role in advanced cancer by promoting cell proliferation, metastasis and immunosuppression. <em>PMEPA1</em> (prostate transmembrane protein androgen induced 1) has been shown to promote TGF-β oncogenic effects in other tumour types. Thus, we aimed to explore the role of <em>PMEPA1</em> in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>We analysed 1,097 tumours from patients with HCC, including discovery (n = 228) and validation (n = 361) cohorts with genomic and clinicopathological data. <em>PMEPA1</em> levels were assessed by qPCR (n = 228), gene expression data (n = 869) and at the single-cell level (n = 54). Genetically engineered mouse models overexpressing <em>MYC+PMEPA1</em> compared to <em>MYC</em> were generated and molecular analyses were performed on the HCCs obtained.</div></div><div><h3>Results</h3><div><em>PMEPA1</em> was overexpressed in 18% of HCC samples (fold-change >2; n = 201/1,097), a feature associated with TGF-β signalling activation (<em>p <</em>0.05) and absence of gene body hypomethylation (<em>p <</em>0.01). HCCs showing both TGF-β signalling and high <em>PMEPA1</em> levels (12% of cases) were linked to immune exhaustion, late TGF-β activation, aggressiveness and higher recurrence rates after resection, in contrast to HCCs with only TGF-β signalling (8%) or <em>PMEPA1</em> overexpression (9%). Single-cell RNA sequencing analysis identified <em>PMEPA1</em> expression in HCC and stromal cells. <em>PMEPA1</em>-expressing tumoural cells were predicted to interact with CD4<sup>+</sup> regulatory T cells and CD4<sup>+</sup> CXCL13<sup>+</sup> and CD8<sup>+</sup> exhausted T cells. <em>In vivo</em>, overexpression of <em>MYC</em>+<em>PMEPA1</em> led to HCC development in ∼60% of mice and a decreased survival compared to mice overexpressing <em>MYC</em> alone (<em>p =</em> 0.014). <em>MYC</em>+<em>PMEPA1</em> tumours were enriched in TGF-β signalling, paralleling our human data.</div></div><div><h3>Conclusions</h3><div>In human HCC, <em>PMEPA1</em> upregulation is linked to TGF-β activation, immune exhaustion, and an aggressive phenotype. Overexpression of <em>PMEPA1+MYC</em> led to tumoural development <em>in vivo</em>, demonstrating the oncogenic role of <em>PMEPA1</em> in HCC for the first time.</div></div><div><h3>Impact and implications:</h3><div><em>PMEPA1</em> can enhance the tumour-promoting effects of TGF-β in cancer. In this study, we demonstrate that <em>PMEPA1</em> is highly expressed in ∼18% of patients with hepatocellular carcinoma (HCC), a feature associated with poor prognosis, TGF-β activation and exhaustion of immune cells. Similarly, in mouse models, <em>PMEPA1</em> overexpression promotes HCC development, which demonstrates its oncogenic role. The identification of <em>PMEPA1</em> as oncogenic driver in HCC and its role in immune exhaustion and poor clinical outcomes enhances our under","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.jhepr.2024.101213
Background & Aims
Liver stiffness measurement (LSM) has been shown to adequately predict outcomes in patients with liver disease. However, the value of LSM as a predictor of disease progression in autoimmune hepatitis (AIH) remains to be determined. This study aimed to evaluate the role of LSM as a predictor of disease progression and decompensation of cirrhosis in patients with AIH.
Methods
This multicentre cohort study included 439 patients with histologically confirmed AIH and at least one LSM during follow-up. The association between the first LSM performed at least 6 months after treatment initiation (baseline LSM [BLSM]) and cirrhosis development and poor outcomes (decompensation, liver transplantation, and/or liver-related death) was assessed using Cox regression and its discriminating capacity with a receiver-operating characteristic curve.
Results
Most patients were female (n = 301, 70%), with a median age of 52 years. BLSM performed after a median of 2.18 (1.19-4.68) years had a median value of 6 kPa (4.5-8.5). At the time of BLSM, 332 (76%) patients had achieved a biochemical response and 57 (13%) had cirrhosis. During follow-up, eight patients (2%) presented with poor outcomes and 26 (7%) developed cirrhosis. BLSM was higher among patients with poor outcomes (13.5 kPa vs. 6 kPa; p <0.001) and was independently associated with cirrhosis development (hazard ratio 1.300; p <0.001), irrespective of the achievement of biochemical response. A cut-off of 8.5 kPa accurately predicted cirrhosis development and poor outcomes, with AUCs of 0.859 (95% CI 0.789-0.929) and 0.900 (95% CI 0.847-0.954), respectively.
Conclusion
BLSM could play a significant role in predicting AIH outcomes, potentially identifying a subgroup of patients at a high risk of progressing to cirrhosis and experiencing decompensation.
Impact and implications:
The value of liver stiffness measurement as a predictor of outcomes in patients with autoimmune hepatitis (AIH) remains to be determined. In this large multicentre study, liver stiffness measurement was found to be an independent predictive factor of adverse clinical outcomes and cirrhosis development in AIH, irrespective of the achievement of biochemical response. A cut-off of 8.5 kPa accurately predicted cirrhosis development and poor outcomes in AIH.
背景& 目的肝脏僵硬度测量（LSM）已被证明能充分预测肝病患者的预后。然而，肝硬度测量作为自身免疫性肝炎（AIH）疾病进展预测指标的价值仍有待确定。本研究旨在评估 LSM 作为自身免疫性肝炎患者疾病进展和肝硬化失代偿的预测指标的作用。方法这项多中心队列研究纳入了 439 例经组织学确诊的自身免疫性肝炎患者，这些患者在随访期间至少接受过一次 LSM 检查。结果大多数患者为女性（n = 301，70%），中位年龄为 52 岁。在中位 2.18（1.19-4.68）年后进行的 BLSM 的中位值为 6 kPa（4.5-8.5）。在进行 BLSM 时，有 332 名（76%）患者获得了生化应答，57 名（13%）患者出现了肝硬化。在随访期间，8 名患者（2%）出现不良反应，26 名患者（7%）发展为肝硬化。无论是否获得生化应答，预后不良患者的 BLSM 均较高（13.5 kPa vs. 6 kPa; p <0.001），并且与肝硬化的发展独立相关（危险比 1.300; p <0.001）。8.5 kPa 临界值可准确预测肝硬化的发展和不良预后，其 AUC 分别为 0.859 (95% CI 0.789-0.929) 和 0.900 (95% CI 0.847-0.954)。影响和意义：肝脏硬度测量作为自身免疫性肝炎（AIH）患者预后预测指标的价值仍有待确定。在这项大型多中心研究中发现，肝脏僵硬度测量是自身免疫性肝炎患者不良临床结局和肝硬化发展的独立预测因素，与生化反应的实现无关。8.5 kPa的临界值可准确预测AIH患者肝硬化的发生和不良预后。
{"title":"Liver stiffness measurement predicts clinical outcomes in autoimmune hepatitis","authors":"","doi":"10.1016/j.jhepr.2024.101213","DOIUrl":"10.1016/j.jhepr.2024.101213","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Liver stiffness measurement (LSM) has been shown to adequately predict outcomes in patients with liver disease. However, the value of LSM as a predictor of disease progression in autoimmune hepatitis (AIH) remains to be determined. This study aimed to evaluate the role of LSM as a predictor of disease progression and decompensation of cirrhosis in patients with AIH.</div></div><div><h3>Methods</h3><div>This multicentre cohort study included 439 patients with histologically confirmed AIH and at least one LSM during follow-up. The association between the first LSM performed at least 6 months after treatment initiation (baseline LSM [BLSM]) and cirrhosis development and poor outcomes (decompensation, liver transplantation, and/or liver-related death) was assessed using Cox regression and its discriminating capacity with a receiver-operating characteristic curve.</div></div><div><h3>Results</h3><div>Most patients were female (n = 301, 70%), with a median age of 52 years. BLSM performed after a median of 2.18 (1.19-4.68) years had a median value of 6 kPa (4.5-8.5). At the time of BLSM, 332 (76%) patients had achieved a biochemical response and 57 (13%) had cirrhosis. During follow-up, eight patients (2%) presented with poor outcomes and 26 (7%) developed cirrhosis. BLSM was higher among patients with poor outcomes (13.5 kPa <em>vs.</em> 6 kPa; <em>p <</em>0.001) and was independently associated with cirrhosis development (hazard ratio 1.300; <em>p <</em>0.001), irrespective of the achievement of biochemical response. A cut-off of 8.5 kPa accurately predicted cirrhosis development and poor outcomes, with AUCs of 0.859 (95% CI 0.789-0.929) and 0.900 (95% CI 0.847-0.954), respectively.</div></div><div><h3>Conclusion</h3><div>BLSM could play a significant role in predicting AIH outcomes, potentially identifying a subgroup of patients at a high risk of progressing to cirrhosis and experiencing decompensation.</div></div><div><h3>Impact and implications:</h3><div>The value of liver stiffness measurement as a predictor of outcomes in patients with autoimmune hepatitis (AIH) remains to be determined. In this large multicentre study, liver stiffness measurement was found to be an independent predictive factor of adverse clinical outcomes and cirrhosis development in AIH, irrespective of the achievement of biochemical response. A cut-off of 8.5 kPa accurately predicted cirrhosis development and poor outcomes in AIH.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1016/S2589-5559(24)00210-6
{"title":"Copyright and information","authors":"","doi":"10.1016/S2589-5559(24)00210-6","DOIUrl":"10.1016/S2589-5559(24)00210-6","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924002106/pdfft?md5=36611aac042aa5927b580993b9e51763&pid=1-s2.0-S2589555924002106-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142148336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-31DOI: 10.1016/j.jhepr.2024.101199
Background & Aims
MRI guidance offers better lesion targeting for microwave ablation of liver lesions with higher soft-tissue contrast, as well as the possibility of real-time thermometry. This study aims to evaluate the correlation of real-time MR thermometry-predicted lesion volume with the ablation zone in postprocedural first-day images.
Methods
This single-center retrospective analysis evaluated prospectively included patients who underwent MRI-guided microwave ablation with real-time thermometry between December 2020 and July 2023. All procedures were performed under general anesthesia on a 1.5 T MRI scanner. Real-time thermometry data were acquired using multi-slice gradient-echo echoplanar imaging sequences, and thermal dose maps (CEM43 of 240 min as a threshold) were created. The volume of tissue exposed to a lethal thermal dose in MR thermometry (thermal dose) was compared with the ablation zone volume in portal phase T1w MRI on the postprocedural first day using the Pearson correlation test, and visual quantitative assessment by radiologists was performed to evaluate the similarity of shapes and volumes.
Results
Out of 30 patients with 33 lesions with thermometry images, six (18.1%) lesions were excluded because of artifacts limiting interpretation of thermal dose volume. Twenty-four patients with 27 lesions (20 male, age 63.1 ± 9.1 years) were evaluated for the volume correlation. The volume of thermal dose-predicted lesions and the postprocedural first-day ablation zones showed a strong correlation (R = 0.89, p <0.001). Similarly, visual similarity of molecular resonance thermometry-predicted shape and the ablation zone shape was graded as perfect in 23 (85.1%) lesions.
Conclusions
Real-time thermal dose-predicted volumes show very good correlation with the ablation zone volumes in images obtained 1 day after the procedure, which could reduce the local recurrence rates with the possibility of re-ablating lesions within the same procedure.
Impact and implications:
Heat-based ablation is an established treatment for liver tumors; however, there is a considerable rate of incomplete treatment because of the lack of real-time visualization of the treated area during treatment. Our results show that MRI-guided ablation enables the visualization of the treatment area in real-time with high accuracy using a special technique of MR thermometry in patients with liver tumors.
{"title":"Predicting liver ablation volumes with real-time MRI thermometry","authors":"","doi":"10.1016/j.jhepr.2024.101199","DOIUrl":"10.1016/j.jhepr.2024.101199","url":null,"abstract":"<div><h3>Background & Aims</h3><div>MRI guidance offers better lesion targeting for microwave ablation of liver lesions with higher soft-tissue contrast, as well as the possibility of real-time thermometry. This study aims to evaluate the correlation of real-time MR thermometry-predicted lesion volume with the ablation zone in postprocedural first-day images.</div></div><div><h3>Methods</h3><div>This single-center retrospective analysis evaluated prospectively included patients who underwent MRI-guided microwave ablation with real-time thermometry between December 2020 and July 2023. All procedures were performed under general anesthesia on a 1.5 T MRI scanner. Real-time thermometry data were acquired using multi-slice gradient-echo echoplanar imaging sequences, and thermal dose maps (CEM43 of 240 min as a threshold) were created. The volume of tissue exposed to a lethal thermal dose in MR thermometry (thermal dose) was compared with the ablation zone volume in portal phase T1w MRI on the postprocedural first day using the Pearson correlation test, and visual quantitative assessment by radiologists was performed to evaluate the similarity of shapes and volumes.</div></div><div><h3>Results</h3><div>Out of 30 patients with 33 lesions with thermometry images, six (18.1%) lesions were excluded because of artifacts limiting interpretation of thermal dose volume. Twenty-four patients with 27 lesions (20 male, age 63.1 ± 9.1 years) were evaluated for the volume correlation. The volume of thermal dose-predicted lesions and the postprocedural first-day ablation zones showed a strong correlation (R = 0.89, <em>p</em> <0.001). Similarly, visual similarity of molecular resonance thermometry-predicted shape and the ablation zone shape was graded as perfect in 23 (85.1%) lesions.</div></div><div><h3>Conclusions</h3><div>Real-time thermal dose-predicted volumes show very good correlation with the ablation zone volumes in images obtained 1 day after the procedure, which could reduce the local recurrence rates with the possibility of re-ablating lesions within the same procedure.</div></div><div><h3>Impact and implications:</h3><div>Heat-based ablation is an established treatment for liver tumors; however, there is a considerable rate of incomplete treatment because of the lack of real-time visualization of the treated area during treatment. Our results show that MRI-guided ablation enables the visualization of the treatment area in real-time with high accuracy using a special technique of MR thermometry in patients with liver tumors.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142427450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1016/j.jhepr.2024.101195
Background & Aims
Chronic liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health burden. Progressive liver fibrosis can lead to severe outcomes; however, there is a lack of effective therapies targeting advanced fibrosis. Hydrogen peroxide-inducible clone-5 (Hic-5), an adaptor protein in focal adhesion, is critical for promoting liver fibrosis in hepatic stellate cells. This study investigated its clinical applicability by examining hepatic Hic-5 expression in human fibrotic tissues, exploring its association with MASH, and assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting Hic-5 in a MASH mouse model.
Methods
Hepatic Hic-5 expression in human fibrotic tissues underwent pathological image analysis and single-cell RNA sequencing. ASOs targeting Hic-5 were developed and tested using in vitro cell models. An in vivo MASH mouse model was used to evaluate the effects of anti-Hic-5 ASOs on advanced fibrosis and steatosis.
Results
Hepatic Hic-5 expression increased with the progression of fibrosis, particularly in advanced stages. Single-cell RNA sequencing revealed Hic-5 expression primarily in hepatic stellate cells. In MASH-associated fibrosis, Hic-5 expression correlated with the expression of fibrotic genes. In the MASH mouse model, hepatic Hic-5 expression increased with disease progression. Anti-Hic-5 ASOs effectively suppressed Hic-5 expression in vitro and attenuated advanced fibrosis and steatosis in vivo, indicating their therapeutic potential.
Conclusions
Hepatic Hic-5 expression is associated with advanced liver fibrosis and MASH. Anti-Hic-5 ASOs are promising therapeutic interventions for MASH accompanied by advanced fibrosis. These findings provide valuable insights into potential clinical treatments for advanced liver fibrosis.
Impact and implications:
This study investigated the role of Hic-5 in liver fibrosis and steatohepatitis, highlighting its potential as a therapeutic target. We developed an antisense oligonucleotide (ASO) that was particularly transportable to the liver, and targeted Hic-5. Anti-Hic-5 ASO exhibited therapeutic efficacy for liver fibrosis and steatosis in vivo, indicating its therapeutic potential for liver fibrosis and steatosis. ASOs have already achieved dramatic therapeutic effects as approved nucleic acid drugs. Thus, anti-Hic-5 ASO is expected to lead the direct generation of seed compounds for the clinical development of drugs for liver fibrosis and steatosis.
{"title":"Hic-5 antisense oligonucleotide inhibits advanced hepatic fibrosis and steatosis in vivo","authors":"","doi":"10.1016/j.jhepr.2024.101195","DOIUrl":"10.1016/j.jhepr.2024.101195","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Chronic liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health burden. Progressive liver fibrosis can lead to severe outcomes; however, there is a lack of effective therapies targeting advanced fibrosis. Hydrogen peroxide-inducible clone-5 (Hic-5), an adaptor protein in focal adhesion, is critical for promoting liver fibrosis in hepatic stellate cells. This study investigated its clinical applicability by examining hepatic Hic-5 expression in human fibrotic tissues, exploring its association with MASH, and assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting Hic-5 in a MASH mouse model.</div></div><div><h3>Methods</h3><div>Hepatic Hic-5 expression in human fibrotic tissues underwent pathological image analysis and single-cell RNA sequencing. ASOs targeting Hic-5 were developed and tested using <em>in vitro</em> cell models. An <em>in vivo</em> MASH mouse model was used to evaluate the effects of anti-<em>Hic-5</em> ASOs on advanced fibrosis and steatosis.</div></div><div><h3>Results</h3><div>Hepatic Hic-5 expression increased with the progression of fibrosis, particularly in advanced stages. Single-cell RNA sequencing revealed Hic-5 expression primarily in hepatic stellate cells. In MASH-associated fibrosis, Hic-5 expression correlated with the expression of fibrotic genes. In the MASH mouse model, hepatic Hic-5 expression increased with disease progression. Anti-<em>Hic-5</em> ASOs effectively suppressed Hic-5 expression <em>in vitro</em> and attenuated advanced fibrosis and steatosis <em>in vivo</em>, indicating their therapeutic potential.</div></div><div><h3>Conclusions</h3><div>Hepatic Hic-5 expression is associated with advanced liver fibrosis and MASH. Anti-<em>Hic-5</em> ASOs are promising therapeutic interventions for MASH accompanied by advanced fibrosis. These findings provide valuable insights into potential clinical treatments for advanced liver fibrosis.</div></div><div><h3>Impact and implications:</h3><div>This study investigated the role of Hic-5 in liver fibrosis and steatohepatitis, highlighting its potential as a therapeutic target. We developed an antisense oligonucleotide (ASO) that was particularly transportable to the liver, and targeted Hic-5. Anti-<em>Hic-5</em> ASO exhibited therapeutic efficacy for liver fibrosis and steatosis <em>in vivo</em>, indicating its therapeutic potential for liver fibrosis and steatosis. ASOs have already achieved dramatic therapeutic effects as approved nucleic acid drugs. Thus, anti-<em>Hic-5</em> ASO is expected to lead the direct generation of seed compounds for the clinical development of drugs for liver fibrosis and steatosis.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142427449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1016/j.jhepr.2024.101196
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of disease states ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), which can eventually lead to the development of cirrhosis and hepatocellular carcinoma. Macrophages have long been implicated in driving the progression from steatosis to end-stage disease, yet we still know relatively little about the precise involvement of these cells in MASLD progression and/or regression. Rather, there are a considerable number of conflicting reports regarding the precise roles of these cells. This confusion stems from the fact that, until recently, macrophages in the liver were considered a homogenous population. However, thanks to recent technological advances including multi-parameter flow cytometry, single-cell RNA sequencing and spatial proteogenomics, we now know that this is not the case. Rather hepatic macrophages, even in the healthy liver, are heterogenous, existing in multiple subsets with distinct transcriptional profiles and hence likely functions. This heterogeneity is even more prominent in MASLD, where the macrophage pool consists of multiple different subsets of resident and recruited cells. To probe the unique functions of these cells and determine if targeting macrophages may be a viable therapeutic strategy in MASLD, we first need to unravel this complexity and decipher which populations and/or activation states are present and what functions each of these may play in driving MASLD progression. In this review, we summarise recent advances in the field, highlighting what is currently known about the hepatic macrophage landscape in MASLD and the questions that remain to be tackled.
{"title":"Understanding the complex macrophage landscape in MASLD","authors":"","doi":"10.1016/j.jhepr.2024.101196","DOIUrl":"10.1016/j.jhepr.2024.101196","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of disease states ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), which can eventually lead to the development of cirrhosis and hepatocellular carcinoma. Macrophages have long been implicated in driving the progression from steatosis to end-stage disease, yet we still know relatively little about the precise involvement of these cells in MASLD progression and/or regression. Rather, there are a considerable number of conflicting reports regarding the precise roles of these cells. This confusion stems from the fact that, until recently, macrophages in the liver were considered a homogenous population. However, thanks to recent technological advances including multi-parameter flow cytometry, single-cell RNA sequencing and spatial proteogenomics, we now know that this is not the case. Rather hepatic macrophages, even in the healthy liver, are heterogenous, existing in multiple subsets with distinct transcriptional profiles and hence likely functions. This heterogeneity is even more prominent in MASLD, where the macrophage pool consists of multiple different subsets of resident and recruited cells. To probe the unique functions of these cells and determine if targeting macrophages may be a viable therapeutic strategy in MASLD, we first need to unravel this complexity and decipher which populations and/or activation states are present and what functions each of these may play in driving MASLD progression. In this review, we summarise recent advances in the field, highlighting what is currently known about the hepatic macrophage landscape in MASLD and the questions that remain to be tackled.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.jhepr.2024.101192
Background & Aims
We aimed to explore patient expectations regarding their treatments and prognosis in comparison to physicians' assessments in patients with advanced hepatocellular carcinoma (HCC) receiving systemic treatments.
Methods
We prospectively enrolled 205 patients in France and Belgium with Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC receiving systemic treatment (NCT04823754). Patients completed a 28-question survey and the hospital anxiety and depression scale (HADS), while physicians filled a 17-question survey after the initial consultation. Univariate and multivariate models were used to assess factors associated with concordant patient-physician responses, HADS, as well as predicted (by physicians) and observed overall survival.
Results
Patients had a median age of 68 years with 75% having BCLC C HCC; 86.3% received atezolizumab/bevacizumab. 60% of patients did not discuss life expectancy with the physician. 63% of the patients believed they had a life expectancy >5 years. Among shared questions between patients and physicians, 36.4% concordance was observed; major differences centered on life expectancy with patients more optimistic than physicians. A lower patient-physician concordance was seen with shorter-consultations (p = 0.003), female physicians (p = 0.02), BCLC C (p = 0.03) and >100 HCC patients/year per physician (p = 0.008). Compared to France, patients from Belgium were more likely to be satisfied with the consultation (p <0.001) but were less optimistic about life expectancy. Using HADS, 52% of the patients had anxiety/depression that was correlated with alpha-fetoprotein level (p = 0.03). The predicted median overall survival by physicians was 18 months vs. 13 months for the observed overall survival (weak correlation, ρ = 0.31).
Conclusion
Expectations regarding systemic treatments for advanced HCC differ significantly between patients and physicians, showing notable variations across countries.
Impact and implications:
This multicentric prospective study, conducted in France and Belgium, focuses on patients with advanced hepatocellular carcinoma undergoing systemic treatments. The findings of our study underscore the disparities in expectations regarding systemic treatments for advanced hepatocellular carcinoma between patients and physicians, revealing also significant variations between France and Belgium. These results suggest the need for targeted interventions aimed at enhancing patients' comprehension of their disease and fostering better communication between patients and physicians.
Clinical trial number
NCT04823754.
Background & AimsWe aims to explore patients expectations regarding their treatments and prognosis in comparison to physicians' assessments in patients with advanced hepatocellular carcinoma (HCC) in patients receiving systemic treatment.MethodsWe prospectedrolled 205 patients with Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC receiving systemic treatment (NCT04823754).我们在法国和比利时前瞻性地招募了205名接受系统治疗的巴塞罗那肝癌（BCLC）B/C期HCC患者（NCT04823754）。患者填写了一份包含 28 个问题的调查问卷以及医院焦虑抑郁量表（HADS），而医生则在初次会诊后填写了一份包含 17 个问题的调查问卷。结果患者的中位年龄为68岁，75%患有BCLC C型HCC；86.3%接受了阿特珠单抗/贝伐单抗治疗。60%的患者未与医生讨论预期寿命。63%的患者认为自己的预期寿命为 5 年。在患者和医生共同提出的问题中，有 36.4% 的人意见一致；主要差异集中在预期寿命上，患者比医生更乐观。就诊时间较短（p = 0.003）、女医生（p = 0.02）、BCLC C（p = 0.03）和每位医生每年接诊 100 例 HCC 患者（p = 0.008）而言，患者与医生之间的一致性较低。与法国相比，比利时患者对会诊的满意度更高（p = 0.001），但对预期寿命的乐观程度较低。根据 HADS，52% 的患者患有焦虑/抑郁症，而焦虑/抑郁症与甲胎蛋白水平相关（p = 0.03）。医生预测的中位总生存期为 18 个月，而观察到的总生存期为 13 个月（弱相关性，ρ = 0.31）。影响和意义：这项在法国和比利时进行的多中心前瞻性研究主要针对接受系统治疗的晚期肝细胞癌患者。我们的研究结果表明，患者和医生对晚期肝细胞癌系统治疗的期望值存在差异，法国和比利时之间的差异也很大。这些结果表明，有必要采取有针对性的干预措施，以增强患者对自身疾病的理解，并促进患者与医生之间更好的沟通。
{"title":"Patient and physician expectations regarding disease and treatment of advanced HCC: The prospective PERCEPTION1 study","authors":"","doi":"10.1016/j.jhepr.2024.101192","DOIUrl":"10.1016/j.jhepr.2024.101192","url":null,"abstract":"<div><h3>Background & Aims</h3><div>We aimed to explore patient expectations regarding their treatments and prognosis in comparison to physicians' assessments in patients with advanced hepatocellular carcinoma (HCC) receiving systemic treatments.</div></div><div><h3>Methods</h3><div>We prospectively enrolled 205 patients in France and Belgium with Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC receiving systemic treatment (NCT04823754). Patients completed a 28-question survey and the hospital anxiety and depression scale (HADS), while physicians filled a 17-question survey after the initial consultation. Univariate and multivariate models were used to assess factors associated with concordant patient-physician responses, HADS, as well as predicted (by physicians) and observed overall survival.</div></div><div><h3>Results</h3><div>Patients had a median age of 68 years with 75% having BCLC C HCC; 86.3% received atezolizumab/bevacizumab. 60% of patients did not discuss life expectancy with the physician. 63% of the patients believed they had a life expectancy >5 years. Among shared questions between patients and physicians, 36.4% concordance was observed; major differences centered on life expectancy with patients more optimistic than physicians. A lower patient-physician concordance was seen with shorter-consultations (<em>p =</em> 0.003), female physicians (<em>p =</em> 0.02), BCLC C (<em>p =</em> 0.03) and >100 HCC patients/year per physician (<em>p =</em> 0.008). Compared to France, patients from Belgium were more likely to be satisfied with the consultation (<em>p</em> <0.001) but were less optimistic about life expectancy. Using HADS, 52% of the patients had anxiety/depression that was correlated with alpha-fetoprotein level (<em>p =</em> 0.03). The predicted median overall survival by physicians was 18 months <em>vs</em>. 13 months for the observed overall survival (weak correlation, ρ = 0.31).</div></div><div><h3>Conclusion</h3><div>Expectations regarding systemic treatments for advanced HCC differ significantly between patients and physicians, showing notable variations across countries.</div></div><div><h3>Impact and implications:</h3><div>This multicentric prospective study, conducted in France and Belgium, focuses on patients with advanced hepatocellular carcinoma undergoing systemic treatments. The findings of our study underscore the disparities in expectations regarding systemic treatments for advanced hepatocellular carcinoma between patients and physicians, revealing also significant variations between France and Belgium. These results suggest the need for targeted interventions aimed at enhancing patients' comprehension of their disease and fostering better communication between patients and physicians.</div></div><div><h3>Clinical trial number</h3><div>NCT04823754.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142427462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.jhepr.2024.101187
<div><h3>Background & Aims</h3><div>In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells.</div></div><div><h3>Methods</h3><div>Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis.</div></div><div><h3>Results</h3><div>Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, <em>p =</em> 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene <em>HMOX1</em>, and increased <em>CXCL8</em> expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of <em>HMOX1</em>. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced <em>CXCL8</em> expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis.</div></div><div><h3>Impact and implications</h3><div>Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings unde
{"title":"Palmitoylcarnitine impairs immunity in decompensated cirrhosis","authors":"","doi":"10.1016/j.jhepr.2024.101187","DOIUrl":"10.1016/j.jhepr.2024.101187","url":null,"abstract":"<div><h3>Background & Aims</h3><div>In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells.</div></div><div><h3>Methods</h3><div>Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis.</div></div><div><h3>Results</h3><div>Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, <em>p =</em> 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene <em>HMOX1</em>, and increased <em>CXCL8</em> expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of <em>HMOX1</em>. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced <em>CXCL8</em> expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis.</div></div><div><h3>Impact and implications</h3><div>Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings unde","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142533173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.jhepr.2024.101190
Background & Aims
Safety data for patients with hepatocellular carcinoma (HCC) treated with atezolizumab-bevacizumab in the real-world setting remain uncertain. Thus, the aim of this study was to evaluate the incidence of adverse events (AEs) in patients with HCC treated with atezolizumab-bevacizumab in the literature.
Methods
In this systematic review and meta-analysis, we searched PubMed for original studies reporting percentages of AEs in patients with HCC receiving atezolizumab-bevacizumab between 2020 to 2023, using the search terms “Atezolizumab/Bevacizumab”, “HCC” and “Adverse events”. We summarized the incidence of AEs and performed a meta-analysis in order to evaluate the incidence of AEs reported in the literature.
Results
A total of 30 studies (3,867 patients) were included. The analysis revealed heterogeneity in AE reporting, with arterial hypertension, proteinuria, and fatigue being the most frequently reported AEs whereas incidence of bleeding was reported in 66.7% of the studies and rare immune-related AEs were reported in 26.7% of the studies. The meta-analysis revealed pooled incidence rates of 79% for any grade AEs: 56% for grade 1/2 and 30% for grade ≥3. While the pooled rates of hypertension, anorexia, bleeding, pruritus, rash, and thyroid dysfunction were similar to those reported in the IMbrave150 trial, higher rates were observed in the literature for proteinuria, fatigue, ALT and AST elevations and gastrointestinal perforation. For grade ≥3 AEs, the percentages were consistent with the IMbrave150 trial, except for lower incidences of arterial hypertension and thrombosis in the literature. The exposure-adjusted incidence rates for proteinuria (55.7%), hypertension (45.3%) and fatigue (33.6%) were high. Heterogeneity was observed in the analysis of AEs across articles within the same cohorts of patients.
Conclusion
We observed a significant variability in AE reporting for atezolizumab-bevacizumab treatment in HCC in the literature, underscoring the need for standardized reporting practices.
Impact and implications
Considering the demonstrated safety of atezolizumab-bevacizumab in randomized-controlled trials, this meta-analysis offers valuable insights into reported occurrences of adverse events. Our study highlights significant heterogeneity among studies, underscoring the need to improve adverse event recording. Understanding the incidence and severity of treatment-related adverse events beyond clinical trials is essential for prompt intervention and may help in preventing treatment discontinuation and complications, potentially leading to better outcomes without significantly compromising quality of life due to adverse events.
{"title":"Heterogeneity in adverse events related to atezolizumab-bevacizumab for hepatocellular carcinoma reported in real-world studies","authors":"","doi":"10.1016/j.jhepr.2024.101190","DOIUrl":"10.1016/j.jhepr.2024.101190","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Safety data for patients with hepatocellular carcinoma (HCC) treated with atezolizumab-bevacizumab in the real-world setting remain uncertain. Thus, the aim of this study was to evaluate the incidence of adverse events (AEs) in patients with HCC treated with atezolizumab-bevacizumab in the literature.</div></div><div><h3>Methods</h3><div>In this systematic review and meta-analysis, we searched PubMed for original studies reporting percentages of AEs in patients with HCC receiving atezolizumab-bevacizumab between 2020 to 2023, using the search terms “Atezolizumab/Bevacizumab”, “HCC” and “Adverse events”. We summarized the incidence of AEs and performed a meta-analysis in order to evaluate the incidence of AEs reported in the literature.</div></div><div><h3>Results</h3><div>A total of 30 studies (3,867 patients) were included. The analysis revealed heterogeneity in AE reporting, with arterial hypertension, proteinuria, and fatigue being the most frequently reported AEs whereas incidence of bleeding was reported in 66.7% of the studies and rare immune-related AEs were reported in 26.7% of the studies. The meta-analysis revealed pooled incidence rates of 79% for any grade AEs: 56% for grade 1/2 and 30% for grade ≥3. While the pooled rates of hypertension, anorexia, bleeding, pruritus, rash, and thyroid dysfunction were similar to those reported in the IMbrave150 trial, higher rates were observed in the literature for proteinuria, fatigue, ALT and AST elevations and gastrointestinal perforation. For grade ≥3 AEs, the percentages were consistent with the IMbrave150 trial, except for lower incidences of arterial hypertension and thrombosis in the literature. The exposure-adjusted incidence rates for proteinuria (55.7%), hypertension (45.3%) and fatigue (33.6%) were high. Heterogeneity was observed in the analysis of AEs across articles within the same cohorts of patients.</div></div><div><h3>Conclusion</h3><div>We observed a significant variability in AE reporting for atezolizumab-bevacizumab treatment in HCC in the literature, underscoring the need for standardized reporting practices.</div></div><div><h3>Impact and implications</h3><div>Considering the demonstrated safety of atezolizumab-bevacizumab in randomized-controlled trials, this meta-analysis offers valuable insights into reported occurrences of adverse events. Our study highlights significant heterogeneity among studies, underscoring the need to improve adverse event recording. Understanding the incidence and severity of treatment-related adverse events beyond clinical trials is essential for prompt intervention and may help in preventing treatment discontinuation and complications, potentially leading to better outcomes without significantly compromising quality of life due to adverse events.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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