Background: Hepatocellular carcinoma (HCC) is unique among malignancies, and its characteristics on contrast imaging modalities allow for a highly accurate diagnosis. The radiological differentiation of focal liver lesions is playing an increasingly important role, and the Liver Imaging Reporting and Data System adopts a combination of major features including arterial phase hyper-enhancement (APHE) and the washout pattern.
Summary: Specific HCCs such as well or poorly differentiated type, subtypes including fibrolamellar or sarcomatoid and combined hepatocellular-cholangiocarcinoma do not often demonstrate APHE and washout appearance. Meanwhile, hypervascular liver metastases and hypervascular intrahepatic cholangiocarcinoma can demonstrate APHE and washout. There are still other hypervascular malignant liver tumors (i.e., angiosarcoma, epithelioid hemangioendothelioma) and hypervascular benign liver lesions (i.e., adenoma, focal nodular hyperplasia, angiomyolipoma, flash filling hemangioma, reactive lymphoid hyperplasia, inflammatory lesion, arterioportal shunt), which need to be distinguished from HCC. When a patient has chronic liver disease, differential diagnosis of hypervascular liver lesions can be even more complicated. Meanwhile, artificial intelligence (AI) in medicine has been widely explored, and recent advancement in the field of deep learning has provided promising performance for the analysis of medical images, especially radiological imaging data contain diagnostic, prognostic, and predictive information which AI can extract. The AI research studies have demonstrated high accuracy (over 90% accuracy) for classifying lesions with typical imaging features from some hepatic lesions. The AI system has a potential to be implemented in clinical routine as decision support tools. However, for the differential diagnosis of many types of hypervascular liver lesions, further large-scale clinical validation is still required.
Key messages: Clinicians should be aware of the histopathological features, imaging characteristics, and differential diagnoses of hypervascular liver lesions to a precise diagnosis and more valuable treatment plan. We need to be familiar with such atypical cases to prevent a diagnostic delay, but AI-based tools also need to learn a large number of typical and atypical cases.
{"title":"Imaging Diagnosis of Various Hepatocellular Carcinoma Subtypes and Its Hypervascular Mimics: Differential Diagnosis Based on Conventional Interpretation and Artificial Intelligence.","authors":"Yasunori Minami, Naoshi Nishida, Masatoshi Kudo","doi":"10.1159/000528538","DOIUrl":"https://doi.org/10.1159/000528538","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is unique among malignancies, and its characteristics on contrast imaging modalities allow for a highly accurate diagnosis. The radiological differentiation of focal liver lesions is playing an increasingly important role, and the Liver Imaging Reporting and Data System adopts a combination of major features including arterial phase hyper-enhancement (APHE) and the washout pattern.</p><p><strong>Summary: </strong>Specific HCCs such as well or poorly differentiated type, subtypes including fibrolamellar or sarcomatoid and combined hepatocellular-cholangiocarcinoma do not often demonstrate APHE and washout appearance. Meanwhile, hypervascular liver metastases and hypervascular intrahepatic cholangiocarcinoma can demonstrate APHE and washout. There are still other hypervascular malignant liver tumors (i.e., angiosarcoma, epithelioid hemangioendothelioma) and hypervascular benign liver lesions (i.e., adenoma, focal nodular hyperplasia, angiomyolipoma, flash filling hemangioma, reactive lymphoid hyperplasia, inflammatory lesion, arterioportal shunt), which need to be distinguished from HCC. When a patient has chronic liver disease, differential diagnosis of hypervascular liver lesions can be even more complicated. Meanwhile, artificial intelligence (AI) in medicine has been widely explored, and recent advancement in the field of deep learning has provided promising performance for the analysis of medical images, especially radiological imaging data contain diagnostic, prognostic, and predictive information which AI can extract. The AI research studies have demonstrated high accuracy (over 90% accuracy) for classifying lesions with typical imaging features from some hepatic lesions. The AI system has a potential to be implemented in clinical routine as decision support tools. However, for the differential diagnosis of many types of hypervascular liver lesions, further large-scale clinical validation is still required.</p><p><strong>Key messages: </strong>Clinicians should be aware of the histopathological features, imaging characteristics, and differential diagnoses of hypervascular liver lesions to a precise diagnosis and more valuable treatment plan. We need to be familiar with such atypical cases to prevent a diagnostic delay, but AI-based tools also need to learn a large number of typical and atypical cases.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 2","pages":"103-115"},"PeriodicalIF":13.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4b/12/lic-0012-0103.PMC10267566.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9648639","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}
Zhenggang Ren, Guoliang Shao, Jie Shen, Li Zhang, Xu Zhu, Weijia Fang, Guoping Sun, Yuxian Bai, Jianbing Wu, Lianxin Liu, Yuan Yuan, Jingdong Zhang, Zhen Li, Ling Zhang, Tao Yin, Jincai Wu, Xiaoli Hou, Qingyu Wang, Jun Zhu, Jia Fan
Introduction: Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population.
Methods: In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety.
Results: As of April 8, 2021, 20 and 21 patients were enrolled into groups A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval [CI], 11.9-54.3) in group A and 14.3% (95% CI, 3.0-36.3) in group B. Median duration of response was not reached (95% CI, 3.3-not evaluable [NE]) in group A and was 9.0 months (95% CI, 7.9-NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4-5.5) and 4.1 months (95% CI, 1.5-NE), and median overall survival was 11.6 months (95% CI, 6.4-NE) and 14.3 months (95% CI, 8.2-NE) in groups A and B, respectively.
Conclusion: Serplulimab plus HLX04 showed a manageable safety profile and promising antitumor activity in patients with previously treated advanced HCC.
{"title":"Phase 2 Study of the PD-1 Inhibitor Serplulimab plus the Bevacizumab Biosimilar HLX04 in Patients with Previously Treated Advanced Hepatocellular Carcinoma.","authors":"Zhenggang Ren, Guoliang Shao, Jie Shen, Li Zhang, Xu Zhu, Weijia Fang, Guoping Sun, Yuxian Bai, Jianbing Wu, Lianxin Liu, Yuan Yuan, Jingdong Zhang, Zhen Li, Ling Zhang, Tao Yin, Jincai Wu, Xiaoli Hou, Qingyu Wang, Jun Zhu, Jia Fan","doi":"10.1159/000526638","DOIUrl":"https://doi.org/10.1159/000526638","url":null,"abstract":"<p><strong>Introduction: </strong>Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population.</p><p><strong>Methods: </strong>In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety.</p><p><strong>Results: </strong>As of April 8, 2021, 20 and 21 patients were enrolled into groups A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval [CI], 11.9-54.3) in group A and 14.3% (95% CI, 3.0-36.3) in group B. Median duration of response was not reached (95% CI, 3.3-not evaluable [NE]) in group A and was 9.0 months (95% CI, 7.9-NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4-5.5) and 4.1 months (95% CI, 1.5-NE), and median overall survival was 11.6 months (95% CI, 6.4-NE) and 14.3 months (95% CI, 8.2-NE) in groups A and B, respectively.</p><p><strong>Conclusion: </strong>Serplulimab plus HLX04 showed a manageable safety profile and promising antitumor activity in patients with previously treated advanced HCC.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 2","pages":"116-128"},"PeriodicalIF":13.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4f/b3/lic-0012-0116.PMC10267516.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9648643","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}
Introduction: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial.
Methods: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib.
Results: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without.
Conclusion: Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.
{"title":"Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment.","authors":"Shunichi Hosoda, Goki Suda, Takuya Sho, Koji Ogawa, Megumi Kimura, Zijian Yang, Sonoe Yoshida, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Akihisa Nakamura, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Jun Ito, Takuto Miyagishima, Naoya Sakamoto","doi":"10.1159/000527759","DOIUrl":"https://doi.org/10.1159/000527759","url":null,"abstract":"<p><strong>Introduction: </strong>Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial.</p><p><strong>Methods: </strong>Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (<i>n</i> = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; <i>n</i> = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (<i>n</i> = 60) and evaluated in patients treated with lenvatinib.</p><p><strong>Results: </strong>No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, <i>p</i> = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without.</p><p><strong>Conclusion: </strong>Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 2","pages":"156-170"},"PeriodicalIF":13.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a3/a1/lic-0012-0156.PMC10267515.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9654524","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}
Heewon Bae, Je Ryung Gil, Moon Hyung Lee, Taekyu Lim
A patient with hepatocellular carcinoma(HCC) staged Barcelona Clinic for Liver Cancer stage B started chemotherapy because of intrahepatic recurrence after hepatic segmentectomy. Regorafenib was started as a second-line treatment due to refractory to sorafenib treatment, but was discontinued after 26 months due to side effects. After two years of follow-up, the patients achieved unexpected long-term regression. We present the potential of regorafenib effect for anti-tumor immunity through possible pharmacological mechanisms.
{"title":"Long-Term Regression after Discontinuation of Regorafenib Administered for Sorafenib-Refractory Hepatocellular Carcinoma.","authors":"Heewon Bae, Je Ryung Gil, Moon Hyung Lee, Taekyu Lim","doi":"10.1159/000529139","DOIUrl":"https://doi.org/10.1159/000529139","url":null,"abstract":"A patient with hepatocellular carcinoma(HCC) staged Barcelona Clinic for Liver Cancer stage B started chemotherapy because of intrahepatic recurrence after hepatic segmentectomy. Regorafenib was started as a second-line treatment due to refractory to sorafenib treatment, but was discontinued after 26 months due to side effects. After two years of follow-up, the patients achieved unexpected long-term regression. We present the potential of regorafenib effect for anti-tumor immunity through possible pharmacological mechanisms.","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 2","pages":"184-187"},"PeriodicalIF":13.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ba/69/lic-0012-0184.PMC10267512.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9654528","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}
Philippe Merle, Masatoshi Kudo, Stanimira Krotneva, Kirhan Ozgurdal, Yun Su, Irina Proskorovsky
Introduction: The tyrosine kinase inhibitors regorafenib and cabozantinib remain the mainstay in second-line treatment of advanced hepatocellular carcinoma (HCC). There is currently no clear evidence of superiority in efficacy or safety to guide choice between the two treatments.
Methods: We conducted an anchored matching-adjusted indirect comparison using individual patient data from the RESORCE trial of regorafenib and published aggregate data from the CELESTIAL trial of cabozantinib. Second-line HCC patients with prior sorafenib exposure of ≥3 months were included in the analyses. Hazard ratios (HRs) and restricted mean survival time (RMST) were estimated to quantify differences in overall survival (OS) and progression-free survival (PFS). Safety outcomes compared were rates of grade 3 or 4 adverse events (AEs), occurring in >10% of patients, and discontinuation or dose reduction due to treatment-related AEs.
Results: After matching adjustment for differences in baseline patient characteristics, regorafenib showed a favorable OS (HR, 0.80; 95% CI: 0.54, 1.20) and ∼3-month-longer RMST over cabozantinib (RMST difference, 2.76 months; 95% CI: -1.03, 6.54), although not statistically significant. For PFS, there was no numerical difference in HR (HR, 1.00; 95% CI: 0.68, 1.49) and no clinically meaningful difference based on RMST analyses (RMST difference, -0.59 months; 95% CI: -1.83, 0.65). Regorafenib showed a significantly lower incidence of discontinuation (risk difference, -9.2%; 95% CI: -17.7%, -0.6%) and dose reductions (-15.2%; 95% CI: -29.0%, -1.5%) due to treatment-related AEs (any grade). Regorafenib was also associated with a lower incidence (not statistically significant) of grade 3 or 4 diarrhea (risk difference, -7.1%; 95% CI: -14.7%, 0.4%) and fatigue (-6.3%; 95% CI: -14.6%, 2.0%).
Conclusion: This indirect treatment comparison suggests, relative to cabozantinib, that regorafenib could be associated with favorable OS (not statistically significant), lower rates of dose reductions and discontinuation due to treatment-related AEs, and lower rates of severe diarrhea and fatigue.
{"title":"Regorafenib versus Cabozantinib as a Second-Line Treatment for Advanced Hepatocellular Carcinoma: An Anchored Matching-Adjusted Indirect Comparison of Efficacy and Safety.","authors":"Philippe Merle, Masatoshi Kudo, Stanimira Krotneva, Kirhan Ozgurdal, Yun Su, Irina Proskorovsky","doi":"10.1159/000527403","DOIUrl":"https://doi.org/10.1159/000527403","url":null,"abstract":"<p><strong>Introduction: </strong>The tyrosine kinase inhibitors regorafenib and cabozantinib remain the mainstay in second-line treatment of advanced hepatocellular carcinoma (HCC). There is currently no clear evidence of superiority in efficacy or safety to guide choice between the two treatments.</p><p><strong>Methods: </strong>We conducted an anchored matching-adjusted indirect comparison using individual patient data from the RESORCE trial of regorafenib and published aggregate data from the CELESTIAL trial of cabozantinib. Second-line HCC patients with prior sorafenib exposure of ≥3 months were included in the analyses. Hazard ratios (HRs) and restricted mean survival time (RMST) were estimated to quantify differences in overall survival (OS) and progression-free survival (PFS). Safety outcomes compared were rates of grade 3 or 4 adverse events (AEs), occurring in >10% of patients, and discontinuation or dose reduction due to treatment-related AEs.</p><p><strong>Results: </strong>After matching adjustment for differences in baseline patient characteristics, regorafenib showed a favorable OS (HR, 0.80; 95% CI: 0.54, 1.20) and ∼3-month-longer RMST over cabozantinib (RMST difference, 2.76 months; 95% CI: -1.03, 6.54), although not statistically significant. For PFS, there was no numerical difference in HR (HR, 1.00; 95% CI: 0.68, 1.49) and no clinically meaningful difference based on RMST analyses (RMST difference, -0.59 months; 95% CI: -1.83, 0.65). Regorafenib showed a significantly lower incidence of discontinuation (risk difference, -9.2%; 95% CI: -17.7%, -0.6%) and dose reductions (-15.2%; 95% CI: -29.0%, -1.5%) due to treatment-related AEs (any grade). Regorafenib was also associated with a lower incidence (not statistically significant) of grade 3 or 4 diarrhea (risk difference, -7.1%; 95% CI: -14.7%, 0.4%) and fatigue (-6.3%; 95% CI: -14.6%, 2.0%).</p><p><strong>Conclusion: </strong>This indirect treatment comparison suggests, relative to cabozantinib, that regorafenib could be associated with favorable OS (not statistically significant), lower rates of dose reductions and discontinuation due to treatment-related AEs, and lower rates of severe diarrhea and fatigue.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 2","pages":"145-155"},"PeriodicalIF":13.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/14/24/lic-0012-0145.PMC10267565.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9661031","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}
Sandra Bufe, Artur Zimmermann, Sarina Ravens, Immo Prinz, Laura Elisa Buitrago-Molina, Robert Geffers, Norman Woller, Florian Kühnel, Steven R Talbot, Fatih Noyan, Michael Peter Manns, Heiner Wedemeyer, Matthias Hardtke-Wolenski, Elmar Jaeckel, Ana C Davalos-Misslitz
Background: Checkpoint inhibitors act on exhausted CD8+ T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood.
Methods: Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8+ tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells.
Results: The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8+ TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8+ TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8+ TILs, while terminally exhausted CD8+ TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8+ TILs. Unexpectedly, progenitor-exhausted CD8+ TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile.
Conclusion: In our model, few doses of checkpoint inhibitors during the priming of transferred CD8+ tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8+ T cells while preventing their development into terminally exhausted CD8+ TILs in the TME. This finding could have important implications for future T-cell therapies.
{"title":"PD-1/CTLA-4 Blockade Leads to Expansion of CD8<sup>+</sup>PD-1<sup>int</sup> TILs and Results in Tumor Remission in Experimental Liver Cancer.","authors":"Sandra Bufe, Artur Zimmermann, Sarina Ravens, Immo Prinz, Laura Elisa Buitrago-Molina, Robert Geffers, Norman Woller, Florian Kühnel, Steven R Talbot, Fatih Noyan, Michael Peter Manns, Heiner Wedemeyer, Matthias Hardtke-Wolenski, Elmar Jaeckel, Ana C Davalos-Misslitz","doi":"10.1159/000526899","DOIUrl":"https://doi.org/10.1159/000526899","url":null,"abstract":"<p><strong>Background: </strong>Checkpoint inhibitors act on exhausted CD8<sup>+</sup> T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood.</p><p><strong>Methods: </strong>Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8<sup>+</sup> tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells.</p><p><strong>Results: </strong>The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8<sup>+</sup> TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8<sup>+</sup> TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8<sup>+</sup> TILs, while terminally exhausted CD8<sup>+</sup> TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8<sup>+</sup> TILs. Unexpectedly, progenitor-exhausted CD8<sup>+</sup> TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile.</p><p><strong>Conclusion: </strong>In our model, few doses of checkpoint inhibitors during the priming of transferred CD8<sup>+</sup> tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8<sup>+</sup> T cells while preventing their development into terminally exhausted CD8<sup>+</sup> TILs in the TME. This finding could have important implications for future T-cell therapies.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 2","pages":"129-144"},"PeriodicalIF":13.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/08/c4/lic-0012-0129.PMC10267567.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9648640","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}
Jens Mittler, Stefan Heinrich, Martina Koch, Maria Hoppe-Lotichius, Ali Hadian, Arndt Weinmann, Roman Kloeckner, Peter Robert Galle, Hauke Lang
Introduction: The literature on liver transplantation (LT) for cirrhosis-associated hepatocellular carcinoma (cirr-HCC) in elderly patients (≥65 years of age) is scarce. The aim of this study was therefore to analyze the outcome after LT for cirr-HCC in elderly patients in our single-center experience.
Methods: All consecutive patients who underwent LT for cirr-HCC at our center were identified from our prospectively collected LT database and stratified into an elderly (≥65 years) and a younger (<65 years) cohort. Perioperative mortality as well as Kaplan-Meier estimations of overall (OS) and recurrence-free survival (RFS) were compared between age strata. A subgroup analysis was performed for patients with HCC only inside Milan criteria. For further oncological comparison, outcome in the subgroup of elderly LT recipients with HCC inside Milan was also compared to a group of elderly patients undergoing liver resection for cirr-HCC inside Milan extracted from our institutional liver resection database.
Results: Out of 369 consecutive patients with cirr-HCC who underwent LT between 1998 and 2022 at our center, we identified 97 elderly (with a subgroup of 14 septuagenarians) and 272 younger LT patients. 5- and 10-year OS in elderly compared to younger LT patients was 63% and 52% versus 63% and 46% (p = 0.67), respectively, while 5- and 10-year RFS was 58% and 49% versus 58% and 44% (p = 0.69). 5-/10-year OS and RFS in 50 elderly LT recipients with HCC inside Milan were 68%/55% and 62%/54%, respectively, which compared to 46%/38% (p = 0.07) and 26%/14% (p < 0.0001) in elderly patients after liver resection for cirr-HCC inside Milan.
Conclusion: Our results in almost 100 elderly patients after LT for cirr-HCC show that older age per se should not be considered a contraindication to LT and that selected elderly patients older than 65 and even 70 years benefit from LT as much as younger ones.
{"title":"Elderly Patients with Hepatocellular Carcinoma Benefit from Liver Transplantation as Much as Younger Ones.","authors":"Jens Mittler, Stefan Heinrich, Martina Koch, Maria Hoppe-Lotichius, Ali Hadian, Arndt Weinmann, Roman Kloeckner, Peter Robert Galle, Hauke Lang","doi":"10.1159/000528830","DOIUrl":"https://doi.org/10.1159/000528830","url":null,"abstract":"<p><strong>Introduction: </strong>The literature on liver transplantation (LT) for cirrhosis-associated hepatocellular carcinoma (cirr-HCC) in elderly patients (≥65 years of age) is scarce. The aim of this study was therefore to analyze the outcome after LT for cirr-HCC in elderly patients in our single-center experience.</p><p><strong>Methods: </strong>All consecutive patients who underwent LT for cirr-HCC at our center were identified from our prospectively collected LT database and stratified into an elderly (≥65 years) and a younger (<65 years) cohort. Perioperative mortality as well as Kaplan-Meier estimations of overall (OS) and recurrence-free survival (RFS) were compared between age strata. A subgroup analysis was performed for patients with HCC only inside Milan criteria. For further oncological comparison, outcome in the subgroup of elderly LT recipients with HCC inside Milan was also compared to a group of elderly patients undergoing liver resection for cirr-HCC inside Milan extracted from our institutional liver resection database.</p><p><strong>Results: </strong>Out of 369 consecutive patients with cirr-HCC who underwent LT between 1998 and 2022 at our center, we identified 97 elderly (with a subgroup of 14 septuagenarians) and 272 younger LT patients. 5- and 10-year OS in elderly compared to younger LT patients was 63% and 52% versus 63% and 46% (<i>p</i> = 0.67), respectively, while 5- and 10-year RFS was 58% and 49% versus 58% and 44% (<i>p</i> = 0.69). 5-/10-year OS and RFS in 50 elderly LT recipients with HCC inside Milan were 68%/55% and 62%/54%, respectively, which compared to 46%/38% (<i>p</i> = 0.07) and 26%/14% (<i>p</i> < 0.0001) in elderly patients after liver resection for cirr-HCC inside Milan.</p><p><strong>Conclusion: </strong>Our results in almost 100 elderly patients after LT for cirr-HCC show that older age per se should not be considered a contraindication to LT and that selected elderly patients older than 65 and even 70 years benefit from LT as much as younger ones.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 2","pages":"171-177"},"PeriodicalIF":13.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9654521","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 : 2023-05-10eCollection Date: 2023-09-01DOI: 10.1159/000529608
Malte B Monin, Leona I Baier, Jens G Gorny, Moritz Berger, Taotao Zhou, Robert Mahn, Farsaneh Sadeghlar, Christian Möhring, Christoph Boesecke, Kathrin van Bremen, Jürgen K Rockstroh, Christian P Strassburg, Anna-Maria Eis-Hübinger, Matthias Schmid, Maria A Gonzalez-Carmona
Introduction: Data on immune response rates following vaccination for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in patients with hepatobiliary carcinoma (HBC) are rare. However, impaired immunogenicity must be expected due to the combination of chronic liver diseases (CLDs) with malignancy and anticancer treatment.
Methods: In this prospective, longitudinal study, 101 patients were included, of whom 59 were patients with HBC under anticancer treatment. A cohort of patients with a past medical history of gastrointestinal cancer, of whom 28.6% had HBC without detectable active tumor disease having been off therapy for at least 12 months, served as control. Levels of SARS-CoV-2 anti-spike IgG, surrogate neutralization antibodies (sNABs), and cellular immune responses were compared. In uni- and multivariable subgroup analyses, risk factors for impaired immunogenicity were regarded. Data on rates and clinical courses of SARS-CoV-2 infections were documented.
Results: In patients with HBC under active treatment, levels of SARS-CoV-2 anti-spike IgG were significantly lower (2.55 log10 BAU/mL; 95% CI: 2.33-2.76; p < 0.01) than in patients in follow-up care (3.02 log10 BAU/mL; 95% CI: 2.80-3.25) 4 weeks after two vaccinations. Antibody levels decreased over time, and differences between the groups diminished. However, titers of SARS-CoV-2 sNAB were for a longer time significantly lower in patients with HBC under treatment (64.19%; 95% CI: 55.90-72.48; p < 0.01) than in patients in follow-up care (84.13%; 95% CI: 76.95-91.31). Underlying CLD and/or liver cirrhosis Child-Pugh A or B (less than 8 points) did not seem to further impair immunogenicity. Conversely, chemotherapy and additional immunosuppression were found to significantly reduce antibody levels. After a third booster vaccination for SARS-CoV-2, levels of total and neutralization antibodies were equalized between the groups. Moreover, cellular response rates were balanced. Clinically, infection rates with SARS-CoV-2 were low, and no severe courses were observed.
Conclusion: Patients with active HBC showed significantly impaired immune response rates to basic vaccinations for SARS-CoV-2, especially under chemotherapy, independent of underlying cirrhotic or non-cirrhotic CLD. Although booster vaccinations balanced differences, waning immunity was observed over time and should be monitored for further recommendations. Our data help clinicians decide on individual additional booster vaccinations and/or passive immunization or antiviral treatment in patients with HBC getting infected with SARS-CoV-2.
{"title":"Deficient Immune Response following SARS-CoV-2 Vaccination in Patients with Hepatobiliary Carcinoma: A Forgotten, Vulnerable Group of Patients.","authors":"Malte B Monin, Leona I Baier, Jens G Gorny, Moritz Berger, Taotao Zhou, Robert Mahn, Farsaneh Sadeghlar, Christian Möhring, Christoph Boesecke, Kathrin van Bremen, Jürgen K Rockstroh, Christian P Strassburg, Anna-Maria Eis-Hübinger, Matthias Schmid, Maria A Gonzalez-Carmona","doi":"10.1159/000529608","DOIUrl":"https://doi.org/10.1159/000529608","url":null,"abstract":"<p><strong>Introduction: </strong>Data on immune response rates following vaccination for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in patients with hepatobiliary carcinoma (HBC) are rare. However, impaired immunogenicity must be expected due to the combination of chronic liver diseases (CLDs) with malignancy and anticancer treatment.</p><p><strong>Methods: </strong>In this prospective, longitudinal study, 101 patients were included, of whom 59 were patients with HBC under anticancer treatment. A cohort of patients with a past medical history of gastrointestinal cancer, of whom 28.6% had HBC without detectable active tumor disease having been off therapy for at least 12 months, served as control. Levels of SARS-CoV-2 anti-spike IgG, surrogate neutralization antibodies (sNABs), and cellular immune responses were compared. In uni- and multivariable subgroup analyses, risk factors for impaired immunogenicity were regarded. Data on rates and clinical courses of SARS-CoV-2 infections were documented.</p><p><strong>Results: </strong>In patients with HBC under active treatment, levels of SARS-CoV-2 anti-spike IgG were significantly lower (2.55 log<sub>10</sub> BAU/mL; 95% CI: 2.33-2.76; <i>p</i> < 0.01) than in patients in follow-up care (3.02 log<sub>10</sub> BAU/mL; 95% CI: 2.80-3.25) 4 weeks after two vaccinations. Antibody levels decreased over time, and differences between the groups diminished. However, titers of SARS-CoV-2 sNAB were for a longer time significantly lower in patients with HBC under treatment (64.19%; 95% CI: 55.90-72.48; <i>p</i> < 0.01) than in patients in follow-up care (84.13%; 95% CI: 76.95-91.31). Underlying CLD and/or liver cirrhosis Child-Pugh A or B (less than 8 points) did not seem to further impair immunogenicity. Conversely, chemotherapy and additional immunosuppression were found to significantly reduce antibody levels. After a third booster vaccination for SARS-CoV-2, levels of total and neutralization antibodies were equalized between the groups. Moreover, cellular response rates were balanced. Clinically, infection rates with SARS-CoV-2 were low, and no severe courses were observed.</p><p><strong>Conclusion: </strong>Patients with active HBC showed significantly impaired immune response rates to basic vaccinations for SARS-CoV-2, especially under chemotherapy, independent of underlying cirrhotic or non-cirrhotic CLD. Although booster vaccinations balanced differences, waning immunity was observed over time and should be monitored for further recommendations. Our data help clinicians decide on individual additional booster vaccinations and/or passive immunization or antiviral treatment in patients with HBC getting infected with SARS-CoV-2.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 4","pages":"339-355"},"PeriodicalIF":13.8,"publicationDate":"2023-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71412861","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}
Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people.
Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer.
Key messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."
{"title":"Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition).","authors":"Jian Zhou, Huichuan Sun, Zheng Wang, Wenming Cong, Mengsu Zeng, Weiping Zhou, Ping Bie, Lianxin Liu, Tianfu Wen, Ming Kuang, Guohong Han, Zhiping Yan, Maoqiang Wang, Ruibao Liu, Ligong Lu, Zhenggang Ren, Zhaochong Zeng, Ping Liang, Changhong Liang, Min Chen, Fuhua Yan, Wenping Wang, Jinlin Hou, Yuan Ji, Jingping Yun, Xueli Bai, Dingfang Cai, Weixia Chen, Yongjun Chen, Wenwu Cheng, Shuqun Cheng, Chaoliu Dai, Wengzhi Guo, Yabing Guo, Baojin Hua, Xiaowu Huang, Weidong Jia, Qiu Li, Tao Li, Xun Li, Yaming Li, Yexiong Li, Jun Liang, Changquan Ling, Tianshu Liu, Xiufeng Liu, Shichun Lu, Guoyue Lv, Yilei Mao, Zhiqiang Meng, Tao Peng, Weixin Ren, Hongcheng Shi, Guoming Shi, Ming Shi, Tianqiang Song, Kaishan Tao, Jianhua Wang, Kui Wang, Lu Wang, Wentao Wang, Xiaoying Wang, Zhiming Wang, Bangde Xiang, Baocai Xing, Jianming Xu, Jiamei Yang, Jianyong Yang, Yefa Yang, Yunke Yang, Shenglong Ye, Zhenyu Yin, Yong Zeng, Bixiang Zhang, Boheng Zhang, Leida Zhang, Shuijun Zhang, Ti Zhang, Yanqiao Zhang, Ming Zhao, Yongfu Zhao, Honggang Zheng, Ledu Zhou, Jiye Zhu, Kangshun Zhu, Rong Liu, Yinghong Shi, Yongsheng Xiao, Lan Zhang, Chun Yang, Zhifeng Wu, Zhi Dai, Minshan Chen, Jianqiang Cai, Weilin Wang, Xiujun Cai, Qiang Li, Feng Shen, Shukui Qin, Gaojun Teng, Jiahong Dong, Jia Fan","doi":"10.1159/000530495","DOIUrl":"https://doi.org/10.1159/000530495","url":null,"abstract":"<p><strong>Background: </strong>Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people.</p><p><strong>Summary: </strong>Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer.</p><p><strong>Key messages: </strong>The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the \"Health China 2030 Blueprint.\"</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 5","pages":"405-444"},"PeriodicalIF":13.8,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71412867","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 : 2023-03-28eCollection Date: 2023-10-01DOI: 10.1159/000529824
Darren Jun Hao Tan, Ansel Shao Pin Tang, Wen Hui Lim, Cheng Han Ng, Benjamin Nah, Clarissa Fu, Jieling Xiao, Benjamin Koh, Phoebe Wen Lin Tay, Eunice X Tan, Margaret Teng, Nicholas Syn, Mark D Muthiah, Nobuharu Tamaki, Sung Won Lee, Beom Kyung Kim, Thomas Yau, Arndt Vogel, Rohit Loomba, Daniel Q Huang
Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC.
Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6-11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8-10.7) months in studies before 2015 to 13.4 (95% CI: 11.03-15.24) months in studies from 2015 onwards (p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9-4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (p < 0.001). There was minimal heterogeneity in the estimates for OS (all I2 ≤ 33).
Key messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.
{"title":"Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials.","authors":"Darren Jun Hao Tan, Ansel Shao Pin Tang, Wen Hui Lim, Cheng Han Ng, Benjamin Nah, Clarissa Fu, Jieling Xiao, Benjamin Koh, Phoebe Wen Lin Tay, Eunice X Tan, Margaret Teng, Nicholas Syn, Mark D Muthiah, Nobuharu Tamaki, Sung Won Lee, Beom Kyung Kim, Thomas Yau, Arndt Vogel, Rohit Loomba, Daniel Q Huang","doi":"10.1159/000529824","DOIUrl":"10.1159/000529824","url":null,"abstract":"<p><strong>Background: </strong>Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC.</p><p><strong>Summary: </strong>In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6-11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8-10.7) months in studies before 2015 to 13.4 (95% CI: 11.03-15.24) months in studies from 2015 onwards (<i>p</i> < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9-4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (<i>p</i> < 0.001). There was minimal heterogeneity in the estimates for OS (all <i>I</i><sup>2</sup> ≤ 33).</p><p><strong>Key messages: </strong>Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":"12 5","pages":"445-456"},"PeriodicalIF":11.6,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71412870","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}