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Ben Khaled N, Zarka V, Hobeika B, Schneider J, Rau M, Weich A, Leicht HB, Ye L, Piseddu I, Dill MT, Kandulski A, Pinter M, Ehmer U, Schirmacher P, Marquardt JU, Mayerle J, De Toni EN, Geier A, Reiter FP. Therapeutic Sequences of Systemic Therapy After Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma: Real-World Analysis of the IMMUreal Cohort. Aliment Pharmacol Ther 2025; 61:1755-1766. [PMID: 40181694 PMCID: PMC12074566 DOI: 10.1111/apt.70090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/25/2024] [Accepted: 03/09/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND The introduction of several new systemic therapies in recent years has significantly altered the treatment landscape for advanced hepatocellular carcinoma. However, while the approval of the combination of atezolizumab and bevacizumab as the preferred first-line therapy over sorafenib represents progress, it has also raised uncertainties regarding optimal treatment sequencing for advanced disease. AIMS This study evaluates the sequential treatment of hepatocellular carcinoma following therapy with atezolizumab and bevacizumab, providing evidence from a prospective real-world cohort. METHODS Data were derived from the ongoing IMMUreal cohort, which investigates immunotherapy in hepatocellular carcinoma across two tertiary centres in Bavaria. A total of 124 patients treated with atezolizumab and bevacizumab as first-line therapy between June 2020 and December 2023 were analysed. Feasibility, treatment patterns, and outcomes of sequential therapy were assessed, with a focus on defined prognostic subgroups. RESULTS The median overall survival under real-world conditions was 19.8 months. Less than half of the patients (41.2%) proceeded to second-line therapy, and only 19.2% were eligible for third-line treatment. This decline in treatment eligibility corresponded to a marked reduction in therapy duration and progressive deterioration in liver function, as indicated by Albumin-Bilirubin and Child-Pugh scores. While patients with worse baseline liver function, such as patients with Child-Pugh B or ALBI > 1, had a significantly lower probability of transitioning to 2nd line therapy, no significant association was found between the number of treatment lines and factors such as liver cirrhosis, poor physical condition, extrahepatic disease, or macrovascular invasion. CONCLUSIONS Sequential therapy following atezolizumab and bevacizumab is feasible only for selected patients. However, preserving liver function seems crucial to optimising multi-line therapy and improving outcomes in advanced hepatocellular carcinoma.
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Affiliation(s)
- Najib Ben Khaled
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Valentina Zarka
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Bernard Hobeika
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Julia Schneider
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Monika Rau
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Alexander Weich
- Division of Gastroenterology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Hans Benno Leicht
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Liangtao Ye
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
- Digestive Diseases CenterThe Seventh Affiliated Hospital, Sun Yat‐Sen UniversityShenzhenChina
| | - Ignazio Piseddu
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Michael T. Dill
- Department of Gastroenterology, Infectious Diseases and IntoxicationHeidelberg University HospitalHeidelbergGermany
- National Center for Tumor Diseases (NCT)NCT Heidelberg, a Partnership Between DKFZ and Heidelberg University HospitalHeidelbergGermany
- German Cancer Research Center (DKFZ) HeidelbergResearch Group Experimental Hepatology, Inflammation and CancerHeidelbergGermany
| | - Arne Kandulski
- Gastroenterology, Hepatology, Endocrinology, Rheumatology and Infectious Diseases, Department of Internal Medicine IUniversity Hospital RegensburgRegensburgGermany
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Ursula Ehmer
- Clinical Department for Internal Medicine II, Department of Clinical Medicine, TUM School of Medicine and Health, University Medical Center, Technical University of MunichMunichGermany
| | | | | | - Julia Mayerle
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Enrico N. De Toni
- Department of Medicine IIUniversity Hospital, LMU MunichMunichGermany
| | - Andreas Geier
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
| | - Florian P. Reiter
- Division of Hepatology, Department of Medicine IIUniversity Hospital WürzburgWürzburgGermany
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Scheiner B, Kang B, Balcar L, Radu IP, Reiter FP, Adžić G, Guo J, Gao X, Yuan X, Cheng L, Gorgulho J, Schultheiss M, Peeters F, Hucke F, Ben Khaled N, Piseddu I, Philipp A, Sinner F, D'Alessio A, Pomej K, Saborowski A, Bathon M, Schwacha-Eipper B, Zarka V, Lampichler K, Nishida N, Lee PC, Krall A, Saeed A, Himmelsbach V, Tesini G, Huang YH, Vivaldi C, Masi G, Vogel A, Schulze K, Trauner M, Djanani A, Stauber R, Kudo M, Parikh ND, Dufour JF, Prejac J, Geier A, Bengsch B, von Felden J, Venerito M, Weinmann A, Peck-Radosavljevic M, Finkelmeier F, Dekervel J, Ji F, Wang HW, Rimassa L, Pinato DJ, Bouattour M, Chon HJ, Pinter M. Outcome and management of patients with hepatocellular carcinoma who achieved a complete response to immunotherapy-based systemic therapy. Hepatology 2025; 81:1714-1727. [PMID: 39643944 DOI: 10.1097/hep.0000000000001163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 09/12/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND AND AIMS The outcome of patients with HCC who achieved complete response (CR) to immune-checkpoint inhibitor (ICI)-based systemic therapies is unclear. APPROACH AND RESULTS Retrospective study of patients with HCC who had CR according to modified Response Evaluation Criteria in Solid Tumors (CR-mRECIST) to ICI-based systemic therapies from 28 centers in Asia, Europe, and the United States. Of 3933 patients with HCC treated with ICI-based noncurative systemic therapies, 174 (4.4%) achieved CR-mRECIST, and 97 (2.5%) had CR according to RECISTv1.1 (CR-RECISTv1.1) as well. The mean age of the total cohort (male, 85%; Barcelona-Clinic Liver Cancer-C, 70%) was 65.9±9.8 years. The majority (83%) received ICI-based combination therapies. Median follow-up was 32.2 (95% CI: 29.9-34.4) months. One- and 3-year overall survival rates were 98% and 86%. One- and 3-year recurrence-free survival rates were excellent in patients with CR-mRECIST-only and CR-RECISTv1.1 (78% and 55%; 70% and 42%). Among patients who discontinued ICIs for reasons other than recurrence, those who received immunotherapy for ≥6 months after the first mRECIST CR had a longer recurrence-free survival than those who discontinued immunotherapy earlier ( p =0.008). Of 9 patients who underwent curative surgical conversion therapy, 8 (89%) had pathological CR (CR-RECISTv1.1, n= 2/2; CR-mRECIST-only, n= 6/7). CONCLUSIONS Overall survival and recurrence-free survival of patients with CR-mRECIST-only and CR-RECISTv1.1 were excellent, and 6 of 7 patients with CR-mRECIST-only who underwent surgical conversion therapy had pathological CR. Despite potential limitations, these findings support the use of mRECIST in the context of immunotherapy for clinical decision-making. When considering ICI discontinuation, treatment for at least 6 months beyond CR seems advisable.
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Affiliation(s)
- Bernhard Scheiner
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Beodeul Kang
- Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Centre, CHA University, Seongnam, Republic of Korea
| | - Lorenz Balcar
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Iuliana-Pompilia Radu
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Florian P Reiter
- Department of Medicine II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Gordan Adžić
- Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Jiang Guo
- Department of Oncology Interventional Radiology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xu Gao
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiao Yuan
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Long Cheng
- Department of Oncology Interventional Radiology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Joao Gorgulho
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Medical Center-University of Freiburg, Germany, Faculty of Medicine, University of Freiburg, Germany
| | - Frederik Peeters
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat, Leuven, Belgium
| | - Florian Hucke
- Internal Medicine and Gastroenterology (IMuG), including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Ignazio Piseddu
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Alexander Philipp
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Friedrich Sinner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, Magdeburg, Germany
| | - Antonio D'Alessio
- Department of Surgery and Cancer, Division of Cancer, Imperial College London, London, United Kingdom
- Department of Translational Medicine, Division of Oncology, University of Piemonte Orientale, Novara, Italy
| | - Katharina Pomej
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Melanie Bathon
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Schwacha-Eipper
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Valentina Zarka
- Department of Medicine II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Katharina Lampichler
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Pei-Chang Lee
- Department of Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Anja Krall
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh (UPMC), Pittsburgh, Pennsylvania, USA
| | - Vera Himmelsbach
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Giulia Tesini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Yi-Hsiang Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
- Healthcare and Services Center, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Gianluca Masi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Arndt Vogel
- Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, Canada
- Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
- Hannover Medical School, Hannover, Germany
| | - Kornelius Schulze
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Trauner
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Angela Djanani
- Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Rudolf Stauber
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Juraj Prejac
- Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia
- University of Zagreb, School of Dental Medicine, Zagreb, Croatia
| | - Andreas Geier
- Department of Medicine II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Bertram Bengsch
- Department of Medicine II, Medical Center-University of Freiburg, Germany, Faculty of Medicine, University of Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Johann von Felden
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, Magdeburg, Germany
| | - Arndt Weinmann
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Markus Peck-Radosavljevic
- Internal Medicine and Gastroenterology (IMuG), including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Fabian Finkelmeier
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Jeroen Dekervel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat, Leuven, Belgium
| | - Fanpu Ji
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
| | - Hung-Wei Wang
- Department of Internal Medicine, Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - David J Pinato
- Department of Surgery and Cancer, Division of Cancer, Imperial College London, London, United Kingdom
- Department of Translational Medicine, Division of Oncology, University of Piemonte Orientale, Novara, Italy
| | - Mohamed Bouattour
- Liver Cancer and Innovative Therapy, AP-HP, Hôpital Beaujon, Clichy, France
| | - Hong Jae Chon
- Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Centre, CHA University, Seongnam, Republic of Korea
| | - Matthias Pinter
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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Mohamed NM, Mohamed RH, Kennedy JF, Elhefnawi MM, Hamdy NM. A comprehensive review and in silico analysis of the role of survivin (BIRC5) in hepatocellular carcinoma hallmarks: A step toward precision. Int J Biol Macromol 2025; 311:143616. [PMID: 40306500 DOI: 10.1016/j.ijbiomac.2025.143616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/25/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.
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Affiliation(s)
- Nermin M Mohamed
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - John F Kennedy
- Chembiotech Laboratories, Kyrewood House, Tenbury Wells, Worcestershire, United Kingdom
| | - Mahmoud M Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
| | - Nadia M Hamdy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
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Aoki T, Kudo M, Nishida N, Ueshima K, Tsuchiya K, Tada T, Morita M, Chishina H, Takita M, Hagiwara S, Ida H, Minami Y, Kuroda H, Nakamura N, Hiraoka A, Tomonari T, Tani J, Naganuma A, Kakizaki S, Ogawa C, Hatanaka T, Ishikawa T, Kawata K, Takebe A, Matsumoto I, Hidaka M, Kurosaki M, Kumada T, Izumi N. Proposal of discontinuation criteria of atezolizumab plus bevacizumab after curative conversion therapy for unresectable early-to-intermediate-stage hepatocellular carcinoma: a multicenter proof-of-concept study. J Gastroenterol 2025; 60:738-753. [PMID: 40055288 PMCID: PMC12095402 DOI: 10.1007/s00535-025-02233-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 02/18/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Achieving complete response (CR) is a desirable goal in early-to-intermediate-stage hepatocellular carcinoma (HCC). While systemic and locoregional therapies show promise, optimal drug discontinuation criteria remain unclear. This study aims to investigate drug-off criteria for atezolizumab plus bevacizumab as a proof-of-concept study. METHODS This retrospective multicenter study included child-pugh class A patients with unresectable HCC without extrahepatic spread or macrovascular invasion who received atezolizumab plus bevacizumab as first-line therapy. Modified clinical CR (mCCR) was defined as CR per mRECIST with sustained normal alpha-fetoprotein (AFP) levels (< 10.0 ng/dl). Recurrence-free survival (RFS) and overall survival (OS) were analyzed based on the "drug-off" criteria defined by following: (1) mRECIST CR with locoregional therapies, (2) sustained normalization of AFP/AFP-L3/ des-gamma-carboxy prothrombin (DCP) for 12-24 weeks, and (3) complete tumor vascularity disappearance by contrast-enhanced ultrasonography (CEUS) or pathological curative resection. RESULTS The median follow-up was 16.5 months (95% CI 15.2-17.8). Among 51 patients achieving mCCR, 11 underwent surgery, with pathological CR in three cases. In contrast, viable lesions were observed in 7 of 40 cases assessed using CEUS. All patients meeting the drug-off criteria (n = 9) showed no recurrence and none of them experienced mortality, while 45.2% (19/42) of those not meeting the criteria experienced recurrence (median RFS: 12.8 months, p = 0.007). The median OS was not reached in dug-off criteria met patients (n = 9), 37.7 months (95% CI: NA) in non-criteria met patients (n = 42), and 27.1 months (95% CI 16.7-37.6) in non-mCCR patients (n = 184) (p < 0.001). CONCLUSION In patients with unresectable and TACE-unsuitable early-to-intermediate-stage HCC who met the drug-off criteria, significantly improved RFS and OS were observed compared those who did not meet the criteria. However, further validation studies are required to confirm the utility of the criteria.
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Affiliation(s)
- Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Masahiro Morita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Hirokazu Chishina
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan
| | - Hidekatsu Kuroda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Noriaki Nakamura
- Department of General Surgery, Shuuwa General Hospital, Saitama, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Tetsu Tomonari
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, NHO Takasaki General Medical Center, Takasaki, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, NHO Takasaki General Medical Center, Takasaki, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsushi Takebe
- Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ippei Matsumoto
- Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther 2025; 10:170. [PMID: 40383803 PMCID: PMC12086256 DOI: 10.1038/s41392-025-02249-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/09/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.
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Affiliation(s)
- Chunsik Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea.
| | - Myung-Jin Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea
| | - Anil Kumar
- Center for Research and Innovations, Adichunchanagiri University, Mandya, Karnataka, India
| | - Han-Woong Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonghwan Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
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6
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Xu X, Jiang X, Jiang H, Yuan X, Zhao M, Wang Y, Chen G, Li G, Duan Y. Prediction of prognosis of immune checkpoint inhibitors combined with anti-angiogenic agents for unresectable hepatocellular carcinoma by machine learning-based radiomics. BMC Cancer 2025; 25:888. [PMID: 40389888 PMCID: PMC12087138 DOI: 10.1186/s12885-025-14247-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 04/29/2025] [Indexed: 05/21/2025] Open
Abstract
OBJECTIVES This study aims to develop and validate a novel radiomics model utilizing magnetic resonance imaging (MRI) to predict progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (uHCC) who are receiving a combination of immune checkpoint inhibitors (ICIs) and antiangiogenic agents. This is an area that has not been previously explored using MRI-based radiomics. METHODS 111 patients with uHCC were enrolled in this study. After performing univariate cox regression and the least absolute shrinkage and selection operator (LASSO) algorithms to extract radiological features, the Rad-score was calculated through a Cox proportional hazards regression model and a random survival forest (RSF) model. The optimal calculation method was selected by comparing the Harrell's concordance index (C-index) values. The Rad-score was then combined with independent clinical risk factors to create a nomogram. C-index, time-dependent receiver operating characteristics (ROC) curves, calibration curves, and decision curve analysis were employed to assess the forecast ability of the risk models. RESULTS The combined nomogram incorporated independent clinical factors and Rad-score calculated by RSF demonstrated better prognosis prediction for PFS, with C-index of 0.846, 0.845, separately in the training and the validation cohorts. This indicates that our model performs well and has the potential to enable more precise patient stratification and personalized treatment strategies. Based on the risk level, the participants were classified into two distinct groups: the high-risk signature (HRS) group and the low-risk signature (LRS) group, with a significant difference between the groups (P < 0.01). CONCLUSION The effective clinical-radiomics nomogram based on MRI imaging is a promising tool in predicting the prognosis in uHCC patients receiving ICIs combined with anti-angiogenic agents, potentially leading to more effective clinical outcomes.
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Affiliation(s)
- Xuni Xu
- Department of Radiology, Shaoxing Central Hospital, The Central Affiliated Hospital, Shaoxing University, Shaoxing, 312000, China
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xue Jiang
- Department of Pathology, Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Haoran Jiang
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiaoye Yuan
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Mengjing Zhao
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yuqi Wang
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
| | - Gang Li
- Department of Radiation and Chemotherapy Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Yuxia Duan
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
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Jiang Y, Dong X, Zhang Y, Su F, Zhao L, Shi X, Zhong J. Navigating the complexities: challenges and opportunities in conversion therapy for advanced hepatocellular carcinoma. Clin Exp Med 2025; 25:169. [PMID: 40382739 PMCID: PMC12086121 DOI: 10.1007/s10238-025-01698-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 04/14/2025] [Indexed: 05/20/2025]
Abstract
Primary liver cancer ranks as the sixth most prevalent malignant tumor and stands as the second leading cause of cancer-related mortality globally, posing a significant threat to public health. Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Surgical resection remains the cornerstone treatment for achieving radical cure and prolonged survival in HCC patients. Contrary to Western countries, the majority of HCC patients in China present with hepatitis B virus infection and consequent liver cirrhosis, with most cases diagnosed at an intermediate or advanced stage. This complexity results in a poor prognosis. Recent advancements in local therapeutic techniques and the introduction of systemic therapies, including targeted and immunotherapy agents, have provided new avenues for both clinical and basic conversion therapy for advanced HCC. Integrating multi-dimensional local and systemic therapies, multi-modal sequential, and comprehensive multidisciplinary approaches into the management of HCC patients has demonstrated promising conversion success rates. This holistic management strategy involves combining multiple treatment modalities vertically and coordinating various disciplines horizontally. However, significant challenges remain, including the precise selection of patients eligible for conversion therapy, the optimal choice of conversion therapy regimens, and the accurate determination of surgical timing post-conversion therapy. Addressing these challenges is crucial for hepatobiliary surgeons. High-quality, randomized controlled trials are urgently needed to generate robust evidence for clinical practice. This review aims to synthesize the latest research developments both in China and internationally and examines key issues in the realm of HCC conversion therapy.
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Affiliation(s)
- Yubo Jiang
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, Shandong Province, China
| | - Xiaofeng Dong
- Department of Hepatobiliary, Pancreas and Spleen Surgery, the People's Hospital of Guangxi Zhuang Autonomous Region (Guangxi Academy of Medical Sciences), Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yingying Zhang
- Department of Oncology, Binzhou People's Hospital Affiliated to Shandong First Medical University, Binzhou, Shandong Province, China
| | - Feiyan Su
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Lei Zhao
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Xuetao Shi
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jingtao Zhong
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
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8
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Wang Z, Sheng J, Zhang X. Characterization of adverse reactions to four common targeted drugs for hepatocellular carcinoma in WHO-VigiAccess. Sci Rep 2025; 15:16188. [PMID: 40346128 PMCID: PMC12064674 DOI: 10.1038/s41598-025-00004-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/24/2025] [Indexed: 05/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality, with limited therapeutic options available for advanced stages of the disease. Treatment strategies for HCC are multimodal and largely depend on the disease stage, liver function, and individual patient factors. Based on the WHO's VigiAccess database, this study employed a retrospective descriptive analysis of adverse drug reaction (ADR) reports associated with four widely used tyrosine kinase inhibitors (TKIs) for HCC, including Sorafenib, Cabozantinib, Lenvatinib, and Regorafenib. The analysis included demographic data such as patient age, gender, and geographical distribution, alongside clinical information on the systems and symptoms associated with ADR reports. A total of 112,975 ADR reports related to the four TKI-targeted drugs were identified. Sorafenib exhibited the highest ADR reporting rate (30.7%), followed by Cabozantinib (29.4%), Lenvatinib (24.5%), and Regorafenib (15.4%). The odds ratio method was employed to assess the statistical correlation between the use of these targeted drugs and the occurrence of ADRs. Notably, Sorafenib (3,746) and Regorafenib (2,496) served to have the highest number of reported palmar-plantar erythrodysaesthesia syndrome. Chi-square analyses suggested that ADRs related to Lenvatinib were reported significantly more frequently in female patients compared to their male counterparts. The findings of this study can enhance public awareness of drug-related adverse events and provide an evidence-based foundation for prioritizing the management of ADRs associated with TKIs in second-line HCC therapy.
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Affiliation(s)
- Zeyu Wang
- Department of the Hepatobiliary and Pancreatic Surgery, Jilin University Second Hospital, Changchun, 130000, China
| | - Jiyao Sheng
- Department of the Hepatobiliary and Pancreatic Surgery, Jilin University Second Hospital, Changchun, 130000, China.
| | - Xuewen Zhang
- Department of the Hepatobiliary and Pancreatic Surgery, Jilin University Second Hospital, Changchun, 130000, China.
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9
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Lei W, Zhou K, Lei Y, Li Q, Zhu H. Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects. Mol Cancer Ther 2025; 24:692-708. [PMID: 39417575 DOI: 10.1158/1535-7163.mct-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.
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Affiliation(s)
- Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Lei
- College of Liberal Arts, Neijiang Normal University, Neijiang, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Vogel A, Chan SL, Dawson LA, Kelley RK, Llovet JM, Meyer T, Ricke J, Rimassa L, Sapisochin G, Vilgrain V, Zucman-Rossi J, Ducreux M. Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2025; 36:491-506. [PMID: 39986353 DOI: 10.1016/j.annonc.2025.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/10/2025] [Accepted: 02/11/2025] [Indexed: 02/24/2025] Open
Affiliation(s)
- A Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Division of Hepatology, Toronto General Hospital, Toronto, Canada; Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
| | - S L Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - L A Dawson
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada
| | - R K Kelley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA
| | - J M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - T Meyer
- Department of Oncology, Royal Free Hospital, London, UK; UCL Cancer Institute, University College London, London, UK
| | - J Ricke
- Klinik und Poliklinik für Radiologie, Ludwig-Maximilians-Universität München, Munich, Germany
| | - L Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - G Sapisochin
- Department of Surgery, University of Toronto, Toronto, Canada
| | - V Vilgrain
- Centre de Recherche sur l'Inflammation U 1149, Université Paris Cité, Paris, France; Department of Radiology, Beaujon Hospital, APHP Nord, Clichy, France
| | - J Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, INSERM, Paris, France
| | - M Ducreux
- INSERM U1279, Université Paris-Saclay, Villejuif, France; Department of Cancer Medicine, Gustave Roussy, Villejuif, France
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11
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Toyoda H, Hiraoka A, Ochi H, Tsuji K, Tajiri K, Tani J, Tada T, Okubo T, Atsukawa M, Hirooka M, Itobayashi E, Hatanaka T, Kariyama K, Ishikawa T, Kuroda H, Takaguchi K, Kosaka H, Kawada K, Kakizaki S, Yada Y, Ogawa C, Nishimura T, Yasuda S, Deguchi A, Morishita A, Itokawa N, Arai T, Tsutsui A, Naganuma A, Enomoto H, Kaibori M, Nouso K, Hiasa Y, Kumada T, Akita T, Tanaka J, Johnson PJ. Prognostic Significance of the BALAD Serological Model in Systemic Therapies for Hepatocellular Carcinoma: A Personalized Approach to the Prediction of Survival Benefit. JCO Clin Cancer Inform 2025; 9:e2400175. [PMID: 40354590 DOI: 10.1200/cci-24-00175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/27/2025] [Accepted: 03/05/2025] [Indexed: 05/14/2025] Open
Abstract
PURPOSE The BALAD model, a scoring system for staging hepatocellular carcinoma (HCC), is based on five serum markers: bilirubin, albumin, lens culinaris agglutinin-reactive alpha-fetoprotein [AFP], AFP, and des-gamma-carboxy prothrombin. It has shown good ability to predict survival in patients with HCC irrespective of stage and treatment, a high BALAD value being associated with a poor prognosis. However, its prognostic significance is unclear in patients with advanced unresectable HCC (uHCC) who undergo systemic therapies. We assessed the prognostic ability of BALAD in this subpopulation. METHODS In a multicenter cohort of 1,510 patients with advanced uHCC treated with first-line systemic therapies, the baseline BALAD score was calculated on the basis of pretreatment serum levels. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated and related to the BALAD score. RESULTS In all, 502 patients were treated with sorafenib, 435 with lenvatinib, and 573 with atezolizumab plus bevacizumab. Irrespective of treatment regimen, OS, PFS, ORR, and DCR were all independently negatively correlated with the BALAD score. The beneficial effects of specific systemic therapy regimens differed according to the BALAD score. CONCLUSION The BALAD score had good prognostic ability for predicting OS and PFS in patients with advanced uHCC who underwent systemic therapies and was associated with treatment response. Application of the BALAD score offers increased precision in the prediction of outcome both for individual patients and for specific subgroups of patients with HCC.
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Affiliation(s)
- Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Hironori Ochi
- Hepato-biliary Center, Japanese Red Cross Matsuyama Hospital, Matsuyama, Japan
| | - Kunihiko Tsuji
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Toyama, Japan
| | - Joji Tani
- Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Tomomi Okubo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School Chiba Hokuso Hospital, Inzai, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Kazuya Kariyama
- Department of Hepatology, Okayama City Hospital, Okayama, Japan
| | - Toru Ishikawa
- Department of Hepatology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Hidekatsu Kuroda
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, School of Medicine, Morioka, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Hisashi Kosaka
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Kazuhito Kawada
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Yutaka Yada
- Department of Gastroenterology, Hanwa Memorial Hospital, Osaka, Japan
| | - Chikara Ogawa
- Department of Gastroenterology, Japanese Red Cross Takamatsu Hospital, Takamatsu, Japan
| | - Takashi Nishimura
- Department of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Hepatology, Kagawa University, Kagawa, Japan
| | - Norio Itokawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Taeang Arai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Hirayuki Enomoto
- Department of Gastroenterology and Hepatology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masaki Kaibori
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Kazuhiro Nouso
- Department of Hepatology, Okayama City Hospital, Okayama, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan
| | - Philip J Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
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Almasoud H, Alzahrani FA, Alarifi S, Aldahmash B, Almutairi B, AlKahtane AA, Yaseen KN, Aljuhani B, Alkahtani S. Enhancing hepatocellular carcinoma treatment: synergistic cytotoxicity and mechanistic insights of Ramucirumab and 5-Azacytidine combination therapy. Saudi Pharm J 2025; 33:6. [PMID: 40397219 DOI: 10.1007/s44446-025-00001-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 02/11/2025] [Indexed: 05/22/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited therapeutic options and poor prognosis for advanced stages. This study investigates the synergistic anticancer effects of Ramucirumab (RAM), a VEGFR-2 inhibitor, and 5-Azacytidine (5-Aza), a hypomethylating agent, on HCC cells, focusing on mechanisms of cytotoxicity, DNA damage, apoptosis, and cell cycle modulation. HuH-7 cells were treated with RAM and 5-Aza, alone and in combination, across varying concentrations. Cell viability was assessed using the Neutral Red Uptake assay, while DNA damage and apoptosis were evaluated through the TUNEL assay and protein array analysis. The expression of cell cycle and inflammatory genes was analyzed using quantitative real-time PCR (qRT-PCR). Result shows combination treatment significantly enhanced cytotoxicity compared to individual dose-dependent therapies. DNA damage was markedly increased in RAM-treated cells, with upregulation of apoptotic proteins CAS3, BID, BAD, p53, and FAS observed. In contrast, apoptotic proteins were markedly decreased in combination-treated cells. Cell cycle arrest was evident through the downregulation of key regulatory genes, including MCM2, MCM3, cyclin B1, and CDK2. Inflammatory cytokines IL-1β and IL-6 were repressed, while COX2 expression was elevated, suggesting oxidative stress as a possible mechanism. In conclusion, the synergistic effects of RAM and 5-Aza in HCC cells are mediated through increased damage to DNA, apoptosis, and arrest of cell cycle, offering potential treatment strategy for advanced HCC. Further experiments conducted in vivo are warranted to validate these findings and optimize treatment regimens.
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Affiliation(s)
- Hadeel Almasoud
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia.
| | - Fares A Alzahrani
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
| | - Saud Alarifi
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
| | - Badr Aldahmash
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
| | - Bader Almutairi
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
| | - Abdullah A AlKahtane
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
| | - Khadijah N Yaseen
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
| | - Bashayer Aljuhani
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
| | - Saad Alkahtani
- Department of Zoology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
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Pinter M, Fulgenzi CAM, Pinato DJ, Scheiner B. Systemic treatment in patients with hepatocellular carcinoma and advanced liver dysfunction. Gut 2025:gutjnl-2025-334928. [PMID: 40301119 DOI: 10.1136/gutjnl-2025-334928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 04/12/2025] [Indexed: 05/01/2025]
Abstract
Systemic therapy represents the standard of care treatment for patients with advanced hepatocellular carcinoma (HCC). Given the increased risk of death from cirrhosis-related complications in patients with advanced liver dysfunction, pivotal phase III trials traditionally limited inclusion to patients with Child-Pugh class A, where death is more likely to be attributed to HCC progression. Therefore, Western guidelines recommend the use of systemic therapies primarily in patients with preserved liver function. However, patients with HCC and Child-Pugh class B are commonly encountered in clinical practice, but due to limited prospective evidence, there is no clear guidance on their optimal management.In this recent advances article, we discuss how the clinical course of cirrhosis can affect eligibility to treatment in the modern era of systemic therapy for HCC, elaborate on strategies to improve liver function in HCC patients by targeting cirrhosis-related and tumour-related factors and summarise the current literature on systemic therapy in HCC patients with Child-Pugh class B. Based on this information, we finally propose a clinical algorithm on how to systematically approach patients with HCC and advanced liver dysfunction in clinical practice.
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Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology & Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Claudia A M Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Translational Medicine, Division of Oncology, University of Piemonte Orientale, Novara, Italy
| | - Bernhard Scheiner
- Division of Gastroenterology & Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Wang Y, Pan S, Tian J, Wang J, Yu Y, Wang S, Li F, Yang L, Liu X, Shen Y, Qiu Q, Luan J, Jia M, Xiong C, Duan X, Wang FS, Meng F. Cadonilimab, a PD-1/CTLA-4 bispecific antibody in unresectable hepatocellular carcinoma: a real-world study. Cancer Immunol Immunother 2025; 74:186. [PMID: 40293533 PMCID: PMC12037968 DOI: 10.1007/s00262-025-04038-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/26/2025] [Indexed: 04/30/2025]
Abstract
OBJECTIVE This study retrospectively evaluated the safety and efficacy of cadonilimab combined with tyrosine kinase inhibitors (TKI) for the treatment of unresectable hepatocellular carcinoma (uHCC). PATIENTS AND METHODS Seventy-eight patients who received cadonilimab + TKI were included; 42 and 36 received it as first-line (1 L) and second-line and above (≥ 2 L) systemic treatment, respectively. Besides, ninety-five patients who received PD-1 inhibitor + TKI as first-line treatments were included. Safety was the primary endpoint; secondary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). RESULTS Treatment-related adverse events (TRAEs) of any grade occurred in 84.6% of the patients, with grade ≥ 3 in 20.5%. In patients with a Child-Pugh score of ≥ 8 (CP ≥ 8), any grade TRAEs occurred in 88.2%, and grade ≥ 3 in 20.6%. The overall cohort's median progression-free survival (mPFS) was 3.6 months, whereas the median overall survival (mOS) was 8.8 months. In the 1 L group, mPFS was 6.7 months versus 2.3 months in ≥ 2 L. In the 1 L group, mOS was 13.7 months versus 3.2 months in ≥ 2 L. For CP < 8, 1 L mPFS was 7.6 months, mOS not reached; CP ≥ 8 had mPFS of 5.2 months, mOS of 5.6 months. For CP < 8 in ≥ 2 L, mPFS was 3.1 months, mOS 8.8 months; CP ≥ 8 had mPFS of 1.4 months, mOS of 2.2 months. After propensity score matching (PSM), the incidence of TRAEs of any grade was 77.1%, with grade ≥ 3 accounting for 17.1% in the PD-1 group. In the PD-1/CTLA-4 group, the incidence of TRAEs of any grade was 80.0%, and that of grade ≥ 3 TRAEs was 17.1%. The mPFS was 6.7 months in the PD-1/CTLA-4 group versus 3.3 months in the PD-1 group. The mOS was 13.7 months in the PD-1/CTLA-4 group versus 6.7 months in the PD-1 group. CONCLUSION Cadonilimab + TKI showed a favorable trend in safety and efficacy, especially when applied as first-line systemic therapy for uHCC. This study offers a clinical reference for its use in systemic uHCC therapy, particularly in patients with advanced liver dysfunction.
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Affiliation(s)
- Yilin Wang
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Shida Pan
- Capital Medical University, Beijing, 100069, China
| | - Jiahe Tian
- Peking University 302 Clinical Medical School, Beijing, 100191, China
| | - Jianing Wang
- Peking University 302 Clinical Medical School, Beijing, 100191, China
| | - Yingying Yu
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Siyu Wang
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Fengyi Li
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Luo Yang
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Xiaomeng Liu
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Yingjuan Shen
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Qin Qiu
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Junqing Luan
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China
| | - Mengdie Jia
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China
| | - Chuyue Xiong
- Peking University 302 Clinical Medical School, Beijing, 100191, China
| | - Xuanxuan Duan
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China
| | - Fu-Sheng Wang
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China.
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China.
| | - Fanping Meng
- Medical School of Chinese PLA, No. 28, Fuxing Road, Beijing, 100853, China.
- Department of Infectious Diseases, The Fifth Medical Centre of Chinese PLA General Hospital, National Clinical Research Centre for Infectious Diseases, Beijing, 100853, China.
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15
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Sequeira LM, Ozturk NB, Sierra L, Gurakar M, Toruner MD, Zheng M, Simsek C, Gurakar A, Kim AK. Hepatocellular Carcinoma and the Role of Liver Transplantation: An Update and Review. J Clin Transl Hepatol 2025; 13:327-338. [PMID: 40206277 PMCID: PMC11976436 DOI: 10.14218/jcth.2024.00432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/25/2025] [Accepted: 02/08/2025] [Indexed: 04/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Multiple treatment modalities are available for the management of HCC, depending on its stage as determined by the Barcelona Clinic Liver Cancer staging system. Because liver transplantation (LT) theoretically removes the cancer and replaces the organ at risk for future malignancy, LT is often considered the most definitive and one of the most efficacious treatment options for HCC. Nevertheless, the success and efficacy of liver transplantation depend on various tumor characteristics. As a result, multiple criteria have been developed to assess the appropriateness of a case of HCC for LT, with the pioneering Milan Criteria established in 1996. Over the past 20 to 30 years, these criteria have been critically evaluated, expanded, and often liberalized to make LT for patients with HCC a more universally applicable option. Furthermore, the development of other treatment modalities has enabled downstaging and bridging strategies for HCC prior to LT. In this narrative and comprehensive review, we provided an update on recent trends in the epidemiology of HCC, selection criteria for LT, implementation of LT across different regions, treatment modalities available as bridges, downstaging strategies, alternatives to LT, and, finally, post-LT surveillance.
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Affiliation(s)
- Lynette M. Sequeira
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - N. Begum Ozturk
- Department of Internal Medicine, Beaumont Hospital, Royal Oak, MI, USA
| | - Leandro Sierra
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Merve Gurakar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Melanie Zheng
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cem Simsek
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy K. Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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16
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Ikeda M, Morizane C, Ueno M, Okusaka T, Ishii H, Furuse J. Systemic therapy for hepatocellular carcinoma, from the early to the advanced stage: a Japanese perspective. Jpn J Clin Oncol 2025; 55:465-476. [PMID: 39895083 PMCID: PMC12034026 DOI: 10.1093/jjco/hyaf017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 01/16/2025] [Indexed: 02/04/2025] Open
Abstract
Systemic therapy has now become mainstream for the treatment of hepatocellular carcinoma (HCC) and is also changing from molecular-targeted therapy, such as with sorafenib and lenvatinib, to immunotherapy, such as with the atezolizumab plus bevacizumab and durvalumab plus tremelimumab combination regimens. Molecular-targeted therapy is selected as the first-line treatment when immunotherapy is not indicated or as second- or later-line treatment when immunotherapy is ineffective. It is necessary to select the appropriate treatment taking into consideration the expected treatment efficacy and adverse events, as well as the hepatic reserve. Currently, newer agents and combination regimens as first-line/second-line treatment for advanced-stage HCC, combined therapy with transarterial chemoembolization for intermediate-stage HCC, and perioperative adjuvant therapy for curative treatment for early-stage HCC are being developed. Therefore, systemic therapy is now indicated for any stage of the disease. While local therapies were previously used as the main treatment strategy for HCC, systemic therapy in combination with local therapies is being actively attempted at present. Systemic therapy is currently the main focus of development of novel treatments for HCC.
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Affiliation(s)
- Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, 2-3-2, Nakao 2-chome, Asahi-ku, Yokohama 241-8515, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Hiroshi Ishii
- Gastrointestinal Medical Oncology, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba 260-8717, Japan
| | - Junji Furuse
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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Wang W, Gao X, Niu W, Yin J, He K. Targeting Metabolism: Innovative Therapies for MASLD Unveiled. Int J Mol Sci 2025; 26:4077. [PMID: 40362316 PMCID: PMC12071536 DOI: 10.3390/ijms26094077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/01/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.
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Affiliation(s)
- Weixin Wang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Xin Gao
- School of Public Health, Jilin University, Changchun 130021, China;
| | - Wentong Niu
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Jinping Yin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130041, China;
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
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18
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Yang J, Xu Q, Luo S, Wu J. Comparative efficacy of tislelizumab plus lenvatinib and tislelizumab alone against advanced hepatocellular carcinoma after lenvatinib failure: a real-world study. BMC Cancer 2025; 25:708. [PMID: 40240993 PMCID: PMC12004550 DOI: 10.1186/s12885-025-14092-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 04/04/2025] [Indexed: 04/18/2025] Open
Abstract
This study evaluated the effectiveness and safety of tislelizumab plus lenvatinib (TL group) and tislelizumab monotherapy (T group) in patients with stage C hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) staging system after lenvatinib failure, and it analyzed the factors influencing the effectiveness of TL as a second-line treatment. This retrospective analysis involved 51 patients treated at a single center between January 2019 and July 2023. Survival outcomes and tumor responses were compared between the TL and T monotherapy groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were identified using Cox proportional hazard regression models. Among patients with BCLC stage C advanced HCC who experienced lenvatinib treatment failure, median PFS was significantly longer in the TL group than in the T group (6.8 months vs. 4.5 months, p = 0.003), and OS was notably extended in the TL group (14.0 months vs. 10.4 months, p = 0.012). Although the disease control rate (64% vs. 53.8%, p = 0.461) and objective response rate (20% vs. 7.7%, p = 0.202) were numerically higher in the TL group, these differences did not reach significance. Child-Pugh B liver function and tislelizumab monotherapy were independent prognostic factors for poor OS, whereas only tislelizumab monotherapy was an independent prognostic factor for poor PFS, Child-Pugh B was not a prognostic factor for PFS. Subgroup analysis demonstrated the OS benefit of tislelizumab plus lenvatinib in patients with Child-Pugh A liver function (14.0 months vs. 12.0 months, p = 0.013) but not in those with Child-Pugh B liver function (7.7 months vs. 6.1 months, p = 0.225). In the TL group, the most frequent treatment-related adverse events (AEs) were hand-foot skin reaction (32%), hypertension (28%), diarrhea (32%), and hypothyroidism (20%). Grade 3 or higher AEs occurred in 24% of patients in the TL group, and hand-foot skin reaction and diarrhea were the most frequent grade 3 or higher AEs. The incidence of AEs was comparable between the two groups. As a second-line treatment, the combination of tislelizumab and lenvatinib was well tolerated and associated with improved OS and PFS versus tislelizumab alone for patients with advanced HCC, particularly in those with Child-Pugh A liver function.
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Affiliation(s)
- Jiajin Yang
- Department of Oncology, Fengcheng People's Hospital, Fengcheng, 331100, Jiangxi Province, China
| | - Qiuping Xu
- Department of Oncology, Fengcheng People's Hospital, Fengcheng, 331100, Jiangxi Province, China
| | - Sihao Luo
- Department of Oncology, Fengcheng People's Hospital, Fengcheng, 331100, Jiangxi Province, China
| | - Jianbing Wu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330006, Jiangxi Province, China.
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19
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Kushwaha NK, Sreenath ND. From Present to Future: The Shifting Paradigm of Advanced Hepatocellular Carcinoma. JCO Oncol Pract 2025:OP2500198. [PMID: 40239127 DOI: 10.1200/op-25-00198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 03/05/2025] [Accepted: 03/12/2025] [Indexed: 04/18/2025] Open
Affiliation(s)
- Naveen Kumar Kushwaha
- Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Nihanthy D Sreenath
- Department of Medical Oncology, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India
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20
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Pomej K, Frick A, Scheiner B, Balcar L, Pajancic L, Klotz A, Kreuter A, Lampichler K, Regnat K, Zinober K, Trauner M, Tamandl D, Gasche C, Pinter M. Study protocol: Fecal Microbiota Transplant combined with Atezolizumab/Bevacizumab in Patients with Hepatocellular Carcinoma who failed to achieve or maintain objective response to Atezolizumab/Bevacizumab - the FAB-HCC pilot study. PLoS One 2025; 20:e0321189. [PMID: 40233040 PMCID: PMC11999108 DOI: 10.1371/journal.pone.0321189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/13/2025] [Indexed: 04/17/2025] Open
Abstract
BACKGROUND The gut microbiota is often altered in chronic liver diseases and hepatocellular carcinoma (HCC), and increasing evidence suggests that it may influence response to cancer immunotherapy. Strategies to modulate the gut microbiome (i.e., fecal microbiota transplant (FMT)) may help to improve efficacy of immune checkpoint inhibitors (ICIs) or even overcome resistance to ICIs. Here, we describe the design and rationale of FAB-HCC, a single-center, single-arm, phase II pilot study to assess safety, feasibility, and efficacy of FMT from patients with HCC who responded to PD-(L)1-based immunotherapy or from healthy donors to patients with HCC who failed to achieve or maintain a response to atezolizumab plus bevacizumab. METHODS In this single-center, single-arm, phase II pilot study (ClinicalTrials.gov identifier: NCT05750030), we plan to include 12 patients with advanced HCC who failed to achieve or maintain a response to atezolizumab/bevacizumab. Patients will receive a single FMT via colonoscopy from donors with HCC who responded to PD-(L)1-based immunotherapy or from healthy individuals, followed by atezolizumab/bevacizumab every 3 weeks. The primary endpoint is safety, measured by incidence and severity of treatment-related adverse events. The main secondary endpoint is efficacy, as assessed by best radiological response according to RECISTv1.1 and mRECIST. Additional exploratory endpoints include data on the effect of FMT on recipient gut microbiota, as well as metagenomic analysis of stool samples, analyses of circulating immune cells and serum and stool proteomic, metabolomic and lipidomic signatures. DISCUSSION The results of this study will help to define the potential of FMT as add-on intervention in the systemic treatment of advanced HCC, with the potential to improve efficacy of immunotherapy or even overcome resistance. TRIAL REGISTRATION EudraCT Number: 2022-000234-42 Clinical trial registry & ID: ClinicalTrials.gov identifier: NCT05750030 (Registration date: 16.01.2023).
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Affiliation(s)
- Katharina Pomej
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Adrian Frick
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Larissa Pajancic
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Anton Klotz
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Abelina Kreuter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
| | - Katharina Lampichler
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Katharina Regnat
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Kerstin Zinober
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Dietmar Tamandl
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Christoph Gasche
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Vienna Liver Cancer Study Group, Medical University of Vienna, Vienna, Austria
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21
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Li Y, Liu X, Dong Y, Zhou Y. Angiogenesis causes and vasculogenic mimicry formation in the context of cancer stem cells. Biochim Biophys Acta Rev Cancer 2025; 1880:189323. [PMID: 40239849 DOI: 10.1016/j.bbcan.2025.189323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 04/18/2025]
Abstract
Tumor occurrence, development, invasion, and metastasis are regulated by multiple mechanisms. Among these, angiogenesis promotes tumor progression mainly by supplying tumor tissue and providing channels for tumor metastasis. Cancer stem cells (CSCs) are another important factor affecting tumor progression by involving in tumor initiation and development, while remaining insensitive to conventional antitumor treatments. Among treatment strategies for them, owing to the existence of alternative angiogenic pathways or the risk of damaging normal stem cells, the clinical effect is not ideal. Angiogenesis and CSCs may influence each other in this process. Tumor angiogenesis can support CSC self-renewal by providing a suitable microenvironment, whereas CSCs can regulate tumor neovascularization and mediate drug resistance to anti-angiogenic therapy. This review summarized the role of vascular niche formed by angiogenesis in CSC self-renewal and stemness maintenance, and the function of CSCs in endothelial progenitor cell differentiation and pro-angiogenic factor upregulation. We also elucidated the malignant loop between CSCs and angiogenesis promoting tumor progression. Additionally, we summarized and proposed therapeutic targets, including blocking tumor-derived endothelial differentiation, inhibiting pro-angiogenic factor upregulation, and directly targeting endothelial-like cells comprising CSCs. And we analyzed the feasibility of these strategies to identify more effective methods to improve tumor treatment.
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Affiliation(s)
- Ying Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Xiaofang Liu
- Department of Anus and Intestine Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Yaodong Dong
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
| | - Yingying Zhou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
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22
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Guo X, Zhao Z, Zhu L, Liu S, Zhou L, Wu F, Fang S, Chen M, Zheng L, Ji J. The evolving landscape of biomarkers for systemic therapy in advanced hepatocellular carcinoma. Biomark Res 2025; 13:60. [PMID: 40221793 PMCID: PMC11993949 DOI: 10.1186/s40364-025-00774-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 03/29/2025] [Indexed: 04/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. With the approval of multiple first- and second-line agents, especially the combination therapies based on immune checkpoint inhibitor (ICI) regimens, the landscape of systemic therapy for advanced HCC (aHCC) is more diverse than ever before. The efficacy of current systemic therapies shows great heterogeneity in patients with aHCC, thereby identifying biomarkers for response prediction and patient stratification has become an urgent need. The main biomarkers for systemic therapy in hepatocellular carcinoma are derived from peripheral blood, tissues, and imaging. Currently, the understanding of the clinical response to systemic therapy indicates unequivocally that a single biomarker cannot be used to identify patients who are likely to benefit from these treatments. In this review, we provide an integrated landscape of the recent development in molecular targeted therapies and ICIs-based therapies, especially focusing on the role of clinically applicable predictive biomarkers. Additionally, we further highlight the latest advancements in biomarker-driven therapies, including targeted treatments, adoptive cell therapies, and bispecific antibodies.
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Affiliation(s)
- Xinyu Guo
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Zhongwei Zhao
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingyi Zhu
- The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Shuang Liu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingling Zhou
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Fazong Wu
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Shiji Fang
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Minjiang Chen
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Liyun Zheng
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
| | - Jiansong Ji
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
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Honma Y, Shibata M, Ikemi M, Yoshitomi K, Shinohara N, Ogino N, Oe S, Miyagawa K, Abe S, Harada M. Usefulness of the Early Increase of Peripheral Blood Lymphocyte Count in Predicting Clinical Outcomes for Patients with Advanced Hepatocellular Carcinoma Treated with Durvalumab Plus Tremelimumab. Cancers (Basel) 2025; 17:1274. [PMID: 40282450 PMCID: PMC12025802 DOI: 10.3390/cancers17081274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/05/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Durvalumab plus Tremelimumab (Dur/Tre) therapy is expected to have good therapeutic efficacy for patients with advanced hepatocellular carcinoma (HCC). However, the predictors of clinical response and prognosis have not been established. Here, we retrospectively investigated the predictors for therapeutic response and clinical prognosis of Dur/Tre therapy. METHODS This retrospective single-center study, which included 30 patients, aimed to evaluate predictors of treatment efficacy of Dur/Tre therapy for advanced HCC. Factors associated with an objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-mediated adverse events (imAEs) were examined. We especially focused on the initial change in peripheral lymphocyte count at 2 weeks after Dur/Tre introduction from baseline (Δlymphocyte). RESULTS Seventeen patients (56.7%) diagnosed with HCC BCLC stage C were enrolled. The median observational period was 11 months. The ORR and disease control rate (DCR) were 30.0% and 53.3%, respectively. The median PFS was 3.7 months and OS was not reached. The high Δlymphocyte was an independent predictor of objective response (hazard ratio [HR], 1.004; p = 0.016). The high Δlymphocyte (above +245/µL) was an independent predictive factor for better PFS (HR, 0.308; 95% CI, 0.095-0.998; p = 0.049), and the median PFS was significantly prolonged in the high Δlymphocyte (above +245/µL) compared to low Δlymphocyte (less than +245/µL) (not reached vs. 1.96 months, log-rank p = 0.003). CONCLUSIONS In Dur/Tre therapy, the early increase in peripheral blood lymphocyte count was useful for predicting clinical response and prognosis.
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Affiliation(s)
- Yuichi Honma
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan; (M.S.); (M.I.); (K.Y.); (N.S.); (N.O.); (S.O.); (K.M.); (S.A.); (M.H.)
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Ding Y, Yu Y. Therapeutic potential of flavonoids in gastrointestinal cancer: Focus on signaling pathways and improvement strategies (Review). Mol Med Rep 2025; 31:109. [PMID: 40017144 PMCID: PMC11884236 DOI: 10.3892/mmr.2025.13474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/30/2025] [Indexed: 03/01/2025] Open
Abstract
Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.
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Affiliation(s)
- Ye Ding
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yong Yu
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Zhong BY, Fan W, Guan JJ, Peng Z, Jia Z, Jin H, Jin ZC, Chen JJ, Zhu HD, Teng GJ. Combination locoregional and systemic therapies in hepatocellular carcinoma. Lancet Gastroenterol Hepatol 2025; 10:369-386. [PMID: 39993404 DOI: 10.1016/s2468-1253(24)00247-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 02/26/2025]
Abstract
Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.
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Affiliation(s)
- Bin-Yan Zhong
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China; Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wenzhe Fan
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Justin J Guan
- Division of Interventional Radiology, Department of Radiology, Cleveland Clinic, Cleveland, OH, USA
| | - Zhenwei Peng
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhongzhi Jia
- Department of Interventional and Vascular Surgery, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
| | - Haojie Jin
- Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Cheng Jin
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Jian-Jian Chen
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Hai-Dong Zhu
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Gao-Jun Teng
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
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26
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Lee CK, Yoo C, Hong JY, Park SJ, Kim JW, Tai DWM, Kim H, Korphaisarn K, Tanasanvimon S, Chen SC, Kim JW, Kim I, Kim M, Choo J, Oh SB, Chen CT, Bae WK, Kim H, Huh SJ, Yen CJ, Park S, Lee DK, Chan LL, Kang B, Kang M, Sundar R, Choi HJ, Chan SL, Chon HJ, Lee MA. Real-World Study of Systemic Treatment after First-Line Atezolizumab plus Bevacizumab for Hepatocellular Carcinoma in Asia-Pacific Countries. Liver Cancer 2025; 14:127-141. [PMID: 40255875 PMCID: PMC12005689 DOI: 10.1159/000540969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 08/11/2024] [Indexed: 10/11/2024] Open
Abstract
INTRODUCTION Atezolizumab plus bevacizumab is a commonly used first-line regimen for advanced hepatocellular carcinoma (HCC) treatment owing to its superior outcomes compared to sorafenib. However, optimal subsequent treatment options for patients with HCC who progressed on first-line atezolizumab plus bevacizumab remain unclear. METHODS This multinational, multi-institutional, retrospective study included patients with HCC from 22 centers in five Asia-Pacific countries who were treated with first-line atezolizumab plus bevacizumab, which was discontinued for any reason. The endpoints included progression-free survival (PFS) and overall survival (OS) according to patient characteristics and second-line regimens. RESULTS Between June 2016 and May 2023, 1,141 patients were treated with first-line atezolizumab plus bevacizumab, of whom 629 (55.1%) received subsequent treatment. Sorafenib and lenvatinib were the most commonly administered second-line regimens (53.9% and 25.6%, respectively). Overall, the median PFS and OS were 2.9 and 8.0 months, respectively. Lenvatinib had longer PFS (4.0 vs. 2.3 months) and OS (8.0 vs. 6.3 months) than sorafenib. Patients treated with tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI) (n = 50, 8.3%) showed PFS and OS of 5.4 and 12.6 months, respectively. Lower tumor burden and lenvatinib or TKI plus ICI use were associated with longer second-line PFS. Preserved liver function was associated with improved OS. CONCLUSIONS In patients with HCC who progressed on first-line atezolizumab plus bevacizumab, sorafenib and lenvatinib were the most commonly used second-line regimens in Asia-Pacific countries, with lenvatinib resulting in longer OS than sorafenib. The second-line TKI plus ICI combination exhibited promising efficacy, suggesting the potential role of continuing ICIs beyond disease progression.
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Affiliation(s)
- Choong-kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
- Sondang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jung Yong Hong
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Se Jun Park
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, Cancer Research Institute, The Catholic University of Korea, Seoul, South Korea
| | - Jin Won Kim
- Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | - David Wai Meng Tai
- Division of Medical Oncology, National Cancer Center Singapore, Singapore, Singapore
| | - Hyeyeong Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea
| | - Krittiya Korphaisarn
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - San-Chi Chen
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ju Won Kim
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Seoul, South Korea
| | - Ilhwan Kim
- Division of Oncology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, South Korea
| | - Moonho Kim
- Department of Hematology and Oncology, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, South Korea
| | - Joan Choo
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Sang-Bo Oh
- Division of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Yangsan Pusan National University Hospital, Busan, South Korea
| | - Ching-Tso Chen
- National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Woo Kyun Bae
- Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Medical School and Hwasun Hospital, Gwangju, South Korea
| | - Hongsik Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, South Korea
| | | | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Sejung Park
- Sondang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Ki Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Landon Long Chan
- Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Beodeul Kang
- Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea
| | - Minsu Kang
- Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | - Raghav Sundar
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Hye Jin Choi
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Stephen Lam Chan
- Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
| | - Hong Jae Chon
- Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea
| | - Myung-Ah Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, Cancer Research Institute, The Catholic University of Korea, Seoul, South Korea
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Zanuso V, Rimassa L, Braconi C. The rapidly evolving landscape of HCC: Selecting the optimal systemic therapy. Hepatology 2025; 81:1365-1386. [PMID: 37695554 DOI: 10.1097/hep.0000000000000572] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 08/04/2023] [Indexed: 09/12/2023]
Abstract
Over the past years, there has been a remarkable advance in the systemic treatment options for advanced HCC. The overall survival has gradually increased over time, with larger benefits for patients with sensitive tumors and preserved liver function, the latter being an essential condition for the delivery of sequential lines of treatment and optimization of clinical outcomes. With the approval of new first-line agents and the introduction of immune checkpoint inhibitor-based therapies, the treatment landscape of advanced HCC is becoming wider than ever. Atezolizumab plus bevacizumab and, more recently, durvalumab plus tremelimumab have entered the clinical practice and are the current standard of care for treatment-naïve patients, surpassing sorafenib and lenvatinib monopoly. As no head-to-head comparisons are available among all the first-line treatment options, the recommendation for the most appropriate choice and sequence is patient-driven and integrates efficacy data with clinical comorbidities, background liver disease, and the safety profile of available drugs. In addition, predictive biomarkers for successful patients' stratification are yet to be available and constitute the focus of ongoing research. The treatment algorithm is likely to become even more complex since systemic therapeutic approaches are now being translated into earlier stages of the disease, with an impact on the evolution of the sequential treatment of patients with HCC.
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Affiliation(s)
- Valentina Zanuso
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Beatson West of Scotland Cancer Centre, Glasgow, UK
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28
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Ma L, Zhang Y, Fang Y, Hao C, Fan Q, Jiang D, Lu L, Su F, Yang C, Liu Z, Tian J, Sun X, Sun S, Cheng Y. Anti-PD-L1 envafolimab combined with anti-VEGF suvemcitug in pretreated solid tumors and hepatocellular carcinoma: an open-label phase II study with safety run-in stage. Invest New Drugs 2025; 43:181-190. [PMID: 39883265 DOI: 10.1007/s10637-025-01506-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 01/07/2025] [Indexed: 01/31/2025]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC. METHODS This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR). RESULTS As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%. CONCLUSIONS The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.
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Affiliation(s)
- Lixia Ma
- Department of Internal Medicine, Jilin Cancer Hospital, Changchun, China
| | - Yu Zhang
- Department of Oncology, Mianyang Central Hospital, Mianyang, China
| | - Yong Fang
- Medical Oncology Dept, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chunyi Hao
- Department of Hepato-Pancreato-Biliary Surgery, Key Laboratory of Carcinogenesis and Translational Research, MinistryofEducation/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Qingxia Fan
- Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Da Jiang
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Liqin Lu
- Department of Medical Oncology, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Fang Su
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Chen Yang
- Clinical Science, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Zhenru Liu
- Clinical Science, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Ji Tian
- Clinical Science, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Xiyang Sun
- Clinical Pharmacology, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Shuguang Sun
- Clinical Statistics, Shandong Simcere Biopharmaceutical Co., Ltd, Shandong, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Ying Cheng
- Department of Internal Medicine, Jilin Cancer Hospital, Changchun, China.
- Department of Thoracic Oncology, Jilin Cancer Hospital, No.1066 Jinhu Road, Changchun City, Jilin Province, 130000, China.
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Zhang F, Wang YS, Li SP, Zhao B, Huang N, Song RP, Meng FZ, Feng ZW, Zhang SY, Song HC, Chen XP, Liu LX, Wang JZ. Alpha-fetoprotein combined with initial tumor shape irregularity in predicting the survival of patients with advanced hepatocellular carcinoma treated with immune-checkpoint inhibitors: a retrospective multi-center cohort study. J Gastroenterol 2025; 60:442-455. [PMID: 39714631 PMCID: PMC11922967 DOI: 10.1007/s00535-024-02202-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/07/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are playing a significant role in the treatment of hepatocellular carcinoma (HCC). This study aims to explore the prognostic value of alpha-fetoprotein (AFP) and initial tumor shape irregularity in patients treated with ICIs. METHODS In this retrospective, multi-center study, 296 HCC patients were randomly divided into the training set and the validation set in a 3:2 ratio. The training set was used to evaluate prognostic factors and to develop an easily applicable ATSI (AFP and Tumor Shape Irregularity) score, which was verified in the validation set. RESULTS The ATSI score was developed from two independent prognostic risk factors: baseline AFP ≥ 400 ng/ml (HR 1.73, 95% CI 1.01-2.96, P = 0.046) and initial tumor shape irregularity (HR 1.94, 95% CI 1.03-3.65, P = 0.041). The median overall survival (OS) was not reached (95% CI 28.20-NA) in patients who met no criteria (0 points), 25.8 months (95% CI 14.17-NA) in patients who met one criterion (1 point), and 17.03 months (95% CI 11.73-23.83) in patients who met two criteria (2 points) (P = 0.001). The median progression-free survival (PFS) was 10.83 months (95% CI 9.27-14.33) for 0 points, 8.03 months (95% CI 6.77-10.57) for 1 point, and 5.03 months (95% CI 3.83-9.67) for 2 points (P < 0.001). The validation set effectively verified these results (median OS, 37.43/24.27/14.03 months for 0/1/2 points, P = 0.028; median PFS, 13.93/8.30/4.90 months for 0/1/2 points, P < 0.001). CONCLUSIONS The ATSI score can effectively predict prognosis in HCC patients receiving ICIs.
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Affiliation(s)
- Feng Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Yong-Shuai Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Shao-Peng Li
- Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Bin Zhao
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Nan Huang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Rui-Peng Song
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Fan-Zheng Meng
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Zhi-Wen Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241000, China
| | - Shen-Yu Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Hua-Chuan Song
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Xiao-Peng Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241000, China.
| | - Lian-Xin Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China.
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China.
| | - Ji-Zhou Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China.
- Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China.
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Zhu W, Fan C, Zhao Y, Liu Y, Cheng Y, Zhou W. Breaking bottlenecks: the future of hepatocellular carcinoma clinical trials and therapeutic targets. Hepatol Int 2025:10.1007/s12072-025-10799-2. [PMID: 40156659 DOI: 10.1007/s12072-025-10799-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/15/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND To provide a reference for hepatocellular carcinoma (HCC) clinical trials, we analyzed HCC clinical trials and therapeutic targets. METHODS Using the Informa database, we analyzed the global and China HCC clinical trials. We then explored TACE, Apatinib, and emerging strategies (CAR T/NK). Additionally, we analyzed the oncogenic biomarkers and therapeutic targets. We conducted a joint analysis of therapeutic target safety using HPA-RNA, HPA-Proteins, and GTEx-RNA datasets. Finally, we analyzed the specificity and prospects of therapeutic targets using HPA pathology data and CPTAC data. RESULTS HCC clinical trials have developed rapidly over the past decade but have now reached a bottleneck, with most breakthroughs focusing on combination therapies. China and the USA dominate in the number of trials. TACE combined with systemic therapy has become an effective treatment strategy for intermediate to advanced HCC. Apatinib and TACE combined with systemic therapy are characteristic of China, while the latter is also mainly conducted in Japan and the USA. Currently, targeted immune therapies dominate the field, and CAR T/NK still in the early stages. Most therapeutic targets are related to the VEGF pathway, which indirectly confirms the predominant role of TKI-ICI combination therapy in HCC treatment. Most targets have low safety and poor specificity. However, RRM2, KDR, and AURKA have strong safety and specificity, showing excellent prospects for targeted HCC therapy. CONCLUSIONS This study analyzed and summarized the overview of HCC clinical trials and the safety and specificity of therapeutic targets, providing a reference for HCC clinical research.
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Affiliation(s)
- Weixiong Zhu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Chuanlei Fan
- Department of Gastrointestinal Surgery, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, People's Republic of China
| | - Yongqing Zhao
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Youtao Liu
- School of Stomatology, Lanzhou University, Lanzhou, China
| | - Yusheng Cheng
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.
| | - Wence Zhou
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China.
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.
- Key Laboratory of Environmental Oncology of Gansu Province, Chengguan District, Lanzhou City, Gansu Province, China.
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Kudo M. Systemic Therapy Combined with Locoregional Therapy in Intermediate-stage Hepatocellular Carcinoma. INTERVENTIONAL RADIOLOGY (HIGASHIMATSUYAMA-SHI (JAPAN) 2025; 10:e20230035. [PMID: 40384918 PMCID: PMC12078074 DOI: 10.22575/interventionalradiology.2023-0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 02/24/2024] [Indexed: 05/20/2025]
Abstract
Recent advances in systemic therapy for hepatocellular carcinoma are remarkable. The treatment goal for advanced hepatocellular carcinoma is to prolong survival, while for intermediate-stage hepatocellular carcinoma, it is to achieve a cancer-free and drug-free status. Patients unsuitable for transarterial chemoembolization may benefit from prior systemic therapy with lenvatinib or atezolizumab plus bevacizumab. The TACTICS-L trial, a prospective phase II trial, demonstrated favorable progression-free and overall survival by lenvatinib-transarterial chemoembolization sequential therapy. The REPLACEMENT trial, a multicenter, prospective, single-arm phase II trial, confirmed combination immunotherapy efficacy with atezolizumab plus bevacizumabin a population exceeding up-to-seven criteria. In a proof-of-concept study, atezolizumab plus bevacizumab plus curative therapy showed a 35% complete response rate and 23% drug-free status in intermediate-stage hepatocellular carcinoma patients with a tumor burden exceeding up-to-seven criteria.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Japan
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Anders MM, Mattos AZ, Debes JD, Beltran O, Coste P, Marín JI, Chagas AL, Menéndez J, Estupiñan EC, Ferrer JD, Mattos AA, Piñero F. Latin American expert opinion letter on the feasibility of systemic therapies in combination with locoregional therapies for hepatocellular carcinoma. Ann Hepatol 2025; 30:101905. [PMID: 40122521 DOI: 10.1016/j.aohep.2025.101905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/26/2024] [Accepted: 01/10/2025] [Indexed: 03/25/2025]
Abstract
Recent advances in the systemic treatment of advanced hepatocellular carcinoma (HCC) with immunotherapy have once again reignited discussion over the role of combined therapy in earlier stages. This year, different international meetings have presented recent results from clinical trials on adjuvant therapy alone (IMBrave-050) and combined with transarterial chemoembolization (EMERALD-1 and LEAP-12). Increased enthusiasm for the use of adjuvant and neoadjuvant therapy for liver transplantation, surgery, and local-regional treatment of HCC has been shown. However, the initial results from these trials should be interpreted cautiously as we wait for final analyses and effects on overall survival. In this position paper from the special interest group from the Latin American Association for the Study of Liver Diseases (ALEH), we underline the caveats of the applicability of these potential treatments in our region, explore points of agreement, and highlight areas of uncertainty. Moreover, we underscore the role of hepatologists in the clinical decision-making process and management of these patients.
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Affiliation(s)
| | - Angelo Z Mattos
- Graduate Program in Medicine: Hepatology. Federal University of Health Sciences of Porto Alegre, Brazil
| | - José D Debes
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | | | - Pablo Coste
- Programa Nacional de Trasplante Hepático, Hospital R.A. Calderón Guardia, Costa Rica
| | | | - Aline Lopes Chagas
- Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Josemaría Menéndez
- Programa Nacional de Trasplante Hepático, Hospital Militar, Montevideo, Uruguay
| | - Enrique Carrera Estupiñan
- Hospital Eugenio Espejo, Departamento de Gastroenterología. Universidad San Francisco de Quito, Ecuador
| | | | - Angelo A Mattos
- Graduate Program in Medicine: Hepatology. Federal University of Health Sciences of Porto Alegre, Brazil
| | - Federico Piñero
- Hospital Universitario Austral, Austral University, School of Medicine, Buenos Aires, Argentina
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Li S, Wen Q, Huang W, Qiu Z, Feng L, Yi F. A real-world study of the efficacy of second-line treatment of unresectable hepatocellular carcinoma with esophagogastric varices after progression on first-line lenvatinib combined with PD-1 inhibitor. World J Surg Oncol 2025; 23:83. [PMID: 40082982 PMCID: PMC11905572 DOI: 10.1186/s12957-025-03742-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 03/07/2025] [Indexed: 03/16/2025] Open
Abstract
PURPOSE The incidence and mortality of hepatocellular carcinoma are still high according to National Cancer Center of China. Atezolizumab plus bevacizumab has become one of the standard regimens for the first-line treatment of unresectable hepatocellular carcinoma. However, some patients still use lenvatinib in combination with immunotherapy instead of a standard "atezolizumab-bevacizumab" regimen as a lower risk of bleeding in patients with esophagogastric varices. However, there is no evidence for second-line therapy after progression on lenvatinib combined with PD-1 inhibitor in unresectable hepatocellular carcinoma till now. Herein, we aim to investigate second-line treatment among these patients. PATIENTS AND METHODS Thirty-three patients with unresectable hepatocellular carcinoma with esophagogastric varices were admitted to the Second Affiliated Hospital of Nanchang University from January 2019 to December 2023. They were treated with lenvatinib in combination with PD-1 inhibitor as first line. The efficacy was conducted according to the RECIST1.1 criteria. The endpoints included objective response rate (ORR), disease control rate (DCR), median overall survival (OS), and median progression free survival (PFS). RESULTS We identified a total of 225 patients with unresectable hepatocellular carcinoma with esophagogastric varices who received first-line lenvatinib in combination with PD-1 inhibitor, of whom 33 (14.7%) received second-line therapy. 21 patients (63.6%) were treated with regorafenib combined with PD-1 inhibitor, 6 patients (18.2%) with apatinib plus PD-1 inhibitor, 4 patients (12.1%) with bevacizumab plus PD-1 inhibitor, and the remaining 2 patients with regorafenib or sorafenib as monotherapy, respectively. Of the 33 patients, 2 (6.1%) were evaluated as partial response (PR), 16 (48.5%) had stable disease (SD), and 15 (45.4%) experienced progression (PD). The ORR was 6.1%, and the DCR was 54.6%. Median PFS was 4.5 months, median OS was 7.2 months, and the 12-month OS rate was 27.3%. Overall survival follow-up was done in 37 patients without second line treatment whose baseline levels were matched with those of the treatment group. The OS was 7.2 months in second line treatment group versus 3.0 months in control group (p = 0.04). As for different treatments in a second line, The ORR of regorafenib in combination with PD-1 inhibitor was 9.5%, the DCR was 47.6%, the median PFS was 4.2 months, and the median OS was 5.9 months. None of the patients treated with apatinib plus PD-1 inhibitor got PR, the DCR was 83.3%, the median PFS was 8.7 months, and the median OS was 9.1 months. None of the patients treated with bevacizumab plus PD-1 inhibitor got PR, the DCR was 25.0%, the median PFS was 2.2 months, and the median OS was 6.0 months. CONCLUSION The second-line treatment of unresectable hepatocellular carcinoma with esophagogastric varices after progression on first-line lenvatinib combined with PD-1 inhibitor is effective. Regorafenib or apatinib combined with PD-1 inhibitor might be the preferred options.
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Affiliation(s)
- Saifeng Li
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China
- Jiangxi Medical College of Nanchang University, Nanchang, 330006, P. R. China
| | - Qin Wen
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China
- Jiangxi Medical College of Nanchang University, Nanchang, 330006, P. R. China
| | - Wenwu Huang
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China
- Jiangxi Medical College of Nanchang University, Nanchang, 330006, P. R. China
| | - Zeyu Qiu
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China
| | - Long Feng
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China.
| | - Fengming Yi
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Minde Road 1, Nanchang, 330006, P. R. China.
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Möhring C, Berger M, Sadeghlar F, Zhou X, Zhou T, Monin MB, Shmanko K, Welland S, Sinner F, Schwacha-Eipper B, Bauer U, Roderburg C, Pirozzi A, Ben Khaled N, Schrammen P, Balcar L, Pinter M, Ettrich TJ, Saborowski A, Berres ML, De Toni EN, Lüdde T, Rimassa L, Ehmer U, Venerito M, Radu IP, Schmidt-Wolf IGH, Weinmann A, Vogel A, Schmid M, Kalff JC, Strassburg CP, Gonzalez-Carmona MA. Evaluating Sorafenib (SORA-2) as Second-Line Treatment for Unresectable Hepatocellular Carcinoma: A European Retrospective Multicenter Study. Cancers (Basel) 2025; 17:972. [PMID: 40149306 PMCID: PMC11940497 DOI: 10.3390/cancers17060972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/03/2025] [Accepted: 03/11/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Systemic treatment for unresectable hepatocellular carcinoma (HCC) has rapidly advanced, with immune checkpoint inhibitors now the preferred first-line option. However, with multiple agents available and no established treatment sequence, selecting the most suitable second-line (2L) therapy remains challenging. While sorafenib is frequently chosen for 2L treatment, comprehensive data supporting its use is limited. This study evaluates the effectiveness of sorafenib as 2L therapy and factors influencing outcomes following first-line treatment failure in advanced HCC patients. METHODS This is a retrospective, multicenter study, including 81 patients with unresectable HCC from 12 European centers who received sorafenib as 2L treatment. Median overall survival (mOS), median progression-free survival (mPFS), radiological response to treatment, and toxicity were evaluated. Univariable and multivariable analyses were performed to identify potential predictors of clinical benefit. RESULTS In this cohort, some patients were treated with 2L sorafenib mOS for 7.4 months (95% CI: 6.6-13.6) and other patients were treated with mPFS for 3.7 months (95% CI: 3.0-4.8). Multivariable analysis revealed the best median OS for patients with CP A and AFP levels < 400 ng/mL (15.5 months). Adverse events (AE) of grade ≥ 3 were reported in 59.4% of patients. CONCLUSIONS In this real-world cohort of European patients with unresectable HCC, the outcome of sorafenib treatment in the 2L setting was comparable to that of the other established 2L treatment options in patients with preserved liver function and good performance status. This study contributes to the understanding of the role of sorafenib in the 2L setting and underscores the need for further research to identify predictive factors for response and survival in order to optimize treatment algorithms for advanced HCC.
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Affiliation(s)
- Christian Möhring
- Department of Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (C.M.); (F.S.); (X.Z.); (T.Z.); (M.B.M.); (C.P.S.)
- Department IB of Internal Medicine, German Armed Forces Central Hospital, 56072 Koblenz, Germany
| | - Moritz Berger
- Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, 53127 Bonn, Germany; (M.B.); (M.S.)
- Core Facility Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany
| | - Farsaneh Sadeghlar
- Department of Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (C.M.); (F.S.); (X.Z.); (T.Z.); (M.B.M.); (C.P.S.)
| | - Xin Zhou
- Department of Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (C.M.); (F.S.); (X.Z.); (T.Z.); (M.B.M.); (C.P.S.)
| | - Taotao Zhou
- Department of Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (C.M.); (F.S.); (X.Z.); (T.Z.); (M.B.M.); (C.P.S.)
| | - Malte Benedikt Monin
- Department of Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (C.M.); (F.S.); (X.Z.); (T.Z.); (M.B.M.); (C.P.S.)
- Infektionsmedizinisches Centrum Hamburg (ICH), 20146 Hamburg, Germany
| | - Kateryna Shmanko
- 1st Department of Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany; (K.S.); (A.W.)
| | - Sabrina Welland
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (S.W.); (A.S.); (A.V.)
| | - Friedrich Sinner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von-Guericke University Hospital, 39120 Magdeburg, Germany (M.V.)
| | - Birgit Schwacha-Eipper
- Hepatology-Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland; (B.S.-E.); (I.-P.R.)
| | - Ulrike Bauer
- Department of Clinical Medicine—Clinical Department for Internal Medicine II, TUM School of Medicine and Health, Technical University of Munich, 80333 Munich, Germany; (U.B.); (U.E.)
| | - Christoph Roderburg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, 40225 Düsseldorf, Germany; (C.R.)
| | - Angelo Pirozzi
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (A.P.); (L.R.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany; (N.B.K.); (E.N.D.T.)
| | - Peter Schrammen
- Medical Department III, University Hospital of Aachen, 52074 Aachen, Germany (M.-L.B.)
| | - Lorenz Balcar
- Division of Gastroenterology & Hepatology, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (L.B.); (M.P.)
| | - Matthias Pinter
- Division of Gastroenterology & Hepatology, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (L.B.); (M.P.)
| | - Thomas J. Ettrich
- Department of Internal Medicine I, University Hospital Ulm, 89081 Ulm, Germany;
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (S.W.); (A.S.); (A.V.)
| | - Marie-Luise Berres
- Medical Department III, University Hospital of Aachen, 52074 Aachen, Germany (M.-L.B.)
| | - Enrico N. De Toni
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany; (N.B.K.); (E.N.D.T.)
| | - Tom Lüdde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, 40225 Düsseldorf, Germany; (C.R.)
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (A.P.); (L.R.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Ursula Ehmer
- Department of Clinical Medicine—Clinical Department for Internal Medicine II, TUM School of Medicine and Health, Technical University of Munich, 80333 Munich, Germany; (U.B.); (U.E.)
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von-Guericke University Hospital, 39120 Magdeburg, Germany (M.V.)
| | - Iuliana-Pompilia Radu
- Hepatology-Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland; (B.S.-E.); (I.-P.R.)
- Department of Visceral Surgery and Medicine, Inselspital, University of Bern, 3012 Bern, Switzerland
| | - Ingo G. H. Schmidt-Wolf
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, 53127 Bonn, Germany;
| | - Arndt Weinmann
- 1st Department of Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany; (K.S.); (A.W.)
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (S.W.); (A.S.); (A.V.)
- Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON M5G 2C4, Canada
| | - Matthias Schmid
- Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, 53127 Bonn, Germany; (M.B.); (M.S.)
| | - Jörg C. Kalff
- Department of Surgery, University Hospital of Bonn, 53127 Bonn, Germany;
| | - Christian P. Strassburg
- Department of Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (C.M.); (F.S.); (X.Z.); (T.Z.); (M.B.M.); (C.P.S.)
| | - Maria A. Gonzalez-Carmona
- Department of Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (C.M.); (F.S.); (X.Z.); (T.Z.); (M.B.M.); (C.P.S.)
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Inoue M, Ogasawara S, Kobayashi K, Okubo T, Itokawa N, Obu M, Fujimoto K, Unozawa H, Yumita S, Fujiwara K, Nakagawa M, Kanzaki H, Koroki K, Kiyono S, Nakamura M, Kanogawa N, Kondo T, Nakamoto S, Nagashima K, Itobayashi E, Atsukawa M, Koma Y, Azemoto R, Kato N. Assessment of Macrovascular Invasion in Advanced Hepatocellular Carcinoma: Clinical Implications and Treatment Outcomes with Systemic Therapy. Liver Cancer 2025; 14:8-18. [PMID: 40144472 PMCID: PMC11936442 DOI: 10.1159/000539380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 04/12/2024] [Indexed: 03/28/2025] Open
Abstract
Introduction Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance. Methods Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used MVI progressive disease (MVI-PD) to track MVI progression and Response Evaluation Criteria in Solid Tumors version 1.1 progressive disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD. Results Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. Forty (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than 3 months was analyzed based on the assessment of imaging response during the first 3 months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (p < 0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498). Conclusion Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression.
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Affiliation(s)
- Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomomi Okubo
- Department of Gastroenterology, Nippon Medical School Chibahokusoh Hospital, Chiba, Japan
| | - Norio Itokawa
- Department of Gastroenterology, Nippon Medical School Chibahokusoh Hospital, Chiba, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Masamichi Obu
- Department of Gastroenterology, Kimitsu Chuo Hospital, Chiba, Japan
| | - Kentaro Fujimoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hidemi Unozawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sae Yumita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kisako Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Miyuki Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kengo Nagashima
- Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Chiba, Japan
| | - Masanori Atsukawa
- Department of Gastroenterology, Nippon Medical School Chibahokusoh Hospital, Chiba, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
| | - Yoshihiro Koma
- Department of Gastroenterology, Kimitsu Chuo Hospital, Chiba, Japan
| | - Ryosaku Azemoto
- Department of Gastroenterology, Kimitsu Chuo Hospital, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Al-Hasan M, Mehta N, Yang JD, Singal AG. Role of biomarkers in the diagnosis and management of HCC. Liver Transpl 2025; 31:384-394. [PMID: 38738964 DOI: 10.1097/lvt.0000000000000398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/06/2024] [Indexed: 05/14/2024]
Abstract
For many cancers, biomarkers have served as an important tool across the cancer care continuum from risk stratification and early detection to diagnosis and treatment. Alpha-fetoprotein (AFP) remains one of the few validated biomarkers for patients with HCC. Although AFP has shown potential for each of these steps, its performance, when used alone, has often been suboptimal. There continue to be discordant recommendations about AFP's value when combined with ultrasound for surveillance, as well as its role in diagnostic algorithms. Conversely, high AFP levels are associated with aggressive tumor biology and survival, so it remains a key factor for the selection of candidates for liver transplant. There have been immense efforts to identify and validate additional biomarkers for each of these steps in the HCC care continuum. Indeed, biomarker panels have shown promising data for HCC risk stratification and surveillance among patients with cirrhosis, as well as prognostication and detection of minimal residual disease in patients undergoing HCC treatment. Several large prospective studies are currently ongoing to evaluate the role of these emerging biomarkers in clinical practice.
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Affiliation(s)
- Mohammed Al-Hasan
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Neil Mehta
- Department of Internal Medicine, University of California San Francisco, San Francisco, California, USA
| | - Ju Dong Yang
- Department of Internal Medicine, Cedars Sinai, Los Angeles, California, USA
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Sun R, Wu C, Gou Y, Zhao Y, Huang P. Advancements in second-line treatment research for hepatocellular carcinoma. Clin Transl Oncol 2025; 27:837-857. [PMID: 39162977 DOI: 10.1007/s12094-024-03653-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 07/29/2024] [Indexed: 08/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.
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Affiliation(s)
- Ruirui Sun
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Chenrui Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yang Gou
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Yaowu Zhao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China
| | - Ping Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400000, China.
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Zhai Y, Wang L, Zhao H, Wu F, Xin L, Ye F, Sun W, Song Y, Niu L, Zeng H, Wang J, Tang Y, Song Y, Liu Y, Fang H, Lu N, Jing H, Qi S, Zhang W, Wang S, Li YX, Wu J, Chen B. Phase II study with sorafenib plus radiotherapy for advanced HCC with portal and/or hepatic vein tumor thrombosis. JHEP Rep 2025; 7:101287. [PMID: 39980754 PMCID: PMC11840495 DOI: 10.1016/j.jhepr.2024.101287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/01/2024] [Accepted: 11/20/2024] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND & AIMS Portal and hepatic vein tumor thrombosis is associated with inferior outcomes in patients with hepatocellular carcinoma (HCC), and systemic treatment alone is often insufficient. This phase II trial evaluated the efficacy and safety of combining sorafenib with radiotherapy in advanced HCC with thrombosis. METHODS Registered at ClinicalTrials.gov (NCT03535259), this phase II single-arm prospective trial targeted patients with HCC with portal or hepatic vein tumor thrombosis, liver minus gross tumor volume >700 ml, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1. Participants underwent 40-66 Gy radiotherapy for the hepatic primary tumor and vein tumor thrombosis, with concurrent oral sorafenib (400 mg twice daily) until disease progression or unacceptable adverse events. The primary endpoint was median overall survival (mOS) and the secondary endpoints included overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Modified Response Evaluation Criteria in Solid Tumors (mRECIST), median progression-free survival (mPFS), time to tumor progression (TTP), tumor thrombosis control, and grade ≥3 adverse events. RESULTS Between May 2018 and January 2020, 86 patients were enrolled with a median radiotherapy dose of 54 Gy (40-65 Gy). At a median follow-up of 17.2 months, mOS, mPFS, and TTP stood at 16.5, 6.1, and 6.8 months, respectively. ORR reached 47.7% and 52.3% per RECIST and mRECIST, respectively. For the tumor thrombosis, 2-year control rates per mRECIST were 93.1%. No grade 5 adverse events were noted, whereas thrombocytopenia (22.1%) and leukopenia (14.0%) were the main grade 3 adverse events. CONCLUSIONS Concurrent sorafenib and radiotherapy is an effective and well-tolerated treatment for patients with HCC with portal or hepatic vein tumor thrombosis. IMPACT AND IMPLICATIONS Treatment options for patients with hepatocellular carcinoma (HCC) and vascular tumor thrombus are limited. The efficacy and safety of concurrent sorafenib and radiation for HCC with portal or hepatic vein tumor thrombosis has not been elucidated. This phase II trial shows that concurrent sorafenib and radiotherapy is effective and well-tolerated in the treatment of advanced HCC with portal vein or hepatic vein tumor thrombosis. CLINICAL TRIALS REGISTRATION This study is registered at ClinicalTrials.gov (NCT03535259).
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Affiliation(s)
- Yirui Zhai
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fan Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lingxia Xin
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Feng Ye
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Sun
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Song
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lijuan Niu
- Department of Ultrasound, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huiying Zeng
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingbo Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Tang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongwen Song
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yueping Liu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui Fang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ningning Lu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hao Jing
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shunan Qi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenwen Zhang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shulian Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ye-Xiong Li
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianxiong Wu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Chen
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Barcena-Varela M, Monga SP, Lujambio A. Precision models in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2025; 22:191-205. [PMID: 39663463 DOI: 10.1038/s41575-024-01024-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/11/2024] [Indexed: 12/13/2024]
Abstract
Hepatocellular carcinoma (HCC) represents a global health challenge, and ranks among one of the most prevalent and deadliest cancers worldwide. Therapeutic advances have expanded the treatment armamentarium for patients with advanced HCC, but obstacles remain. Precision oncology, which aims to match specific therapies to patients who have tumours with particular features, holds great promise. However, its implementation has been hindered by the existence of numerous 'HCC influencers' that contribute to the high inter-patient heterogeneity. HCC influencers include tumour-related characteristics, such as genetic alterations, immune infiltration, stromal composition and aetiology, and patient-specific factors, such as sex, age, germline variants and the microbiome. This Review delves into the intricate world of HCC, describing the most innovative model systems that can be harnessed to identify precision and/or personalized therapies. We provide examples of how different models have been used to nominate candidate biomarkers, their limitations and strategies to optimize such models. We also highlight the importance of reproducing distinct HCC influencers in a flexible and modular way, with the aim of dissecting their relative contribution to therapy response. Next-generation HCC models will pave the way for faster discovery of precision therapies for patients with advanced HCC.
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Affiliation(s)
- Marina Barcena-Varela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Satdarshan P Monga
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Buzatu IM, Tataranu LG, Duta C, Stoian I, Alexandru O, Dricu A. A Review of FDA-Approved Multi-Target Angiogenesis Drugs for Brain Tumor Therapy. Int J Mol Sci 2025; 26:2192. [PMID: 40076810 PMCID: PMC11899917 DOI: 10.3390/ijms26052192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/16/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
Neovascularization is an important process in brain tumor development, invasion and metastasis. Several research studies have indicated that the VEGF signaling target has potential for reducing angiogenesis in brain tumors. However, targeting VEGF signaling has not met the expected efficacy, despite initial enthusiasm. This is partly because tumors cleverly use alternative growth factor pathways, other than VEGF signaling, to restore angiogenesis. Multi-target inhibitors have been developed to inhibit several receptor kinases that play a role in the development of angiogenesis. By simultaneously affecting various receptor kinases, these treatments can potentially obstruct various angiogenic pathways that are involved in brain cancer advancement, often offering a more holistic strategy than treatments focusing on just one kinase. Since 2009, the FDA has approved a number of multi-kinase inhibitors that target angiogenic growth factor receptors (e.g., VEGFR, PDGFR, FGFR, RET, c-KIT, MET, AXL and others) for treatment of malignant diseases, including brain cancer. Here, we present some recent results from the literature regarding the preclinical and clinical effects of these inhibitors on brain tumors.
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Affiliation(s)
- Iuliana Mihaela Buzatu
- Department of Microbiology, “Fundeni” Clinical Institute, Șoseaua Fundeni 258, 022328 Bucharest, Romania;
| | - Ligia Gabriela Tataranu
- Department of Neurosurgery, Clinical Emergency Hospital “Bagdasar-Arseni”, Soseaua Berceni 12, 041915 Bucharest, Romania;
- Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Carmen Duta
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 020022 Bucharest, Romania; (C.D.); (I.S.); (A.D.)
| | - Irina Stoian
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 020022 Bucharest, Romania; (C.D.); (I.S.); (A.D.)
| | - Oana Alexandru
- Department of Neurology, University of Medicine and Pharmacy of Craiova, Petru Rares 2, 200349 Craiova, Romania
| | - Anica Dricu
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 020022 Bucharest, Romania; (C.D.); (I.S.); (A.D.)
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Bloom M, Podder S, Dang H, Lin D. Advances in Immunotherapy in Hepatocellular Carcinoma. Int J Mol Sci 2025; 26:1936. [PMID: 40076561 PMCID: PMC11900920 DOI: 10.3390/ijms26051936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/10/2025] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets.
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Affiliation(s)
- Matthew Bloom
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA;
| | - Sourav Podder
- Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (S.P.); (H.D.)
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (S.P.); (H.D.)
| | - Daniel Lin
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA;
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Yin X, Deng N, Ding XY, Chen JL, Sun W. CRAFITY score and nomogram predict the clinical efficacy of lenvatinib combined with immune checkpoint inhibitors in hepatocellular carcinoma. World J Gastroenterol 2025; 31:101672. [PMID: 39991685 PMCID: PMC11755258 DOI: 10.3748/wjg.v31.i7.101672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/03/2024] [Accepted: 12/30/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab, with little investigation in its predictive capacity for alternative regimens, such as lenvatinib and programmed cell death protein 1 (PD-1) inhibitors, which are widely utilized in Chinese clinical practice. AIM To look at the predictive significance of the CRAFITY score in HCC patients taking lenvatinib and PD-1 inhibitors. METHODS The retrospective investigation consisted of 192 patients with incurable HCC who received lenvatinib and PD-1 inhibitors between January 2018 and January 2022. Patients were stratified according to CRAFITY score (based on baseline alpha-fetoprotein and C-reactive protein levels) into CRAFITY-low, CRAFITY-intermediate, and CRAFITY-high groups. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier analysis, and independent prognostic factors were identified through Cox regression analysis. Nomograms were created to forecast survival for a year. RESULTS The median PFS and OS were the longest for patients in the CRAFITY-low group, followed by those in the CRAFITY-intermediate and CRAFITY-high groups (median PFS: 8.4 months, 6.0 months, and 3.1 months, P < 0.0001; median OS: 33.4 months, 19.2 months, and 6.6 months, P < 0.0001). Both the objective response rate (5%, 19.6%, and 22%, P = 0.0669) and the disease control rate (50%, 76.5%, and 80%, P = 0.0023) were considerably lower in the CRAFITY-high group. The findings from the multivariate analysis showed that a nomogram which included the tumor number, prior transarterial chemoembolization history, and CRAFITY score predicted 12-month survival with an area under the curve of 0.788 (95% confidence interval: 0.718-0.859), which was in good agreement with actual data. CONCLUSION The CRAFITY score is a valuable predictor of survival and treatment outcomes in patients receiving lenvatinib and PD-1 inhibitors.
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Affiliation(s)
- Xue Yin
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Na Deng
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xiao-Yan Ding
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Jing-Long Chen
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Sun
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Fung AKY, Chok KSH. Hepatic artery infusion chemotherapy: A resurgence. World J Gastrointest Oncol 2025; 17:99612. [PMID: 39958544 PMCID: PMC11755999 DOI: 10.4251/wjgo.v17.i2.99612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 10/31/2024] [Accepted: 11/25/2024] [Indexed: 01/18/2025] Open
Abstract
In this manuscript, we comment on the article by Zhou et al, who assessed the efficacy of hepatic arterial infusion chemotherapy (HAIC) and its combination strategies for advanced hepatocellular carcinoma (HCC) using network meta-analysis methodology. We focus specifically on the potential advantages and role of HAIC in the treatment algorithm for advanced HCC. However, there remains numerous knowledge gaps before the role of HAIC can be established. There is significant heterogeneity of HAIC regimes with difficult interpretation of the clinical outcomes. Additionally, there is a lack of direct comparative data between HAIC, systemic chemotherapy, novel immunotherapies and targeted therapies. The underlying biochemical mechanisms that might explain the efficacy of HAIC and its effect on the HCC microenvironment requires further research. In the developing era of nanotechnology and targeted drug delivery systems, there is potential for integration of HAIC with novel technologies to effectively treat advanced HCC whilst minimising systemic complications.
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Affiliation(s)
- Andrew Kai-Yip Fung
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
| | - Kenneth Siu Ho Chok
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China
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Pu W, Shen X, Fan X, Zheng Y, Liu X, Li J, Zhou JK, He J, Wei R, Gong Y, Zheng Q, Luo Y, Guo Y, Ai M, Ming Y, Ye Z, Zhao Y, Wang C, Peng Y. Structure-Guided Optimization and Preclinical Evaluation of 6- O-Benzylguanine-Based Pin1 Inhibitor for Hepatocellular Carcinoma Treatment. J Med Chem 2025; 68:2869-2889. [PMID: 39868498 DOI: 10.1021/acs.jmedchem.4c02144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths globally, and the need for effective systemic therapies for HCC is urgent. Our previous work reveals that Pin1 is a potential anti-HCC target, which regulates miRNA biogenesis and identifies API-1 as a novel Pin1 inhibitor to suppresses HCC. However, a great demand in HCC therapy as well as the limited chemical stability and pharmacokinetic feature of API-1 motivated us to find improved Pin1 inhibitors. Herein, we designed and synthesized diverse 6-O-benzylguanine derivatives and discovered API-32 as a novel Pin1 inhibitor with better stability and pharmacokinetic property over API-1. API-32 directly interacted with the Pin1 PPIase domain to inhibit Pin1 activity. API-32 significantly suppressed the cell proliferation and migration of HCC cells by blocking Pin1's downstream signal. Moreover, API-32 exhibited an enhanced inhibitory function against the HCC tumor in mice models without obvious toxicity, making it a promising drug candidate for HCC treatment.
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Affiliation(s)
- Wenchen Pu
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Xianyan Shen
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Xin Fan
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Yuanyuan Zheng
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Xuesha Liu
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Jiao Li
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Jian-Kang Zhou
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
| | - Juan He
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Rong Wei
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Qingquan Zheng
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yao Luo
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yingli Guo
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Min Ai
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yue Ming
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Zixia Ye
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yun Zhao
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Chun Wang
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Yong Peng
- Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Finn RS, Iyer R, Kalman RS, Parikh ND, Cabrera R, Babajanyan S, Kaseb AO. Tolerability and Effectiveness of Regorafenib Treatment in Patients with Unresectable Hepatocellular Carcinoma: Real-World Data from the United States. J Hepatocell Carcinoma 2025; 12:231-246. [PMID: 39935697 PMCID: PMC11812560 DOI: 10.2147/jhc.s459983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 01/13/2025] [Indexed: 02/13/2025] Open
Abstract
Introduction While several systemic therapies are available for unresectable hepatocellular carcinoma (uHCC), there is a lack of granular real-world evidence to support the efficacy and safety of these therapies. The REFINE study evaluated safety and effectiveness of regorafenib in a global population under real-world practice conditions. This sub-analysis describes the safety and effectiveness of regorafenib among the United States (US) subset of patients in the REFINE study relative to patients in the non-US subset. Materials and Methods REFINE was an international, prospective, multicenter observational study. Eligible patients were those with uHCC for whom a decision to treat with regorafenib had already been made. The primary study endpoint was the frequency of documented treatment-emergent adverse events (TEAEs). Additional endpoints included overall survival and progression-free survival. Groups were compared descriptively. Results Of 1005 patients, 65 were from the US and 940 were from other countries. 91% of patients in the US subset (n=59) and 92% in the non-US subset (n=862) experienced ≥1 TEAE. Common adverse events (AEs) included gastrointestinal disorders, fatigue, and hand-foot skin reaction. Median overall survival for patients in the US subset was 11.4 months (interquartile range [IQR]: 4.7-25.4) and 13.2 months (IQR: 5.8-26.3) in the non-US subset. Median progression-free survival was 3.4 months (IQR: 2.4-6.1) for patients in the US subset and 3.9 months (IQR: 2.2-8.5) in the non-US subset. Conclusion Regorafenib was associated with similar safety and effectiveness outcomes for patients in the US and non-US subsets of the REFINE study. Differences in the incidence of certain AEs may be due to differences in treatment management between study sites or baseline disease status. These findings are consistent with the phase 3 RESORCE trial and corroborate the safety and effectiveness of regorafenib as a subsequent-line treatment in US patients with uHCC.
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Affiliation(s)
- Richard S Finn
- Department of Medicine, University of California, Los Angeles, CA, USA
| | - Renuka Iyer
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Richard S Kalman
- Department of Medicine, Einstein Medical Center, Philadelphia, PA, USA
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Roniel Cabrera
- Department of Medicine, University of Florida Health, Gainesville, FL, USA
| | | | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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47
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Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Guo Y, Wang H, Dong E, Xiao J. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10:33. [PMID: 39904973 PMCID: PMC11794951 DOI: 10.1038/s41392-024-02072-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/06/2024] [Accepted: 11/12/2024] [Indexed: 02/06/2025] Open
Abstract
As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.
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Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhang Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangxin Kong
- Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yangkun Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
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48
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Piscaglia F, Masi G, Martinelli E, Cabibbo G, Di Maio M, Gasbarrini A, Iavarone M, Antonuzzo L, Mazzaferro V, Ballestrero A, Garufi C, Bergamo F, Celsa C, Marino D, Tovoli F, Ponziani FR, Pressiani T, Astolfi C, Gazzoli GC, Ciardiello F, Daniele B, Rimassa L. Atezolizumab plus bevacizumab as first-line treatment of unresectable hepatocellular carcinoma: interim analysis results from the phase IIIb AMETHISTA trial. ESMO Open 2025; 10:104110. [PMID: 39874903 PMCID: PMC11799967 DOI: 10.1016/j.esmoop.2024.104110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND The treatment of advanced hepatocellular carcinoma (HCC) with atezolizumab and bevacizumab led to significant improvements in overall survival (OS), progression-free survival (PFS), and response rate compared with sorafenib in the phase III IMbrave150 trial. The etiology of background liver disease can differ between Eastern and Western populations, leading to a potentially different impact of systemic therapies; therefore the unequal representation must be considered in the IMbrave150 trial. To provide further data on the safety and effectiveness of atezolizumab and bevacizumab, the phase IIIb AMETHISTA (Atezolizumab plus bevacizumab in METastatic HCC Italian Safety TriAl) ran in a Western (Italian) population of patients with advanced HCC. The results of the interim analysis are presented in this paper. METHODS AMETHISTA is a multicenter, phase IIIb, single-arm study evaluating the safety and effectiveness of atezolizumab and bevacizumab in an Italian population of patients with systemic treatment-naive HCC (ClinicalTrials.gov: NCT04487067). The primary objective was safety (incidence of grade 3-5 bleeding/hemorrhages). The main secondary objective was effectiveness. RESULTS A total of 152 patients were enrolled and 149 were treated. At the cut-off date, the median observation time was 13.4 months (interquartile range 8.3-15.5 months). The incidence of grade 3-5 bleeding/hemorrhages was 11.4%. Besides, results of other safety endpoints were consistent with the safety profile of atezolizumab plus bevacizumab, and the underlying disease, without any new safety observation. The median OS was 18.2 months (95% confidence interval 15.4 months to not evaluable); the median PFS was 8.5 months (95% confidence interval 7.5-11.2 months). CONCLUSION Results from the interim analysis are consistent with data from the IMbrave150 trial, and further confirm first-line atezolizumab plus bevacizumab as a standard of care for patients with systemic treatment-naive advanced and unresectable HCC.
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Affiliation(s)
- F Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Disease, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - G Masi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - E Martinelli
- Medical Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania "L. Vanvitelli", Napoli, Italy
| | - G Cabibbo
- Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - M Di Maio
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Turin, Italy
| | - A Gasbarrini
- Liver Unit, Internal Medicine and Gastroenterology Center - CEMAD, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - M Iavarone
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - L Antonuzzo
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Clinical Oncology Unit, AOU Careggi, Florence, Italy
| | - V Mazzaferro
- Department of Surgery, Gastro-Intestinal, HPB Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - A Ballestrero
- Department of Internal Medicine and Medical Specialties, University of Genoa, IRCCS Policlinico San Martino Hospital, Genoa, Italy
| | - C Garufi
- Oncology Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
| | - F Bergamo
- Oncology 1 Unit, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - C Celsa
- Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy; Department of Surgical, Oncological, and Oral Sciences, University of Palermo, Palermo, Italy
| | - D Marino
- Division of Medical Oncology, Ordine Mauriziano Hospital, Turin, Italy
| | - F Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Disease, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - F R Ponziani
- Liver Unit, Internal Medicine and Gastroenterology Center - CEMAD, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - T Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
| | | | | | - F Ciardiello
- Medical Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania "L. Vanvitelli", Napoli, Italy
| | - B Daniele
- Oncology Unit, Ospedale del Mare, ASL Napoli 1 Centro, Naples, Italy
| | - L Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, (Milan), Italy.
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49
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Travers J, Mahipal A, Chotai P, Gholam PM. Clinical Vignettes Illustrating the Spectrum of Hepatocellular Carcinoma Presentation and Treatment. Clin Liver Dis 2025; 29:125-133. [PMID: 39608952 DOI: 10.1016/j.cld.2024.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
Hepatocellular carcinoma (HCC) presentation reflects a complex interaction between cancer stage, severity of liver disease, and overall functional status. This article provides clinical vignettes that illustrate these complex interactions and how a multidisciplinary approach can result in rational, evidence-based plans of care that factor in the local standard of care as well as patient preference. The vignettes range from a patient with early stage HCC and good liver function to a patient with metastatic disease. The full spectrum of treatments that can be applied ranging from curative surgery and transplantation to locoregional therapy and systemic therapy are shown.
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Affiliation(s)
- Jared Travers
- Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, WRN 5066, Cleveland, OH 44106-5066, USA
| | - Amit Mahipal
- Case Western Reserve University, University Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Cleveland OH 44124, USA
| | - Pranit Chotai
- Division of Transplant and Hepatobiliary Surgery, University Hospitals, Case Western Reserve University, 11100 Euclid Avenue, Lakeside 7th Floor Suite 7500, Cleveland, OH 44106, USA. https://twitter.com/txpchotai
| | - Pierre M Gholam
- Division of Gastroenterology and Liver Disease, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA.
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50
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Groß S, Bitzer M, Albert J, Blödt S, Boda-Heggemann J, Borucki K, Brunner T, Caspari R, Dombrowski F, Evert M, Follmann M, Freudenberger P, Gani C, Gebert J, Geier A, Gkika E, Götz M, Helmberger T, Hoffmann RT, Huppert P, Krug D, Fougère CL, Lang H, Langer T, Lenz P, Lüdde T, Mahnken A, Nadalin S, Nguyen HHP, Nothacker M, Ockenga J, Oldhafer K, Ott J, Paprottka P, Pereira P, Persigehl T, Plentz R, Pohl J, Recken H, Reimer P, Riemer J, Ringe K, Roeb E, Rüssel J, Schellhaas B, Schirmacher P, Schlitt HJ, Schmid I, Schütte K, Schuler A, Seehofer D, Sinn M, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Trojan J, van Thiel I, Utzig M, Vogel A, Vogl T, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wenzel G, Wildner D, Wörns MA, Galle P, Malek N. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:e82-e158. [PMID: 39919781 DOI: 10.1055/a-2460-6347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Affiliation(s)
- Sabrina Groß
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Michael Bitzer
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Jörg Albert
- Katharinenhospital, Klinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie, Infektiologie und Pneumologie, Stuttgart
| | - Susanne Blödt
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | | | - Katrin Borucki
- Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Klinische Chemie und Pathobiochemie
| | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz
| | - Reiner Caspari
- Klinik Niederrhein Erkrankungen des Stoffwechsels der Verdauungsorgane und Tumorerkrankungen, Bad Neuenahr-Ahrweiler
| | | | | | - Markus Follmann
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | | | - Cihan Gani
- Klinik für Radioonkologie, Universitätsklinikum Tübingen
| | - Jamila Gebert
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Andreas Geier
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg
| | - Eleni Gkika
- Klinik für Strahlenheilkunde, Department für Radiologische Diagnostik und Therapie, Universitätsklinikum Freiburg
| | - Martin Götz
- Medizinische Klinik IV - Gastroenterologie/Onkologie, Klinikverbund Südwest, Böblingen
| | - Thomas Helmberger
- Institut für Radiologie, Neuroradiologie und minimal invasive Therapie, München Klinik Bogenhausen
| | - Ralf-Thorsten Hoffmann
- Institut und Poliklinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Dresden
| | - Peter Huppert
- Radiologisches Zentrum, Max Grundig Klinik, Bühlerhöhe
| | - David Krug
- Strahlentherapie Campus Kiel, Universitätsklinikum Schleswig-Holstein
| | - Christian La Fougère
- Nuklearmedizin und Klinische Molekulare Bildgebung, Eberhard-Karls Universität, Tübingen
| | - Hauke Lang
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Johannes Gutenberg-Universität, Mainz
| | - Thomas Langer
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | - Philipp Lenz
- Zentrale Einrichtung Palliativmedizin, Universitätsklinikum Münster
| | - Tom Lüdde
- Medizinische Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf
| | - Andreas Mahnken
- Klinik für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Marburg
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Eberhard-Karls Universität, Tübingen
| | | | - Monika Nothacker
- Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF), Berlin
| | - Johann Ockenga
- Medizinische Klinik II, Gesundheit Nord, Klinikverbund Bremen
| | - Karl Oldhafer
- Klinik für Leber-, Gallenwegs- und Pankreaschirurgie, Asklepios Klinik Barmbek
| | - Julia Ott
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
| | - Philipp Paprottka
- Sektion für Interventionelle Radiologie, Klinikum rechts der Isar, Technische Universität München
| | - Philippe Pereira
- Zentrum für Radiologie, Minimal-invasive Therapien und Nuklearmedizin, SLK-Klinken Heilbronn
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Köln
| | - Ruben Plentz
- Digestive Diseases and Nutrition, Gastroenterology, University of Kentucky
| | - Jürgen Pohl
- Abteilung für Gastroenterologie, Asklepios Klinik Altona
| | | | - Peter Reimer
- Institut für Diagnostische und Interventionelle Radiologie, Städtisches Klinikum Karlsruhe
| | | | - Kristina Ringe
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | - Elke Roeb
- Medizinische Klinik II Pneumologie, Nephrologie und Gastroenterologie, Universitätsklinikum Gießen
| | - Jörn Rüssel
- Medizinische Klinik IV Hämatologie und Onkologie, Universitätsklinikum Halle (Saale)
| | - Barbara Schellhaas
- Medizinische Klinik I Gastroenterologie, Pneumologie und Endokrinologie, Friedrich-Alexander-Universität, Erlangen
| | - Peter Schirmacher
- Allgemeine Pathologie und pathologische Anatomie, Universitätsklinikum Heidelberg
| | | | - Irene Schmid
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU München
| | - Kerstin Schütte
- Klinik für Innere Medizin und Gastroenterologie, Niels-Stensen-Kliniken, Marienhospital Osnabrück
| | - Andreas Schuler
- Medizinische Klinik, Gastroenterologie, Alb-Fils-Kliniken, Geislingen an der Steige
| | - Daniel Seehofer
- Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig
| | - Marianne Sinn
- II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, Knochenmarktransplantation mit Abteilung für Pneumologie), Universitätsklinikum Hamburg-Eppendorf
| | - Andreas Stengel
- Innere Medizin VI - Psychosomatische Medizin und Psychotherapie, Eberhard-Karls Universität, Tübingen
| | | | | | | | - Anne Taubert
- Klinische Sozialarbeit, Universitätsklinikum Heidelberg
| | - Jörg Trojan
- Medizinische Klinik 1: Gastroenterologie und Hepatologie, Pneumologie und Allergologie, Endokrinologie und Diabetologie sowie Ernährungsmedizin, Goethe-Universität, Frankfurt
| | | | - Martin Utzig
- Abteilung Zertifizierung, Deutsche Krebsgesellschaft e.V., Berlin
| | - Arndt Vogel
- Institute of Medical Science, University of Toronto
| | - Thomas Vogl
- Institut für Diagnostische und Interventionelle Radiologie, Goethe-Universität, Frankfurt
| | - Frank Wacker
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover
| | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover
| | - Henning Wege
- Klinik für Allgemeine Innere Medizin, Onkologie/Hämatologie, Gastroenterologie und Infektiologie, Klinikum Esslingen
| | - Gregor Wenzel
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e.V., Berlin
| | - Dane Wildner
- Innere Medizin, Krankenhäuser Nürnberger Land GmbH, Standort Lauf
| | - Marcus-Alexander Wörns
- Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund
| | - Peter Galle
- 1. Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie, Nephrologie, Rheumatologie, Infektiologie, Johannes Gutenberg-Universität, Mainz
| | - Nisar Malek
- Abteilung für Gastroenterologie, Gastrointestinale Onkologie, Hepatologie, Infektiologie und Geriatrie, Eberhard-Karls Universität, Tübingen
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