Introduction: Outcomes of transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (HCC) are diverse because of the heterogeneity of tumor burden. Radiologic pattern is one criterion for determining whether TACE is unsuitable. However, additional evidence is required. This study determined the influence of radiologic morphology on the outcomes of initial and subsequent TACE.
Methods: From January 2007 to September 2021, 633 treatment-naive patients with HCC with intermediate-stage HCC undergoing TACE were retrospectively enrolled. Of these patients, 386 patients received repeated TACE. The radiological features of HCC were evaluated by two radiologists and classified into encapsulated nodular type, simple nodular type with extranodular growth, confluent multinodular type, and infiltrative type. The objective response rate (ORR) and survival rate after initial and subsequent TACE among various radiologic morphologies were compared.
Results: After initial TACE, encapsulated nodular type HCC had the highest ORR (58%), followed by extranodular type (45.8%), confluent multinodular type (29%), and infiltrative type (19.5%). Notably, radiologic pattern was highly associated with tumor burden. Tumor burden and radiologic morphology were significantly associated with ORR and overall survival (OS) in the multivariate analysis. In 386 patients with subsequent TACE, encapsulated nodular type HCC had the highest ORR (48.7%), followed by extranodular type (37.3%), confluent multinodular type (26.2%), and infiltrative type (10%). In the multivariate analysis, radiologic features were significant independent predictors of ORR and OS after receiving subsequent TACE.
Conclusion: Radiologic patterns determine the outcomes of initial and subsequent TACE. Systemic therapy should be considered for patients with intermediate-stage HCC with unfavorable radiologic patterns.
{"title":"Radiologic Patterns Determine the Outcomes of Initial and Subsequent Transarterial Chemoembolization in Intermediate-Stage Hepatocellular Carcinoma.","authors":"Ya-Wen Hung, I-Cheng Lee, Chen-Ta Chi, Rheun-Chuan Lee, Chien-An Liu, Nai-Chi Chiu, Hsuen-En Hwang, Yee Chao, Ming-Chih Hou, Yi-Hsiang Huang","doi":"10.1159/000530950","DOIUrl":"10.1159/000530950","url":null,"abstract":"<p><strong>Introduction: </strong>Outcomes of transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (HCC) are diverse because of the heterogeneity of tumor burden. Radiologic pattern is one criterion for determining whether TACE is unsuitable. However, additional evidence is required. This study determined the influence of radiologic morphology on the outcomes of initial and subsequent TACE.</p><p><strong>Methods: </strong>From January 2007 to September 2021, 633 treatment-naive patients with HCC with intermediate-stage HCC undergoing TACE were retrospectively enrolled. Of these patients, 386 patients received repeated TACE. The radiological features of HCC were evaluated by two radiologists and classified into encapsulated nodular type, simple nodular type with extranodular growth, confluent multinodular type, and infiltrative type. The objective response rate (ORR) and survival rate after initial and subsequent TACE among various radiologic morphologies were compared.</p><p><strong>Results: </strong>After initial TACE, encapsulated nodular type HCC had the highest ORR (58%), followed by extranodular type (45.8%), confluent multinodular type (29%), and infiltrative type (19.5%). Notably, radiologic pattern was highly associated with tumor burden. Tumor burden and radiologic morphology were significantly associated with ORR and overall survival (OS) in the multivariate analysis. In 386 patients with subsequent TACE, encapsulated nodular type HCC had the highest ORR (48.7%), followed by extranodular type (37.3%), confluent multinodular type (26.2%), and infiltrative type (10%). In the multivariate analysis, radiologic features were significant independent predictors of ORR and OS after receiving subsequent TACE.</p><p><strong>Conclusion: </strong>Radiologic patterns determine the outcomes of initial and subsequent TACE. Systemic therapy should be considered for patients with intermediate-stage HCC with unfavorable radiologic patterns.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2023-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10857819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77255720","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: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies.
Methods: This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January 2015 to December 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40%, and tumor growth kinetics ratio ≥4.
Results: The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (p = 0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% confidence interval [CI]: 0.05-3.83) when compared to the anti-PD-1/PD-L1 monotherapy group and 2.93 (95% CI: 0.25-33.79) when compared to the combined VEGF antibody group.
Conclusion: The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.
{"title":"Incidence of Hyper Progressive Disease in Combination Immunotherapy and Anti-Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Monotherapy for Unresectable Hepatocellular Carcinoma.","authors":"Tomoko Aoki, Masatoshi Kudo, Kazuomi Ueshima, Masahiro Morita, Hirokazu Chishina, Masahiro Takita, Satoru Hagiwara, Hiroshi Ida, Yasunori Minami, Masakatsu Tsurusaki, Naoshi Nishida","doi":"10.1159/000531024","DOIUrl":"10.1159/000531024","url":null,"abstract":"<p><strong>Introduction: </strong>Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies.</p><p><strong>Methods: </strong>This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January 2015 to December 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40%, and tumor growth kinetics ratio ≥4.</p><p><strong>Results: </strong>The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (<i>p</i> = 0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% confidence interval [CI]: 0.05-3.83) when compared to the anti-PD-1/PD-L1 monotherapy group and 2.93 (95% CI: 0.25-33.79) when compared to the combined VEGF antibody group.</p><p><strong>Conclusion: </strong>The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2023-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10857830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78394983","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":null,"pages":null},"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}
Pub Date : 2023-04-24eCollection Date: 2024-02-01DOI: 10.1159/000530700
Liangtao Ye, Julia S Schneider, Najib Ben Khaled, Peter Schirmacher, Carolin Seifert, Lea Frey, Yulong He, Andreas Geier, Enrico N De Toni, Changhua Zhang, Florian P Reiter
Background: Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation.
Summary: Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis, and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies.
Key messages: In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.
{"title":"Combined Hepatocellular-Cholangiocarcinoma: Biology, Diagnosis, and Management.","authors":"Liangtao Ye, Julia S Schneider, Najib Ben Khaled, Peter Schirmacher, Carolin Seifert, Lea Frey, Yulong He, Andreas Geier, Enrico N De Toni, Changhua Zhang, Florian P Reiter","doi":"10.1159/000530700","DOIUrl":"10.1159/000530700","url":null,"abstract":"<p><strong>Background: </strong>Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation.</p><p><strong>Summary: </strong>Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis, and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies.</p><p><strong>Key messages: </strong>In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2023-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10857821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83516306","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: A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform.
Methods: A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC.
Results: They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort.
Conclusion: A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.
{"title":"HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in Subgrouping HBV-Related HCC with Distinct Features.","authors":"Chiao-Ling Li, Chia-Lang Hsu, You-Yu Lin, Ming-Chih Ho, Ray-Heng Hu, Chi-Ling Chen, Tung-Ching Ho, Yung-Feng Lin, Shih-Feng Tsai, Sheng-Tai Tzeng, Chin-Fang Huang, Ya-Chun Wang, Shiou-Hwei Yeh, Pei-Jer Chen","doi":"10.1159/000530699","DOIUrl":"10.1159/000530699","url":null,"abstract":"<p><strong>Introduction: </strong>A set of genetic mutations to classify hepatocellular carcinoma (HCC) useful to clinical studies is an unmet need. Hepatitis B virus-related HCC (HBV-HCC) harbors a unique genetic mutation, namely, the HBV integration, among other somatic endogenous gene mutations. We explored a combination of HBV DNA integrations and common somatic mutations to classify HBV-HCC by using a capture-sequencing platform.</p><p><strong>Methods: </strong>A total of 153 HBV-HCCs after surgical resection were subjected to capture sequencing to identify HBV integrations and three common somatic mutations in genomes. Three mutually exclusive mutations, HBV DNA integration into the TERT promoter, HBV DNA integration into MLL4, or TERT promoter point mutation, were identified in HBV-HCC.</p><p><strong>Results: </strong>They were used to classify HBV-HCCs into four groups: G1 with HBV-TERT integration (25.5%); G2 with HBV-MLL4 integration (10.5%); G3 with TERT promoter mutation (30.1%); and G4 without these three mutations (34.0%). Clinically, G3 has the highest male-to-female ratio, cirrhosis rate, and associated with higher early recurrence and mortality after resection, but G4 has the best outcome. Transcriptomic analysis revealed a grouping different from the published ones and G2 with an active immune profile related to immune checkpoint inhibitor response. Analysis of integrated HBV DNA provided clues for HBV genotype and variants in carcinogenesis of different HCC subgroup. This new classification was also validated in another independent cohort.</p><p><strong>Conclusion: </strong>A simple and robust genetic classification was developed to aid in understanding HBV-HCC and in harmonizing clinical studies.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2023-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10857820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73200216","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: Complete resection is the only possible treatment for cholangiocarcinoma in the extrahepatic biliary tree (eCCA), although current imaging modalities are limited in their ability to accurately diagnose longitudinal spread. We aimed to develop fluorescence imaging techniques for real-time identification of eCCA using an enzyme-activatable probe, which emits fluorescence immediately after activation by a cancer-specific enzyme.
Methods: Using lysates and small tissue fragments collected from surgically resected specimens, we selected the most specific probe for eCCA from among 800 enzyme-activatable probes. The selected probe was directly sprayed onto resected specimens and fluorescence images were acquired; these images were evaluated for diagnostic accuracy. We also comprehensively searched for enzymes that could activate the probe, then compared their expression levels in cancer and non-cancer tissues.
Results: Analyses of 19 samples (four cancer lysates, seven non-cancer lysates, and eight bile samples) and 54 tissue fragments (13 cancer tissues and 41 non-cancer tissues) revealed that PM-2MeSiR was the most specific fluorophore for eCCA. Fluorescence images of 7 patients were obtained; these images enabled rapid identification of cancerous regions, which closely matched histopathology findings in 4 patients. Puromycin-sensitive aminopeptidase was identified as the enzyme that might activate the probe, and its expression was upregulated in eCCA.
Conclusion: Fluorescence imaging with PM-2MeSiR, which may be activated by puromycin-sensitive aminopeptidase, yielded generally high accuracy. This technique may be useful for real-time identification of the spread of eCCA during surgery and endoscopic examinations.
{"title":"Real-Time Fluorescence Imaging to Identify Cholangiocarcinoma in the Extrahepatic Biliary Tree Using an Enzyme-Activatable Probe.","authors":"Ryugen Takahashi, Takeaki Ishizawa, Yoshinori Inagaki, Mariko Tanaka, Akira Ogasawara, Yugo Kuriki, Kyohhei Fujita, Mako Kamiya, Tetsuo Ushiku, Yasuteru Urano, Kiyoshi Hasegawa","doi":"10.1159/000530645","DOIUrl":"10.1159/000530645","url":null,"abstract":"<p><strong>Introduction: </strong>Complete resection is the only possible treatment for cholangiocarcinoma in the extrahepatic biliary tree (eCCA), although current imaging modalities are limited in their ability to accurately diagnose longitudinal spread. We aimed to develop fluorescence imaging techniques for real-time identification of eCCA using an enzyme-activatable probe, which emits fluorescence immediately after activation by a cancer-specific enzyme.</p><p><strong>Methods: </strong>Using lysates and small tissue fragments collected from surgically resected specimens, we selected the most specific probe for eCCA from among 800 enzyme-activatable probes. The selected probe was directly sprayed onto resected specimens and fluorescence images were acquired; these images were evaluated for diagnostic accuracy. We also comprehensively searched for enzymes that could activate the probe, then compared their expression levels in cancer and non-cancer tissues.</p><p><strong>Results: </strong>Analyses of 19 samples (four cancer lysates, seven non-cancer lysates, and eight bile samples) and 54 tissue fragments (13 cancer tissues and 41 non-cancer tissues) revealed that PM-2MeSiR was the most specific fluorophore for eCCA. Fluorescence images of 7 patients were obtained; these images enabled rapid identification of cancerous regions, which closely matched histopathology findings in 4 patients. Puromycin-sensitive aminopeptidase was identified as the enzyme that might activate the probe, and its expression was upregulated in eCCA.</p><p><strong>Conclusion: </strong>Fluorescence imaging with PM-2MeSiR, which may be activated by puromycin-sensitive aminopeptidase, yielded generally high accuracy. This technique may be useful for real-time identification of the spread of eCCA during surgery and endoscopic examinations.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2023-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10697719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81197856","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":null,"pages":null},"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}
Introduction: The purpose of this study was to evaluate the treatment efficacy of transcatheter arterial chemoembolization (TACE) for treatment-naive hepatocellular carcinoma (HCC) according to tumor location and burden.
Methods: Between 2010 and 2019, consecutive patients who underwent TACE as the first treatment were enrolled. Tumors were classified into two categories based on their location, as central or peripheral tumors. Tumors in the central zone, which is within 1 cm of the main trunk or the first branch of the portal vein, were classified as central tumors, while those located in the peripheral zone were classified as peripheral tumors. Patients were grouped according to the HCC location and up-to-7 criteria. Patients with central tumors were classified into the central arm and those with only peripheral tumors were classified into the peripheral arm. Patients within and beyond the up-to-7 criteria were classified into the up-to-7 in and up-to-7 out-groups, respectively. Local recurrence-free survival (LRFS) and progression-free survival (PFS) were compared per nodule (central tumor vs. peripheral tumor) and per patient (central arm vs. peripheral arm), respectively. The prognostic factors of LRFS and PFS were analyzed by univariate and multivariate analyses.
Results: A total of 174 treatment-naive patients with 352 HCCs were retrospectively enrolled. Ninety-six patients and 130 lesions were selected by propensity score matching. Median LRFS was longer for peripheral tumors than central tumors (not reached vs. 3.3 months, p < 0.001). Median PFS was 17.1 months (8.3-24.9) in the peripheral arm and up-to-7 in, 7.0 months (3.3-12.7) in the peripheral arm and up-to-7 out, 8.4 months (4.0-12.6) in the central arm and up-to-7 in, and 3.0 months (1.2-4.9) in the central arm and up-to-7 out-groups. The peripheral arm and up-to-7 in-groups had significantly longer PFS than the other three groups (p = 0.013, p = 0.015, p < 0.001, respectively). Multivariate analysis confirmed that the central zone and central arm were associated with high adjusted hazard ratios for tumor recurrence or death (2.87, p < 0.001; 2.89, p < 0.001, respectively).
Conclusion: Treatment-naive HCCs in the peripheral zone had a longer LRFS and PFS following TACE compared to those in the central zone.
摘要:本研究的目的是根据肿瘤部位和负荷,评价经导管动脉化疗栓塞(TACE)治疗初治肝癌(HCC)的疗效。方法:在2010年至2019年期间,连续接受TACE作为首次治疗的患者入组。肿瘤根据其位置分为中枢性和外周性两类。位于门静脉主干或第一分支1cm以内的中心区肿瘤为中心区肿瘤,位于外周区肿瘤为外周区肿瘤。根据HCC的位置和7级标准对患者进行分组。有中枢肿瘤的患者分为中央臂,只有外周肿瘤的患者分为外周臂。达到和超过7级标准的患者分别分为7级以内组和7级以内组。局部无复发生存期(LRFS)和无进展生存期(PFS)分别比较每个结节(中央肿瘤与外周肿瘤)和每个患者(中央臂与外周臂)。通过单因素和多因素分析分析LRFS和PFS的预后因素。结果:共纳入174例未接受治疗的352例hcc患者。采用倾向评分匹配法选择96例患者和130个病灶。外周肿瘤的中位LRFS长于中枢肿瘤(未达到vs. 3.3个月,p < 0.001)。中位PFS外周组为17.1个月(8.3-24.9),至7 in;外周组为7.0个月(3.3-12.7),至7 in;中心组为8.4个月(4.0-12.6),至7 in;中心组为3.0个月(1.2-4.9),至7 in。外周臂组和7岁以内组的PFS明显长于其他三组(p = 0.013, p = 0.015, p < 0.001)。多因素分析证实,中心区和中心臂与肿瘤复发或死亡的高校正危险比相关(2.87,p < 0.001;2.89, p < 0.001)。结论:与中心区相比,外周区未接受治疗的hcc在TACE后的LRFS和PFS更长。
{"title":"Transcatheter Arterial Chemoembolization for Treatment-Naive Hepatocellular Carcinoma Has Different Treatment Effects Depending on Central or Peripheral Tumor Location.","authors":"Kazuo Asano, Ken Kageyama, Akira Yamamoto, Atsushi Jogo, Sawako Uchida-Kobayashi, Etsuji Sohgawa, Kazuki Murai, Norifumi Kawada, Yukio Miki","doi":"10.1159/000530441","DOIUrl":"10.1159/000530441","url":null,"abstract":"<p><strong>Introduction: </strong>The purpose of this study was to evaluate the treatment efficacy of transcatheter arterial chemoembolization (TACE) for treatment-naive hepatocellular carcinoma (HCC) according to tumor location and burden.</p><p><strong>Methods: </strong>Between 2010 and 2019, consecutive patients who underwent TACE as the first treatment were enrolled. Tumors were classified into two categories based on their location, as central or peripheral tumors. Tumors in the central zone, which is within 1 cm of the main trunk or the first branch of the portal vein, were classified as central tumors, while those located in the peripheral zone were classified as peripheral tumors. Patients were grouped according to the HCC location and up-to-7 criteria. Patients with central tumors were classified into the central arm and those with only peripheral tumors were classified into the peripheral arm. Patients within and beyond the up-to-7 criteria were classified into the up-to-7 in and up-to-7 out-groups, respectively. Local recurrence-free survival (LRFS) and progression-free survival (PFS) were compared per nodule (central tumor vs. peripheral tumor) and per patient (central arm vs. peripheral arm), respectively. The prognostic factors of LRFS and PFS were analyzed by univariate and multivariate analyses.</p><p><strong>Results: </strong>A total of 174 treatment-naive patients with 352 HCCs were retrospectively enrolled. Ninety-six patients and 130 lesions were selected by propensity score matching. Median LRFS was longer for peripheral tumors than central tumors (not reached vs. 3.3 months, <i>p</i> < 0.001). Median PFS was 17.1 months (8.3-24.9) in the peripheral arm and up-to-7 in, 7.0 months (3.3-12.7) in the peripheral arm and up-to-7 out, 8.4 months (4.0-12.6) in the central arm and up-to-7 in, and 3.0 months (1.2-4.9) in the central arm and up-to-7 out-groups. The peripheral arm and up-to-7 in-groups had significantly longer PFS than the other three groups (<i>p</i> = 0.013, <i>p</i> = 0.015, <i>p</i> < 0.001, respectively). Multivariate analysis confirmed that the central zone and central arm were associated with high adjusted hazard ratios for tumor recurrence or death (2.87, <i>p</i> < 0.001; 2.89, <i>p</i> < 0.001, respectively).</p><p><strong>Conclusion: </strong>Treatment-naive HCCs in the peripheral zone had a longer LRFS and PFS following TACE compared to those in the central zone.</p>","PeriodicalId":18156,"journal":{"name":"Liver Cancer","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10697731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82787617","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":null,"pages":null},"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}