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Tabrizian P, Holzner ML, Ajmera V, Kim AK, Zhou K, Schnickel GT, Torosian K, Hoteit M, Marino R, Li M, Yao F, Florman SS, Schwartz ME, Mehta N. Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: The multicenter VITALITY study. J Hepatol 2025; 82:512-522. [PMID: 39255928 DOI: 10.1016/j.jhep.2024.09.003] [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: 03/22/2024] [Revised: 08/23/2024] [Accepted: 09/03/2024] [Indexed: 09/12/2024]
Abstract
BACKGROUND & AIMS The use of immune checkpoint inhibitors (ICIs) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention-to-treat (ITT) outcomes in the peri-transplant setting are currently based on small and heterogenous single-center reports. METHODS This first multiregional US study (2016-2023) included 117 consecutive patients with HCC assessed for liver transplantation (LT) and treated preoperatively with ICIs. ITT and survival analyses were conducted with evaluation of post-LT rejection rates. RESULTS In total, 86 (73.5%) patients exceeded Milan criteria (MC) and 65 (75.6%) were successfully downstaged within a median of 5.6 months; 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) who were initially beyond but were downstaged. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included being beyond MC (p <0.001), alpha-fetoprotein doubling from baseline (p = 0.014) and radiographic responses (p <0.001). The 3-year ITT survival rate was 71.1% (73.5% within MC vs. 69.7% beyond MC, p = 0.329), with a 3-year post-LT survival rate of 85%. Post-LT rejection occurred in seven patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. CONCLUSIONS The first multicenter evaluation of patients with HCC receiving ICIs pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of alpha-fetoprotein levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. IMPACT AND IMPLICATIONS Herein, we report results from the first multicenter evaluation of pretransplant immune checkpoint inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune checkpoint inhibitors, either alone or combined with locoregional therapy, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated alpha-fetoprotein levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pretransplant use of immune checkpoint inhibitors, pending results from ongoing trials.
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Affiliation(s)
- Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
| | - Matthew L Holzner
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Veeral Ajmera
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA
| | - Amy K Kim
- Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kali Zhou
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Gabriel T Schnickel
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, University of California San Diego, San Diego, California, USA
| | - Kelly Torosian
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, San Diego, California, USA
| | - Maarouf Hoteit
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rebecca Marino
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Michael Li
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, California, USA
| | - Francis Yao
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, California, USA; Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Sander S Florman
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Myron E Schwartz
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Neil Mehta
- Division of Gastroenterology/Hepatology, University of California San Francisco, San Francisco, California, USA
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Magyar CTJ, O'Kane GM, Aceituno L, Li Z, Vogel A, Bruix J, Mazzaferro V, Sapisochin G. Liver Transplantation for Hepatocellular Carcinoma: An Expanding Cornerstone of Care in the Era of Immunotherapy. J Clin Oncol 2025; 43:589-604. [PMID: 39680821 DOI: 10.1200/jco.24.00857] [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: 04/21/2024] [Revised: 09/20/2024] [Accepted: 10/19/2024] [Indexed: 12/18/2024] Open
Abstract
Liver transplantation (LT) has been accepted as a cornerstone of care in hepatocellular carcinoma (HCC) for almost three decades. In recent years, its role has been evolving to include patients with disease burden beyond the widely used Milan criteria. The integration of dynamic biomarkers such as alpha-fetoprotein together with downstaging approaches and tumor evolution after enlistment has allowed the selection of patients most likely to benefit, resulting in 5-year survival rates greater that 70%. With the increasing use of immune checkpoint inhibitors (ICIs) across all stages of disease, alone or in combination with locoregional therapies, there is now the potential to further expand the patient population with HCC who may benefit from LT. This brings challenges, given the global shortage of organs and the need to better understand the optimal use of ICIs before transplantation. Furthermore, the field of transplant oncology awaits additional biomarkers that can predict those likely to benefit from ICIs. More than ever, a multidisciplinary approach for liver cancer management is critical to ensure all patients are considered for LT where appropriate, and do not miss the opportunity for long-term survival.
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Affiliation(s)
- Christian Tibor Josef Magyar
- HPB Surgical Oncology, University Health Network, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Grainne Mary O'Kane
- University of Toronto, Toronto, ON, Canada
- St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Laia Aceituno
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
- Department of Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Zhihao Li
- HPB Surgical Oncology, University Health Network, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Arndt Vogel
- Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
- Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada
- Department of Hepatology, Gastroenterology, Endocrinology & Infectious Diseases, Hannover Medical School, Hannover, Germany
| | - Jordi Bruix
- BCLC Group, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Vincenzo Mazzaferro
- Istituto Nazionale Tumori IRCCS, Hepato Pancreatic Biliary Surgery & Liver Transplantation Unit, Milano, Italy
- Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy
| | - Gonzalo Sapisochin
- HPB Surgical Oncology, University Health Network, Toronto, ON, Canada
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
- Department of Medicine, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
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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:hyaf017. [PMID: 39895083 DOI: 10.1093/jjco/hyaf017] [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: 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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4
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Tabrizian P, Marino R, Bhoori S, Zeitlhoefler M, Mehta N, Banz V, Gruttadauria S, Iavarone M, Mazzarelli C, Simonotti N, Yao F, Mazzaferro V, Llovet JM. Neoadjuvant atezolizumab plus bevacizumab prior liver transplantation for hepatocellular carcinoma. JHEP Rep 2025; 7:101246. [PMID: 39911942 PMCID: PMC11794155 DOI: 10.1016/j.jhepr.2024.101246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/25/2024] [Accepted: 10/10/2024] [Indexed: 02/07/2025] Open
Abstract
Background & Aims The combination of atezolizumab and bevacizumab offers a novel approach to immunomodulation, showing efficacy as a primary treatment in advanced hepatocellular carcinoma (HCC). Concerns about graft safety and rejection have limited its exploration in the neoadjuvant setting of liver transplantation (LT). In this study, we investigate the clinical efficacy and the safety profile of pre-transplant administration of atezolizumab and bevacizumab for HCC. Methods Herein, we performed a prospective assessment of 17 patients with HCC treated with neoadjuvant preoperative atezolizumab and bevacizumab prior to LT for HCC, obtained from December 2020 and December 2023 at seven Western transplant centers. Results Among the 17 patients with HCC included in the study, 16 (94.1%) had a tumor burden outside of Milan criteria. Neoadjuvant locoregional therapies along with the administration of atezolizumab plus bevacizumab (median: 5 months; discontinued at least 4 weeks prior to LT) led to an objective response rate of 94% (complete response: 59%), downstaging to within Milan criteria (82%) and a pathological response at explant examination of 88%. Grade 3-4 treatment-related adverse events accounted for 17.6% of cases and were manageable. During the 25-month median follow-up period, two cases of mild (rejection activity index ≤4), biopsy-proven rejection were reported but no instances of severe allograft rejection or graft loss were reported. The 1-year and 3-year post-LT survival rates were 94.2% and 88.2%, respectively. Conclusions This study highlights the favorable oncological and survival outcomes associated with atezolizumab and bevacizumab treatment in the pre-LT setting. This immune-based combination was safe in terms of treatment-related adverse events, and absence of severe post-transplant rejection or graft loss. These preliminary results could pave the way for expanding transplant eligibility criteria in patients at more advanced HCC stages. Impact and Implications Studies on the combination of atezolizumab and bevacizumab in the neoadjuvant setting prior to liver transplantation for hepatocellular carcinoma have been limited, despite its potential to enhance anti-tumor responses and downstaging, owing to concerns about its safety profile. Among 17 patients who underwent successful liver transplantation following neoadjuvant atezolizumab/bevacizumab, 82% achieved downstaging to within Milan criteria, 94% radiological objective response and 88% pathology response, without drop-outs due to treatment-related adverse events or graft loss. The neoadjuvant combination of atezolizumab plus bevacizumab prior to liver transplantation for hepatocellular carcinoma shows an encouraging safety profile and stands out as a promising pre-transplant optimization treatment, leading to improved oncological outcomes.
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Affiliation(s)
- Parissa Tabrizian
- Mount Sinai Liver Cancer Program, RMTI and Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rebecca Marino
- Mount Sinai Liver Cancer Program, RMTI and Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sherrie Bhoori
- Division of HPB Surgery, Hepatology and Liver Transplantation, University of Milan and Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Marcus Zeitlhoefler
- Mount Sinai Liver Cancer Program, RMTI and Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Neil Mehta
- Division of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco CA, USA
| | - Vanessa Banz
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Salvatore Gruttadauria
- Department Abdominal Center UPMC (University of Pittsburgh Medical Center), Palermo, and Department of Surgery and Medical and Surgical Specialties, University of Catania, Italy
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, CRC "A. M. and A. Migliavacca" Centre for Liver Disease, University of Milan, Milan, Italy
| | | | - Nicolò Simonotti
- Division of HPB Surgery, Hepatology and Liver Transplantation, University of Milan and Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Francis Yao
- Division of Gastroenterology and Hepatology, University of California, San Francisco, San Francisco CA, USA
| | - Vincenzo Mazzaferro
- Division of HPB Surgery, Hepatology and Liver Transplantation, University of Milan and Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Josep M. Llovet
- Mount Sinai Liver Cancer Program, RMTI and Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
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5
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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. S3-Leitlinie Diagnostik und Therapie biliärer Karzinome – Langversion. 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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6
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Sangro B, Argemi J, Ronot M, Paradis V, Meyer T, Mazzaferro V, Jepsen P, Golfieri R, Galle P, Dawson L, Reig M. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J Hepatol 2025; 82:315-374. [PMID: 39690085 DOI: 10.1016/j.jhep.2024.08.028] [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: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 12/19/2024]
Abstract
Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90% of primary liver cancers. Advances in diagnostic and therapeutic tools, along with improved understanding of their application, are transforming patient treatment. Integrating these innovations into clinical practice presents challenges and necessitates guidance. These clinical practice guidelines offer updated advice for managing patients with HCC and provide a comprehensive review of pertinent data. Key updates from the 2018 EASL guidelines include personalised surveillance based on individual risk assessment and the use of new tools, standardisation of liver imaging procedures and diagnostic criteria, use of minimally invasive surgery in complex cases together with updates on the integrated role of liver transplantation, transitions between surgical, locoregional, and systemic therapies, the role of radiation therapies, and the use of combination immunotherapies at various stages of disease. Above all, there is an absolute need for a multiparametric assessment of individual risks and benefits, considering the patient's perspective, by a multidisciplinary team encompassing various specialties.
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7
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Bredin P, Galvin Z, O'Kane GM. Role of immunotherapy in managing cancers prior to liver transplantation. Curr Opin Organ Transplant 2025; 30:3-11. [PMID: 39620576 DOI: 10.1097/mot.0000000000001187] [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: 12/24/2024]
Abstract
PURPOSE OF REVIEW Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape in advanced hepatocellular carcinoma and increasingly are being evaluated in earlier stage disease. Herein we explore the role of ICIs pre-liver transplant for liver cancers. RECENT FINDINGS Given the high response rates with combination approaches including locoregional treatments, more patients with liver confined disease, without vascular invasion, who have received ICIs are now being rendered eligible for potential liver transplant. This opportunity to expand the population who may benefit from liver transplant has also come with challenges recognizing the global shortage of organs. Post-liver transplant immunosuppression potentially competes with the immune-stimulating effects of ICIs and graft rejection has been a concern. ICIs may provide an opportunity to maintain patients on the waiting list but an understanding of who is likely to benefit is needed, to circumvent possible toxicities. In addition, ICIs are now considered standard of care, in combination with chemotherapy, for advanced cholangiocarcinoma, where the role of liver transplant is evolving. SUMMARY As the eligibility criteria globally for liver transplant in the setting of malignancy continues to expand, the integration of ICIs becomes increasingly important.
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Affiliation(s)
| | - Zita Galvin
- St Vincent's University Hospital, Elm Park
- University College Dublin, Ireland
| | - Grainne M O'Kane
- St Vincent's University Hospital, Elm Park
- University College Dublin, Ireland
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8
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Tabrizian P, Pero A, Schwartz M. Hepatic Resection for Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:59-72. [PMID: 39608958 DOI: 10.1016/j.cld.2024.08.008] [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
Hepatic resection has long been considered the preferred treatment for hepatocellular carcinoma (HCC) when feasible, but its role, as well as the outcomes is evolving rapidly. This article explores the impact of the changing demographics of HCC, reviews current criteria for resection, considers the roles of liver transplantation and nonsurgical locoregional therapies vis-a-vis resection, highlights the potential of new systemic therapies (particularly immune checkpoint inhibitors) to improve outcomes, details the common complications associated with resection, and discusses recurrence of HCC after resection and its management.
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Affiliation(s)
- Parissa Tabrizian
- Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, NY 10029, USA
| | - Adriana Pero
- Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, NY 10029, USA
| | - Myron Schwartz
- Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, NY 10029, USA.
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9
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Cillo U, Gringeri E, D'Amico FE, Lanari J, Furlanetto A, Vitale A. Hepatocellular carcinoma: Revising the surgical approach in light of the concept of multiparametric therapeutic hierarchy. Dig Liver Dis 2025:S1590-8658(24)01123-X. [PMID: 39828438 DOI: 10.1016/j.dld.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/20/2024] [Accepted: 12/02/2024] [Indexed: 01/22/2025]
Abstract
The clinical management of hepatocellular carcinoma (HCC) is strongly influenced by several prognostic factors, mainly tumor stage, patient's health, liver function and specific characteristics of each intervention. The interplay between these factors should be carefully evaluated by a multidisciplinary tumor board. To support this, the novel "multiparametric therapeutic hierarchy" (MTH) concept has been recently proposed. This review will present the main features of available surgical treatments for HCC (liver transplantation, liver resection, ablation). Strengths and weaknesses are reported in the light of clinical decision making and of treatment allocation, with a special focus on the collocation of each treatment in the MTH framework and on how MTH may be useful in supporting clinical decision. Sequential treatments and their role to allow further surgical treatments will also be analyzed.
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Affiliation(s)
- Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.
| | - Enrico Gringeri
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Francesco Enrico D'Amico
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Jacopo Lanari
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Alessandro Furlanetto
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Alessandro Vitale
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
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10
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Suzuki H, Fujiwara N, Singal AG, Baumert TF, Chung RT, Kawaguchi T, Hoshida Y. Prevention of liver cancer in the era of next-generation antivirals and obesity epidemic. Hepatology 2025:01515467-990000000-01139. [PMID: 39808821 DOI: 10.1097/hep.0000000000001227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 10/07/2024] [Indexed: 01/16/2025]
Abstract
Preventive interventions are expected to substantially improve the prognosis of patients with primary liver cancer, predominantly HCC and cholangiocarcinoma. HCC prevention is challenging in the face of the evolving etiological landscape, particularly the sharp increase in obesity-associated metabolic disorders, including metabolic dysfunction-associated steatotic liver disease. Next-generation anti-HCV and HBV drugs have substantially reduced, but not eliminated, the risk of HCC and have given way to new challenges in identifying at-risk patients. The recent development of new therapeutic agents and modalities has opened unprecedented opportunities to refine primary, secondary, and tertiary HCC prevention strategies. For primary prevention (before exposure to risk factors), public health policies, such as universal HBV vaccination, have had a substantial prognostic impact. Secondary prevention (after or during active exposure to risk factors) includes regular HCC screening and chemoprevention. Emerging biomarkers and imaging modalities for HCC risk stratification and detection may enable individual risk-based personalized and cost-effective HCC screening. Clinical studies have suggested the potential utility of lipid-lowering, antidiabetic/obesity, and anti-inflammatory agents for secondary prevention, and some of them are being evaluated in prospective clinical trials. Computational and experimental studies have identified potential chemopreventive strategies directed at diverse molecular, cellular, and systemic targets for etiology-specific and/or agnostic interventions. Tertiary prevention (in conjunction with curative-intent therapies for HCC) is an area of active research with the development of new immune-based neoadjuvant/adjuvant therapies. Cholangiocarcinoma prevention may advance with recent efforts to elucidate risk factors. These advances will collectively lead to substantial improvements in liver cancer mortality rates.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan
| | - Naoto Fujiwara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Amit G Singal
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Thomas F Baumert
- Inserm, Institute for Translational Medicine and Liver Diseases, University of Strasbourg, France
- IHU Strasbourg, Strasbourg, France
- Gastroenterology and Hepatology Service, Strasbourg University Hospitals, Strasbourg, France
| | - Raymond T Chung
- Department of Medicine, GI Division, Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Takumi Kawaguchi
- Department of Medicine, Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan
| | - Yujin Hoshida
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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11
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Altaf A, Khalil M, Akabane M, Rashid Z, Kawashima J, Zindani S, Ruzzenente A, Ratti F, Marques H, Cauchy F, Lam V, Poultsides G, Aucejo F, Kitago M, Popescu I, Martel G, Gleisner A, Bauer TW, Hugh T, Bhimani N, Shen F, Endo I, Pawlik TM. Up-front resection for hepatocellular carcinoma: Assessing futility in the preoperative setting. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109594. [PMID: 39826445 DOI: 10.1016/j.ejso.2025.109594] [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: 12/03/2024] [Revised: 12/28/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025]
Abstract
OBJECTIVE We sought to develop a predictive model to preoperatively identify patients with hepatocellular carcinoma (HCC) at risk of undergoing futile upfront liver resection (LR). METHODS Patients undergoing curative-intent LR for HCC were identified from a large multi-institutional database. Futile LR was defined by death or disease recurrence within six months postoperatively. Backward logistic regression was performed to identify factors associated with futility. Additionally, binary criteria were established for surgical candidacy, aiming to keep the likelihood of futility below 20 %. RESULTS Among 1633 patients with HCC, 264 (16.2 %) underwent futile upfront LR. Tumor burden score (TBS) (coefficient: 0.083, 95%CI: 0.067-0.099), alpha-fetoprotein (AFP) (coefficient: 0.254, 95%CI: 0.195-0.310), and albumin-bilirubin (ALBI) grade 2/3 (coefficient: 0.566, 95%CI: 0.420-0.718) were independently associated with an increased risk of futile LR. The model demonstrated strong discrimination and calibration in both derivation and validation cohorts. Low, intermediate, and high-risk groups were determined based on the risk model, each with an escalating likelihood of futility, worse histological features, and worse survival outcomes. Six distinct conditions based on AFP-adjusted-to-TBS criteria were established, all with a futility likelihood of less than 20 %. Patients fulfilling these criteria had significantly better long-term recurrence-free and overall survival. The futility risk model was made available online for wide clinical applicability: (https://altaf-pawlik-hcc-futilityofsurgery-calculator.streamlit.app/). CONCLUSION A preoperative risk model and AFP-adjusted-to-TBS criteria were developed and validated to predict the likelihood of futile LR among patients with HCC. This pragmatic clinical tool may assist clinicians in preoperative decision-making, helping them avoid futile surgery unlikely to offer long-term benefits.
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Affiliation(s)
- Abdullah Altaf
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Mujtaba Khalil
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Miho Akabane
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Zayed Rashid
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Jun Kawashima
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Shahzaib Zindani
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | | | | | - Hugo Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - François Cauchy
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - George Poultsides
- Department of Surgery, Stanford University, Stanford, CA, United States
| | - Federico Aucejo
- Department of Surgery, Cleveland Clinic., Cleveland, OH, United States
| | - Minoru Kitago
- Department of Surgery, Keio University, Tokyo, Japan
| | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | - Ana Gleisner
- Department of Surgery, University of Colorado, Aurora, CO, United States
| | - Todd W Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Tom Hugh
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, NSW, Australia
| | - Nazim Bhimani
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, NSW, Australia
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Itaru Endo
- Department of Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States.
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12
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Rezaee-Zavareh MS, Yeo YH, Wang T, Guo Z, Tabrizian P, Ward SC, Barakat F, Hassanein TI, Dave S, Ajmera V, Bhoori S, Mazzaferro V, Chascsa DMH, Liu MC, Aby ES, Lake JR, Sogbe M, Sangro B, Abdelrahim M, Esmail A, Schmiderer A, Chouik Y, Rudolph M, Sohal D, Giudicelli H, Allaire M, Akce M, Guadagno J, Tow CY, Massoumi H, De Simone P, Kang E, Gartrell RD, Martinez M, Paz-Fumagalli R, Toskich BB, Tran NH, Solino GA, Poltronieri Pacheco DM, Kalman RS, Agopian VG, Mehta N, Parikh ND, Singal AG, Yang JD. Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis. J Hepatol 2025; 82:107-119. [PMID: 38996924 PMCID: PMC11655254 DOI: 10.1016/j.jhep.2024.06.042] [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: 04/22/2024] [Revised: 06/05/2024] [Accepted: 06/27/2024] [Indexed: 07/14/2024]
Abstract
BACKGROUND & AIMS Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. METHODS In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS Among 91 eligible patients, with a median (IQR) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years 0.72, 95% CI 0.53-0.99, p = 0.044) and ICI washout time (aHR per 1 week 0.92, 95% CI 0.86-0.99, p = 0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p = 0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8] vs. 8.0 [9.0]; p = 0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p = 0.032). CONCLUSION Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitor use prior to liver transplantation suggest acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without immune checkpoint inhibitor exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies.
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Affiliation(s)
| | - Yee Hui Yeo
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA
| | - Tielong Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Parissa Tabrizian
- Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, NY, USA
| | - Stephen C Ward
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fatma Barakat
- Southern California Liver Centers, 131 Orange Avenue, Suite 101, Coronado, CA, 92118, USA
| | - Tarek I Hassanein
- Southern California Liver Centers, 131 Orange Avenue, Suite 101, Coronado, CA, 92118, USA
| | - Shravan Dave
- Division of Gastroenterology & Hepatology, Department of Medicine, University of California, San Diego, La Jolla CA, USA
| | - Veeral Ajmera
- Division of Gastroenterology & Hepatology, Department of Medicine, University of California, San Diego, La Jolla CA, USA
| | - Sherrie Bhoori
- HPB Surgery, Hepatology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - Vincenzo Mazzaferro
- HPB Surgery, Hepatology and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Department of Oncology, and Hemato-Oncology University of Milan, Milan, Italy
| | - David M H Chascsa
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA; Transplant Center, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Margaret C Liu
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA
| | - Elizabeth S Aby
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA
| | - John R Lake
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA
| | - Miguel Sogbe
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA; Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Internal Medicine, Weill Cornell Medical College, New York, NY 10021, USA
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA; Cancer Clinical Trials, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Andreas Schmiderer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Yasmina Chouik
- Cancer Research Center of Lyon (CRCL), INSERM U1052, Centre National de la Recherche Scientifique UMR5286, Lyon, France; Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Mark Rudolph
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Davendra Sohal
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Heloise Giudicelli
- AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France
| | - Manon Allaire
- AP-HP Sorbonne Université, Hôpital Universitaire Pitié-Salpêtrière, Service d'Hépato-gastroentérologie, Paris, France; INSERM UMR 1138, Centre de recherche des Cordeliers, 75006 Paris, France
| | - Mehmet Akce
- Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA
| | - Jessica Guadagno
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Clara Y Tow
- Division of Hepatology, Montefiore Medical Center, Bronx, New York; Albert Einstein College of Medicine, Bronx, NY, USA
| | - Hatef Massoumi
- Division of Hepatology, Northwell 261 East 78th Street, Floor 4, New York, NY 10075, USA
| | - Paolo De Simone
- Hepatobiliary Surgery and liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, Pisa, 56124, Italy
| | - Elise Kang
- Department of Pediatrics, Division of Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, New York, USA
| | - Robyn D Gartrell
- Department of Pediatrics, Division of Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, New York, USA; Department of Oncology, Division of Pediatric Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Mercedes Martinez
- Department of Pediatrics. Vagelos College of Physician and Surgeons. Columbia University, USA
| | | | - Beau B Toskich
- Division of Interventional Radiology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Nguyen H Tran
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Gabriela Azevedo Solino
- Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória - Department of Internal Medicine - Vitória/ES - Brazil
| | - Dra Mariana Poltronieri Pacheco
- Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória - Department of Gastroenterology and Hepatology - Vitória/ES - Brazil
| | - Richard S Kalman
- Division of Hepatology, Department of Medicine, Einstein Healthcare Network, Philadelphia, Pennsylvania, USA
| | - Vatche G Agopian
- The Dumont-University of California, Los Angeles, Transplant Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Neil Mehta
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, USA
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA; Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA.
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13
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Mattiuz R, Boumelha J, Hamon P, Le Berichel J, Vaidya A, Soong BY, Halasz L, Radkevich E, Kim HM, Park MD, Donne R, Troncoso L, D’Souza D, Kaiza ME, MacFawn IP, Belabed M, Mestrallet G, Humblin E, Merand R, Hennequin C, Ioannou G, Ozbey S, Figueiredo I, Hegde S, Tepper A, Merarda H, Nemeth E, Goldstein S, Reid AM, Noureddine M, Tabachnikova A, Ahmed J, Polydorides AD, Bhardwaj N, Lujambio A, Chen Z, Kozlova EG, Kim-Schulze S, Brody JD, Schotsaert M, Moussion C, Gnjatic S, Sautès-Fridman C, Fridman WH, Roudko V, Brown BD, Marron TU, Cyster JG, Salmon H, Bruno TC, Joshi NS, Kamphorst AO, Merad M. Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoid structures in cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.27.628014. [PMID: 39763802 PMCID: PMC11703156 DOI: 10.1101/2024.12.27.628014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Using spatial transcriptomics and multiplex imaging across various human tumors, we found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting us to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, we developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (TFH) and TCF1+PD-1+ progenitor exhausted CD8+ T cells (Tpex). Here we show that, during the early stages of tumor development, TLS formation relies on IFNγ-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4+ and CD8+ T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the TFH cell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer.
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Affiliation(s)
- Raphaël Mattiuz
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jesse Boumelha
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Contributed equally
| | - Pauline Hamon
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Contributed equally
| | - Jessica Le Berichel
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Contributed equally
| | - Abishek Vaidya
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Graduate School of Biomedical Sciences, Icahn school of Medicine at Mount Sinai, New York, NY, USA
| | - Brian Y. Soong
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Laszlo Halasz
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Emir Radkevich
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hye Mi Kim
- Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Matthew D. Park
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Romain Donne
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai
- Tisch Cancer Institute, New York, New York, USA
| | - Leanna Troncoso
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Darwin D’Souza
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Medard Ernest Kaiza
- Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ian P. MacFawn
- Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Meriem Belabed
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Guillaume Mestrallet
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, New York, New York, USA
- Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Etienne Humblin
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Raphaël Merand
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Clotilde Hennequin
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Giorgio Ioannou
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sinem Ozbey
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Igor Figueiredo
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Samarth Hegde
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexander Tepper
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hajer Merarda
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Erika Nemeth
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Simon Goldstein
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amanda M. Reid
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Moataz Noureddine
- Graduate School of Biomedical Sciences, Icahn school of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute and Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexandra Tabachnikova
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jalal Ahmed
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexandros D. Polydorides
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, and Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nina Bhardwaj
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, New York, New York, USA
- Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amaia Lujambio
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai
- Tisch Cancer Institute, New York, New York, USA
| | - Zhihong Chen
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Edgar Gonzalez Kozlova
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Seunghee Kim-Schulze
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joshua D. Brody
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael Schotsaert
- Global Health and Emerging Pathogens Institute and Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Sacha Gnjatic
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Catherine Sautès-Fridman
- Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Universite, INSERM, Université Paris Cité, 75006, Paris, France
| | - Wolf Herman Fridman
- Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Universite, INSERM, Université Paris Cité, 75006, Paris, France
| | - Vladimir Roudko
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brian D. Brown
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Thomas U. Marron
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Institute for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jason G. Cyster
- Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA
| | | | - Tullia C. Bruno
- Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nikhil S. Joshi
- Yale University School of Medicine, Department of Immunobiology, New Haven, CT, USA
| | - Alice O. Kamphorst
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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14
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Arafat Hossain M. A comprehensive review of immune checkpoint inhibitors for cancer treatment. Int Immunopharmacol 2024; 143:113365. [PMID: 39447408 DOI: 10.1016/j.intimp.2024.113365] [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: 08/25/2024] [Revised: 09/28/2024] [Accepted: 10/05/2024] [Indexed: 10/26/2024]
Abstract
Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.
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Affiliation(s)
- Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh.
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15
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Matar AJ, Oppat KM, Bennett FJ, Warren EAK, Wehrle CJ, Li Z, Rajendran L, Rokop ZP, Kubal C, Biesterveld BE, Foley DP, Maeda M, Nguyen MH, Elinoff B, Humar A, Moris D, Sudan D, Klein J, Emamaullee J, Agopian V, Vagefi PA, Dualeh SHA, Sonnenday CJ, Sapisochin G, Aucejo FN, Maithel SK. Hepatic Resection as the Primary Treatment Method for Hepatocellular Carcinoma After Orthotopic Liver Transplantation. Ann Surg Oncol 2024; 31:9159-9167. [PMID: 39172301 DOI: 10.1245/s10434-024-16085-z] [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: 04/29/2024] [Accepted: 08/08/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND Liver transplantation (LT) is the treatment of choice for end-stage liver disease and certain malignancies such as hepatocellular carcinoma (HCC). Data on the surgical management of de novo or recurrent tumors that develop in the transplanted allograft are limited. This study aimed to investigate the perioperative and long-term outcomes for patients undergoing hepatic resection for de novo or recurrent tumors after liver transplantation. METHODS The study enrolled adult and pediatric patients from 12 centers across North America who underwent hepatic resection for the treatment of a solid tumor after LT. Perioperative outcomes were assessed as well as recurrence free survival (RFS) and overall survival (OS) for those undergoing resection for HCC. RESULTS Between 2003 and 2023, 54 patients underwent hepatic resection of solid tumors after LT. For 50 patients (92.6 %), resection of malignant lesions was performed. The most common lesion was HCC (n = 35, 64.8 %), followed by cholangiocarcinoma (n = 6, 11.1 %) and colorectal liver metastases (n = 6, 11.1 %). The majority of the 35 patients underwent resection of HCC did not receive any preoperative therapy (82.9 %) or adjuvant therapy (71.4 %), with resection their only treatment method for HCC. During a median follow-up period of 50.7 months, the median RFS was 21.5 months, and the median OS was 49.6 months. CONCLUSION Hepatic resection following OLT is safe and associated with morbidity and mortality rates that are comparable to those reported for patients undergoing resection in native livers. Hepatic resection as the primary and often only treatment modality for HCC following LT is associated with acceptable RFS and OS and should be considered in well selected patients.
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Affiliation(s)
| | | | | | | | | | - Zhihao Li
- Ajmera Transplant Center and HPB Surgical Oncology, University Health Network, Toronto, ON, Canada
| | - Luckshi Rajendran
- Ajmera Transplant Center and HPB Surgical Oncology, University Health Network, Toronto, ON, Canada
| | | | | | - Ben E Biesterveld
- University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - David P Foley
- University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Mayumi Maeda
- Stanford University Medical Center, Palo Alto, CA, USA
| | | | - Beth Elinoff
- University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Abhinav Humar
- University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | - Debra Sudan
- Duke University School of Medicine, Durham, NC, USA
| | - John Klein
- University of Southern California, Los Angeles, CA, USA
| | | | - Vatche Agopian
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | | | | | | | - Gonzalo Sapisochin
- Ajmera Transplant Center and HPB Surgical Oncology, University Health Network, Toronto, ON, Canada
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16
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Kudo M. Challenges in Adjuvant Immunotherapy after Resection or Ablation for Hepatocellular Carcinoma at High-Risk of Recurrence. Liver Cancer 2024; 13:573-578. [PMID: 39687037 PMCID: PMC11649295 DOI: 10.1159/000542221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/22/2024] [Indexed: 12/18/2024] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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17
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Eleonora A, Lynch EN, Natola LA, Massimo I. Pioneering applications of immunotherapy in the early stages of hepatocellular carcinoma. Dig Liver Dis 2024; 56:2011-2021. [PMID: 38910073 DOI: 10.1016/j.dld.2024.05.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 02/20/2024] [Accepted: 05/28/2024] [Indexed: 06/25/2024]
Affiliation(s)
- Alimenti Eleonora
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Erica Nicola Lynch
- Department of Medical Biotechnologies, University of Siena, Siena, 53100, Italy; Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, 50134, Italy
| | - Leonardo Antonio Natola
- Internal Medicine Section C and Liver Unit, Department of Medicine, University of Verona, Verona, Italy
| | - Iavarone Massimo
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; Department of Pathophysiology and Transplantation, CRC "A. M. and A. Migliavacca" Centre for Liver Disease, University of Milan, Milan, Italy.
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18
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Teng W, Wu TC, Lin SM. Hepatocellular carcinoma systemic treatment 2024 update: from early to advanced stage. Biomed J 2024:100815. [PMID: 39561966 DOI: 10.1016/j.bj.2024.100815] [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: 06/16/2024] [Revised: 10/14/2024] [Accepted: 11/13/2024] [Indexed: 11/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) ranks the sixth most common malignancy but the third leading cause of cancer-related mortality in the world. Significant breakthroughs have been made in systemic treatment for HCC over the past two decades, which have improved treatment outcomes. In addition to multiple tyrosine kinase inhibitors (mTKIs), immune checkpoint inhibitors (ICIs) and antiangiogenic drugs are increasingly being applied. The combination of ICI and antiangiogenic or dual ICIs has become the new standard of care due to remarkable response rates. However, currently available systemic regimens are primarily reserved for certain patients in the intermediate and advanced stages who will not benefit from locoregional treatments. Evidence supporting the use of systemic treatment as neoadjuvant or adjuvant therapies in patients with early-stage HCC, especially the high risk of recurrence after curative treatments, remains limited. This review identified recent developments in systemic therapy, including mTKIs and ICIs, considering results on first- and second-line treatment, role of neoadjuvant and adjuvant settings, and combination with loco-regional therapy. Various ongoing clinical trials regarding the role of systemic therapies and potential novel targets in patients with early-, intermediate-, and advanced-stage HCC were also summarized and revealed that systemic therapy is no longer limited to advanced-stage HCC. Moreover, the introduction of T-cell redirecting strategies, including bispecific antibodies and chimeric antigen receptor T cells, has revolutionized the treatment landscape for HCC. Future research should focus on an in-depth exploration of the mechanisms governing the establishment of tumor barriers.
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Affiliation(s)
- Wei Teng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
| | - Tai-Chi Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
| | - Shi-Ming Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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19
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Mauro E, Rodríguez-Perálvarez M, D'Alessio A, Crespo G, Piñero F, De Martin E, Colmenero J, Pinato DJ, Forner A. New Scenarios in Liver Transplantation for Hepatocellular Carcinoma. Liver Int 2024. [PMID: 39494583 DOI: 10.1111/liv.16142] [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: 06/23/2024] [Revised: 10/03/2024] [Accepted: 10/09/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND AND AIMS Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS. METHODS AND RESULTS In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.
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Affiliation(s)
- Ezequiel Mauro
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, CIBERehd, Córdoba, Spain
| | - Antonio D'Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Gonzalo Crespo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Federico Piñero
- School of Medicine, Hospital Universitario Austral, Austral University, Buenos Aires, Argentina
| | - Eleonora De Martin
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, Université Paris-Saclay, FHU Hepatinov, Villejuif, France
| | - Jordi Colmenero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Transplant Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alejandro Forner
- Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, ICMDM, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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20
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D'Alessio A, Stefanini B, Blanter J, Adegbite B, Crowley F, Yip V, Slater S, Fulgenzi CAM, Celsa C, Manfredi GF, Pai M, Goldin RD, Ward SC, Fiel MI, Shu DH, Su YY, Cortellini A, Baretti M, Anders R, Yarchoan M, Hsu C, Marron TU, Pinato DJ. Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis. Lancet Oncol 2024; 25:1465-1475. [PMID: 39437804 DOI: 10.1016/s1470-2045(24)00457-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/01/2024] [Accepted: 08/15/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND Neoadjuvant use of immune checkpoint inhibitors (ICIs) before liver resection results in pathological tumour regression in patients with hepatocellular carcinoma. We aimed to describe the characteristics of pathological responses after preoperative ICI therapy for hepatocellular carcinoma and to evaluate the association between the depth of tumour regression and relapse-free survival. METHODS In this cross-trial, patient-level analysis, we performed a pooled analysis of data from patients with hepatocellular carcinoma receiving ICI therapy before liver resection as part of a global collaborative consortium (NeoHCC) of five phase 1 and 2 clinical trials and standardised observational protocols conducted in 12 tertiary referral centres across the USA, UK, and Taiwan. Eligible patients were adults (aged ≥18 years) diagnosed with hepatocellular carcinoma by tissue core biopsy before treatment initiation, a Liver Imaging Reporting and Data System score of 5 on imaging, or both, with an Eastern Cooperative Oncology Group performance status score of 0-1, and no extrahepatic spread or previous ICI treatment. Pathological response was measured as the percentage of non-viable tumour in the resected surgical specimen, with major pathological response corresponding to at least 70% tumour regression and pathological complete response corresponding to 100% tumour regression. We correlated pathological response with radiological overall response using RECIST criteria (version 1.1) and relapse-free survival, and evaluated the threshold of tumour regression that could be optimally associated with relapse-free survival. FINDINGS At data cutoff on Jan 31, 2024, 111 patients were included in the study, of whom data on pathological response were available for 104 (94%) patients. Patients received treatment from Oct 5, 2017, to Nov 15, 2023, mostly ICI combinations (76 [69%]), for a median of 1·4 months (IQR 0·7-2·9). 87 (78%) patients were men and 24 (22%) were women. Most patients had underlying viral chronic liver disease (73 [66%]) and Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma (61 [55%]), without portal vein thrombosis (87 [78%]). We observed major pathological response in 33 (32%) patients and pathological complete response in 19 (18%) patients. Radiological overall response was associated with major pathological response, with 23 (74%) of 31 patients with radiological response showing major pathological response compared with ten (14%) of 73 patients without radiological response (p<0·0001). However, ten (30%) of 33 major pathological responses were not predicted by radiological response. After a median follow-up of 27·2 months (95% CI 22·3-32·1), median relapse-free survival for the whole cohort was 43·6 months (95% CI 28·3-not evaluable). Relapse-free survival was significantly longer in patients with major pathological response than in those who did not have a major pathological response (not reached [95% CI not evaluable-not evaluable] vs 28·3 months [12·8-43·8]; hazard ratio 0·26 [0·10-0·66]; p=0·0024) and in patients with pathological complete response than in those who did not have a pathological complete response (NR [95% CI not evaluable-not evaluable] vs 32·8 months [15·0-50·5]; 0·19 [0·05-0·78]; p=0·010). Unbiased recursive partitioning of the cohort for the risk of relapse, death, or both identified a threshold of 90% as the optimal cutoff of pathological tumour regression to predict improved relapse-free survival. INTERPRETATION The extent of tumour regression following neoadjuvant ICI therapy could identify patients with improved relapse-free survival following liver resection. The threshold of at least 90% tumour regression should be validated for its surrogate role for relapse-free survival in phase 3 randomised controlled trials. FUNDING None.
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Affiliation(s)
- Antonio D'Alessio
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Bernardo Stefanini
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Julia Blanter
- Department of Medicine, Division of Hematology-Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
| | - Benjamin Adegbite
- Department of Medicine, Division of Hematology-Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
| | - Fionnuala Crowley
- Department of Medicine, Division of Hematology-Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
| | - Vincent Yip
- Barts and The London HPB Centre, Barts Health NHS Trust, London, UK
| | - Sarah Slater
- Department of Medical Oncology, Barts Health NHS Trust, London, UK
| | | | - Ciro Celsa
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK; Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, University of Palermo, Palermo, Italy
| | - Giulia Francesca Manfredi
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK; Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Novara, Italy
| | - Madhava Pai
- Division of Surgery, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Robert D Goldin
- Department of Digestive Diseases, Imperial College London, St Mary's Hospital, London, UK
| | - Stephen C Ward
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maria Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel H Shu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yung-Yeh Su
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Alessio Cortellini
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK; Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, and Department of Medicine and Surgery, Universitá Campus Bio-Medico di Roma, Rome, Italy
| | - Marina Baretti
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert Anders
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chiun Hsu
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Thomas U Marron
- Department of Medicine, Division of Hematology-Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA
| | - David J Pinato
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK; Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
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21
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Wang Y, Gao B, Jiao T, Zhang W, Shi H, Jiang H, Li X, Li J, Ge X, Pan K, Li C, Mao G, Lu S. CCL5/CCR5/CYP1A1 pathway prompts liver cancer cells to survive in the combination of targeted and immunological therapies. Cancer Sci 2024; 115:3552-3569. [PMID: 39183447 PMCID: PMC11531955 DOI: 10.1111/cas.16320] [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: 03/19/2024] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 08/27/2024] Open
Abstract
Combination therapy of anti-programmed cell death protein-1 (PD-1) antibodies and tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis for hepatocellular carcinoma (HCC), but many patients still have unsatisfactory outcomes. CD8 T cells are known to exert a pivotal function in the immune response against tumors. Nevertheless, most CD8 T cells in HCC tissues are in a state of exhaustion, losing the cytotoxic activity against malignant cells. Cytokines, mainly secreted by immune cells, play an important role in the occurrence and development of tumors. Here, we demonstrated the changes in exhausted CD8T cells during combination therapy by single-cell RNA sequencing (scRNA-seq) analysis on tumor samples before and after treatment. Combination therapy exerted a substantial impact on the exhausted CD8T cells, particularly in terms of cytokine expression. CCL5 was the most abundantly expressed cytokine in CD8T cells and exhausted CD8T cells, and its expression increased further after treatment. Subsequently, we discovered the CCL5/CCR5/CYP1A1 pathway through RNA sequencing (RNA-seq) on CCL5-stimulated Huh7 cells and verified through a series of experiments that this pathway can mediate the resistance of liver cancer cells to lenvatinib. Tissue experiments showed that after combination therapy, the CCL5/CCR5/CYP1A1 pathway was activated, which can benefit the residual tumor cells to survive treatment. Tumor-bearing mouse experiments demonstrated that bergamottin (BGM), a competitive inhibitor of CYP1A1, can enhance the efficacy of both lenvatinib and combination therapy. Our research revealed one mechanism by which hepatoma cells can survive the combination therapy, providing a theoretical basis for the refined treatment of HCC.
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Affiliation(s)
- Yafei Wang
- Nankai University School of Medicine, Nankai UniversityTianjinChina
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Biao Gao
- Nankai University School of Medicine, Nankai UniversityTianjinChina
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Tianyu Jiao
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Wenwen Zhang
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Huizhong Shi
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Hao Jiang
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Xuerui Li
- Nankai University School of Medicine, Nankai UniversityTianjinChina
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Junfeng Li
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Xinlan Ge
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Ke Pan
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Chonghui Li
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Guankun Mao
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
| | - Shichun Lu
- Nankai University School of Medicine, Nankai UniversityTianjinChina
- Faculty of Hepato‐Pancreato‐Biliary SurgeryChinese PLA General HospitalBeijingChina
- Institute of Hepatobiliary Surgery of Chinese PLABeijingChina
- Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLABeijingChina
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22
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Tabrizian P, Marino R, Chow PK. Liver resection and transplantation in the era of checkpoint inhibitors. JHEP Rep 2024; 6:101181. [PMID: 39741696 PMCID: PMC11686060 DOI: 10.1016/j.jhepr.2024.101181] [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: 03/21/2024] [Revised: 06/24/2024] [Accepted: 07/26/2024] [Indexed: 01/03/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionised the treatment landscape for advanced hepatocellular carcinoma (HCC). The combination of atezolizumab and bevacizumab has demonstrated efficacy, establishing a new standard of care for advanced HCC. Neoadjuvant studies have shown promising results with high response rates, increasing research into ICIs' role. In the peri-operative setting, in addition to adjuvant and neo-adjuvant therapies, strategies for "downstaging" and "bridging" patients to liver transplantation (LT) are being investigated, broadening the eligible candidate pool. Furthermore, therapeutic advances have reshaped conversion strategies for hepatic resection, with emerging evidence indicating a role for adjuvant immunotherapy in patients at high risk of postoperative recurrence. In LT, concerns have arisen over the potential conflict between immunosuppression needs and the immune-enhancing effects of ICIs, with reports of severe rejection. However, liver-specific factors may lessen rejection risks, prompting exploration into the safety of pre-transplant ICI administration. Moreover, ongoing trials must prioritise patient selection and vigilant management protocols. Despite the remarkable progress in immunotherapy, the intricate molecular interactions within the tumour microenvironment and their implications on oncogenic pathways remain incompletely understood. This highlights the need for specialised expertise to effectively integrate immunotherapy into the surgical management of HCC. Key challenges include ensuring safety, optimising oncological outcomes, managing the risk of graft rejection in transplant recipients, and refining patient selection criteria. In this review, we aim to provide a comprehensive overview of the evolving role of immunotherapy in the surgical management of HCC, discussing the rationale for its application in both pre- and post-surgical contexts, leveraging current clinical experience, identifying potential limitations, and envisioning future applications. By integrating existing knowledge and highlighting areas for further investigation, this review seeks to inform clinical practice and guide future research endeavours.
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Affiliation(s)
- Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, USA
| | - Rebecca Marino
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, USA
| | - Pierce K.H. Chow
- Department of Hepato-pancreato-Biliary and Transplant Surgery, National Cancer Center Singapore and Singapore General Hospital, Singapore
- Surgery Academic-Clinical Program, Duke-NUS Medical School Singapore, Singapore
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23
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Marzi L, Mega A, Turri C, Gitto S, Ferro F, Spizzo G. Immune Checkpoint Inhibitors in the Pre-Transplant Hepatocellular Carcinoma Setting: A Glimpse Beyond the Liver. Int J Mol Sci 2024; 25:11676. [PMID: 39519230 PMCID: PMC11547112 DOI: 10.3390/ijms252111676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/26/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death worldwide. Liver transplantation (LT) is the best therapy for most patients with non-metastatic HCC. In recent years, the management of patients with HCC has considerably changed, thanks to the improvement of molecular biology knowledge and the introduction of immunotherapy. To date, systemic therapy is authorized in the Western world only in patients with advanced HCC. However, this therapy could not only stabilize the tumour disease or improve survival but could display excellent response and lead to downstaging of the tumour that finally permits LT. There are increasing reports of patients that have performed LT after pretreatment with immune checkpoint inhibitors (ICIs). However, due to the intrinsic mechanism of ICIs, graft rejection might be favoured. In addition, chronic adverse effects affecting other organs may also appear after the end of therapy. This review aims to evaluate the readiness and outcomes of LT in patients with advanced HCC who have previously undergone treatment with ICIs. It seeks to identify the challenges, risks, and benefits associated with this conversion therapy. The integration of ICIs into the treatment paradigm for advanced HCC necessitates a nuanced approach to LT. While early evidence supports the feasibility of LT following ICIs therapy, there is an urgent need for standardized guidelines and more extensive longitudinal studies to optimize patient selection, timing, and post-transplant management.
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Affiliation(s)
- Luca Marzi
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Andrea Mega
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Chiara Turri
- Department of Gastroenterology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy; (A.M.); (C.T.)
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy;
| | - Federica Ferro
- Department of Radiology, Bolzano Regional Hospital (SABES-ASDAA), 39100 Bolzano-Bozen, Italy;
| | - Gilbert Spizzo
- Department of Internal Medicine, Oncologic Day Hospital, Hospital of Bressanone (SABES-ASDAA), 39042 Bressanone-Brixen, Italy;
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24
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Pan H, Zhou L, Cheng Z, Zhang J, Shen N, Ma H, Li Y, Jin R, Zhou W, Wu D, Sun W, Wang R. Perioperative Tislelizumab plus intensity modulated radiotherapy in resectable hepatocellular carcinoma with macrovascular invasion: a phase II trial. Nat Commun 2024; 15:9350. [PMID: 39472470 PMCID: PMC11522700 DOI: 10.1038/s41467-024-53704-5] [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: 01/08/2024] [Accepted: 10/21/2024] [Indexed: 11/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) have dismal prognosis and there are no standard perioperative therapies. This phase 2 trial (ChiCTR2000036385) aimed to investigate the activity and safety of perioperative tislelizumab plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Thirty treatment-naïve patients with MVI received 3 cycles of tislelizumab intravenously (200 mg, every three weeks) and concurrent IMRT (45 Gray in 15 fractions). Primary endpoints were the overall response rate (ORR) and overall survival (OS). Secondary endpoints were the proportion of patients with a complete or major pathological response (pCR or MPR), recurrence-free survival (RFS) and safety. Of patients enrolled, 15 (50%) underwent curative surgery followed by adjuvant tislelizumab. The ORR was 30.0% (90% CI 16.6%-46.5%) and the median OS was 18.7 months. Of the 15 patients underwent surgical resection, 10 (66.7%) achieved pCR or MPR and 8 (53.3%) remained recurrence-free. The median RFS were not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. 4 (13.3%) patients experienced grade 3 treatment-related adverse events. The most common events were thrombocytopenia, leukopenia, and anemia. The trial has met the pre-specified endpoints, and these results support further studies of perioperative immunotherapy plus radiotherapy in HCC.
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Affiliation(s)
- Hongyu Pan
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Liuyu Zhou
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- University of Shanghai for Science and Technology, Shanghai, China
| | - Zhuo Cheng
- Department of Oncology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jin Zhang
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ningjia Shen
- The Second Department of Biliary, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hongbin Ma
- Department of Radiation Oncology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Yao Li
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Riming Jin
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Weiping Zhou
- The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Dong Wu
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wen Sun
- National Center for Liver Cancer, Naval Medical University, Shanghai, China.
| | - Ruoyu Wang
- The First Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
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25
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Xu AX, Zhao ZF, Zhu L, Zhang YH, Li Y, Wei YF, Zhang BY, Jiang B, Gao TZ, Li MS, Liu JY. Promise and challenges of traditional Chinese medicine, specifically Calculus bovis, in liver cancer treatment. World J Gastroenterol 2024; 30:4380-4385. [PMID: 39494098 PMCID: PMC11525868 DOI: 10.3748/wjg.v30.i40.4380] [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: 07/17/2024] [Revised: 09/16/2024] [Accepted: 09/26/2024] [Indexed: 10/16/2024] Open
Abstract
Liver cancer, one of the most common malignancies worldwide, ranks sixth in incidence and third in mortality. Liver cancer treatment options are diverse, including surgical resection, liver transplantation, percutaneous ablation, transarterial chemoembolization, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and traditional Chinese medicine (TCM). A multidisciplinary team (MDT) is essential to customize treatment plans based on tumor staging, liver function, and performance status (PS), ensuring individualized patient care. Treatment decisions require a MDT to tailor strategies based on tumor staging, liver function, and PS, ensuring personalized care. The approval of new first-line and second-line drugs and the establishment of standard treatments based on immune checkpoint inhibitors have significantly expanded treatment options for advanced liver cancer, improving overall prognosis. However, many patients do not respond effectively to these treatments and ultimately succumb to the disease. Modern oncology treatments, while extending patient survival, often come with severe side effects, resistance, and damage to the body, negatively impacting quality of life. Huang et al's study published at World Journal of Gastroenterology rigorously validates the anticancer properties of Calculus bovis, enhancing our understanding of TCM and contributing to new liver cancer treatment strategies. For over 5000 years, TCM has been used in East Asian countries like China to treat various diseases, including liver conditions. Analysis of real-world clinical data suggests that for patients with advanced-stage tumors lacking effective treatments, integrated TCM therapies could provide significant breakthroughs.
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Affiliation(s)
- Ao-Xi Xu
- School of Medicine, Nankai University, Tianjin 300071, China
- Department of General Surgery, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100853, China
- Medical School of Chinese People's Liberation Army, Medical School of Chinese People's Liberation Army, Beijing 100853, China
| | - Zhi-Feng Zhao
- Medical School of Chinese People's Liberation Army, Medical School of Chinese People's Liberation Army, Beijing 100853, China
- Department of Hepatobiliary and Pancreative Surgery, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Li Zhu
- Department of General Surgery, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Yi-Heng Zhang
- Department of General Surgery, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100853, China
- Medical School of Chinese People's Liberation Army, Medical School of Chinese People's Liberation Army, Beijing 100853, China
| | - Yan Li
- Department of General Surgery, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100853, China
| | - Yu-Fan Wei
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Bo-Ya Zhang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Bin Jiang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Tian-Ze Gao
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Meng-Si Li
- Department of Surgery, Mancheng District People's Hospital, Baoding 072150, Hebei Province, China
| | - Jia-Yu Liu
- Department of Neurosurgery, First Medical Centre of Chinese People's Liberation Army General Hospital, Beijing 100853, China
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Stocker D, Hectors S, Marinelli B, Carbonell G, Bane O, Hulkower M, Kennedy P, Ma W, Lewis S, Kim E, Wang P, Taouli B. Prediction of hepatocellular carcinoma response to radiation segmentectomy using an MRI-based machine learning approach. Abdom Radiol (NY) 2024:10.1007/s00261-024-04606-z. [PMID: 39460801 DOI: 10.1007/s00261-024-04606-z] [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: 05/16/2024] [Revised: 09/04/2024] [Accepted: 09/17/2024] [Indexed: 10/28/2024]
Abstract
PURPOSE To evaluate the value of pre-treatment MRI-based radiomics in patients with hepatocellular carcinoma (HCC) for the prediction of response to Yttrium 90 radiation segmentectomy. METHODS This retrospective study included 154 patients (38 female; mean age 66.8 years) who underwent contrast-enhanced MRI prior to radiation segmentectomy. Radiomics features were manually extracted on volumes of interest on post-contrast T1-weighted images at the portal venous phase (PVP). Tumor-based response assessment was evaluated 6 months post-treatment using mRECIST. A logistic regression model was used to predict binary response outcome [complete response at 6 months with no-re-treatment (response group) against the rest (non-response group, including partial response, progressive disease, stable disease and complete response after re-treatment within 6 months after radiation segmentectomy) using baseline clinical parameters and radiomics features. We accessed the value of different sets of predictors using cross-validation technique. AUCs were compared using DeLong tests. RESULTS A total 168 HCCs (mean size 2.9 ± 1.7 cm) were analyzed in 154 patients. The response group consisted of 113 HCCs and the non-response group of 55 HCCs. Baseline clinical parameters (AUC 0.531; sensitivity, 0.781; specificity, 0.279; positive predictive value (PPV), 0.345; negative predictive value (NPV), 0.724) and AFP (AUC 0.632; sensitivity, 0.833; specificity, 0.466; PPV, 0.432; NPV, 0.851) showed poor performance for response prediction. The model using a combination of radiomics features and clinical parameters/AFP showed the best performance (AUC 0.736; sensitivity, 0.706; specificity, 0.662; PPV 0.504; NPV, 0.822), significantly better than the clinical model (p < 0.001) or AFP alone (p < 0.001). CONCLUSION The combination of radiomics features from pre-treatment MRI with clinical parameters and AFP showed fair performance for predicting HCC response to radiation segmentectomy, better than that of AFP. These results need further validation.
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Affiliation(s)
- Daniel Stocker
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.
| | - Stefanie Hectors
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brett Marinelli
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Interventional Radiology, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Guillermo Carbonell
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Radiology, University Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Octavia Bane
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Hulkower
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Paul Kennedy
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Weiping Ma
- Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sara Lewis
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Edward Kim
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Pei Wang
- Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bachir Taouli
- BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Diagnostic, Molecular and Interventional Radiology, 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
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LaPelusa M, Chamseddine S, Tran Cao HS, Xiao L, Hasanov E, Bhosale P, Amin HM, Mohamed YI, Gok Yavuz B, Sakr Y, Xu L, Hu I, Lee SS, Sakamuri D, Jindal S, Nguyen V, Curran MA, Sun R, Rashid A, Duda DG, Sharma P, Qayyum A, Kaseb AO. Tissue and Imaging Biomarkers of Response to Neoadjuvant Nivolumab or Nivolumab plus Ipilimumab in Patients with Resectable Hepatocellular Carcinoma. Oncology 2024:1-8. [PMID: 39427654 DOI: 10.1159/000541250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/13/2024] [Indexed: 10/22/2024]
Abstract
INTRODUCTION Perioperative immunotherapy has shown promise in some patients with early-stage hepatocellular carcinoma (HCC). This study examined tissue and imaging biomarkers associated with pathologic response in a phase II clinical trial in patients with resectable HCC. METHODS Analysis included 18 patients with biopsy-proven resectable HCC treated with neoadjuvant nivolumab plus ipilimumab or nivolumab alone in a phase II clinical trial at MD Anderson Cancer Center (NCT03222076). Liver MRE (to measure tissue fibrosis) and biopsies (to evaluate immune activation markers) were obtained serially pretreatment and after completing neoadjuvant immunotherapy. A major pathologic response (MPR) was defined as tumor necrosis of more than 70%. Data comparing patients with MPR versus those without were summarized using descriptive statistics and compared using the Wilcoxon rank-sum test. RESULTS Patients with MPR after neoadjuvant immunotherapy tended to have larger tumors (mean 9.52 vs. 4.99 centimeters; p = 0.050). They had a significant reduction in tumor size posttreatment (14.67% reduction vs. 9.15% increase in size; p = 0.042) and a nonsignificant decrease in serum AFP (-24.20% vs. -14.00%; p = 0.085). Further, patients with MPR had a greater increase in intratumoral expression levels of CD8 (26.92% vs. -0.04%; p = 0.026), granzyme B (15.56% vs. -2.24%; p = 0.011), and PD-1 (20.17% vs. 0.40%; p = 0.048) but not PD-L1 (7.69% vs. 0.57%; p = 0.26). For imaging biomarkers, tumor and liver fibrosis were comparable before and after neoadjuvant therapy in patients with MPR versus nonresponders. CONCLUSION Changes in tumor size, immune cell infiltration, and immune cell activation are candidate predictive markers of pathologic response to neoadjuvant immunotherapy in patients with resectable HCC.
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Affiliation(s)
- Michael LaPelusa
- Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA,
| | - Shadi Chamseddine
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hop Sanderson Tran Cao
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lianchun Xiao
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Elshad Hasanov
- The Ohio State University Comprehensive Cancer Center - The James, Columbus, Ohio, USA
| | - Priya Bhosale
- Department of Abdominal Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hesham M Amin
- Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yehia I Mohamed
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Betul Gok Yavuz
- University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Yara Sakr
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Li Xu
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ian Hu
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sunyoung S Lee
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Divya Sakamuri
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sonali Jindal
- The Immunotherapy Platform, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Van Nguyen
- Department of Pharmacy Clinical Programs, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michael A Curran
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ryan Sun
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Asif Rashid
- Department of Anatomic Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dan Gabriel Duda
- Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Padmanee Sharma
- Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Aliya Qayyum
- Department of Imaging and Interventional Radiology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Ahmed Omar Kaseb
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Childs A, Aidoo-Micah G, Maini MK, Meyer T. Immunotherapy for hepatocellular carcinoma. JHEP Rep 2024; 6:101130. [PMID: 39308986 PMCID: PMC11414669 DOI: 10.1016/j.jhepr.2024.101130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/19/2024] [Accepted: 05/28/2024] [Indexed: 09/25/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global healthcare challenge, with >1 million patients predicted to be affected annually by 2025. In contrast to other cancers, both incidence and mortality rates continue to rise, and HCC is now the third leading cause of cancer-related death worldwide. Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced HCC, with trials demonstrating a superior overall survival benefit compared to sorafenib in the first-line setting. Combination therapy with either atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) or durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) is now recognised as standard of care for advanced HCC. More recently, two phase III studies of ICI-based combination therapy in the early and intermediate disease settings have successfully met their primary end points of improved recurrence- and progression-free survival, respectively. Despite these advances, and in contrast to other tumour types, there remain no validated predictive biomarkers of response to ICIs in HCC. Ongoing research efforts are focused on further characterising the tumour microenvironment in order to select patients most likely to benefit from ICI and identify novel therapeutic targets. Herein, we review the current understanding of the immune landscape in which HCC develops and the evidence for ICI-based therapeutic strategies in HCC. Additionally, we describe the state of biomarker development and novel immunotherapy approaches in HCC which have progressed beyond the pre-clinical stage and into early-phase trials.
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Affiliation(s)
- Alexa Childs
- Department of Medical Oncology, Royal Free Hospital, London, UK
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| | - Gloryanne Aidoo-Micah
- Department of Medical Oncology, Royal Free Hospital, London, UK
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| | - Mala K. Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| | - Tim Meyer
- Department of Medical Oncology, Royal Free Hospital, London, UK
- UCL Cancer Institute, University College London, UK
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Dong H, Zhang Z, Ni M, Xu X, Luo Y, Wang Y, Zhang H, Chen J. The Trend of the Treatment of Advanced Hepatocellular Carcinoma: Combination of Immunotherapy and Targeted Therapy. Curr Treat Options Oncol 2024; 25:1239-1256. [PMID: 39259476 PMCID: PMC11485193 DOI: 10.1007/s11864-024-01246-9] [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] [Accepted: 07/08/2024] [Indexed: 09/13/2024]
Abstract
OPINION STATEMENT Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy.
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Affiliation(s)
- Heng Dong
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Zhengguo Zhang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Mengjie Ni
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Xiaoyun Xu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Yifeng Luo
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Yaru Wang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Haiyun Zhang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China
| | - Jianxiang Chen
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, People's Republic of China.
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People's Republic of China.
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, 169610, Singapore.
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30
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Stefanini B, Manfredi GF, D’Alessio A, Fulgenzi CA, Awosika N, Celsa C, Pirisi M, Rigamonti C, Burlone M, Vincenzi F, Minisini R, Gennari A, Yip V, Slater S, El-Shakankery K, Jain A, Tovoli F, Piscaglia F, Spalding D, Pai M, Pinato DJ. Delivering adjuvant and neoadjuvant treatments in the early stages of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2024; 18:647-660. [PMID: 39435480 PMCID: PMC11601036 DOI: 10.1080/17474124.2024.2419519] [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: 05/14/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 10/23/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) presents a formidable challenge in oncology, demanding innovative treatment approaches. Both adjuvant and neoadjuvant therapies, thanks to the introduction of immunotherapy, have emerged as promising strategies in the management of HCC, aiming to reduce the risk of relapse and ultimately to improve survival. AREAS COVERED This review considers current evidence, ongoing clinical trials, and future strategies to elucidate the evolving landscape of neoadjuvant and adjuvant treatments in HCC. EXPERT OPINION Both adjuvant and neoadjuvant regimens, notably those incorporating immune checkpoint inhibitors, demonstrated encouraging safety profiles and efficacy outcomes in HCC.While significant challenges persist, including optimizing patient selection and endpoint definition, the evolving landscape of neoadjuvant and adjuvant therapy holds promise for maximizing the therapeutic potential of immunotherapy across all stages of HCC. Further insights into tumor biology and host immunity will shape the role of these approaches which are close to becoming reality in clinical practice.
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Affiliation(s)
- Bernardo Stefanini
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giulia F. Manfredi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Antonio D’Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Claudia A.M. Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Nichola Awosika
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Ciro Celsa
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Mario Pirisi
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Cristina Rigamonti
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Michela Burlone
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Federica Vincenzi
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Rosalba Minisini
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alessandra Gennari
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Vincent Yip
- Barts and the London HPB Centre, Royal London Hospital, Whitechapel, UK
| | - Sarah Slater
- Barts and the London HPB Centre, Royal London Hospital, Whitechapel, UK
| | - Karim El-Shakankery
- Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, UK
| | - Ananya Jain
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Duncan Spalding
- Hepatobiliary Surgery, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - Madhava Pai
- Hepatobiliary Surgery, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - David J. Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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31
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Lv Z, Xiang X, Yong JK, Zhou Y, Wu Y, Li L, Wang Y, Zhang Z, Xia Q, Feng H. Pembrolizumab in combination with LEnvatinib in participants with hepatocellular carcinoma before liver transplant as Neoadjuvant TherapY-PLENTY pilot study. Int J Surg 2024; 110:6647-6657. [PMID: 38995162 PMCID: PMC11487031 DOI: 10.1097/js9.0000000000001813] [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: 04/18/2024] [Accepted: 05/23/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND The high recurrent rate after liver transplantation (LT) remains a clinical challenge, especially for those exceeding the Milan criteria (MC) and with high RETREAT scores. Therefore, the authors aim to investigate whether neoadjuvant systemic therapy allows safely administered and effectively reduces post-LT recurrence for those patients. METHODS In this prospective, randomized, open-label, pilot study, patients with HCC exceeding the MC were randomly assigned to PLENTY or control group before LT. The primary endpoint of the study was the recurrence-free survival after LT. RESULTS Twenty-two patients were enrolled and randomly assigned: 11 to the PLENTY group and 11 to the control group. The 30-month tumor-specific RFS was 37.5% in the PLENTY group and 12.5% in the control group. The 12-month tumor-specific RFS after LT was significantly improved in the PLENTY group (87.5%) compared to the control group (37.5%) ( P =0·0022). The objective response rate in the PLENTY group was 30 and 60% when determined by RECIST 1.1 and mRECIST, respectively. Six patients (60%) had significant tumor necrosis, including three (30%) who had complete tumor necrosis at histopathology. No acute allograft rejection after LT occurred in the PLENTY and Control group. CONCLUSION Neoadjuvant pembrolizumab plus lenvatinib before LT appears to be safe and feasible, associated with significantly better RFS for patients exceeding the MC. Despite the limitations of small sample size, this is the first RCT to evaluate neoadjuvant PD-1 blockade combined with tyrosine kinase inhibitors in LT recipients, the results of this study will inform future research.
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Affiliation(s)
- Zicheng Lv
- Department of Liver Surgery, Renji Hospital (Punan Branch), School of Medicine, Shanghai Jiao Tong University
- Clinical Research Unit, Renji Hospital, School of Medicine, Shanghai Jiao Tong University
| | - Xuelin Xiang
- Shanghai Engineering Research Centre of Transplantation and Immunology
| | - June-kong Yong
- Department of Liver Surgery, Renji Hospital (Punan Branch), School of Medicine, Shanghai Jiao Tong University
| | - Yi Zhou
- Shanghai Engineering Research Centre of Transplantation and Immunology
| | - Yichi Wu
- Shanghai Engineering Research Centre of Transplantation and Immunology
| | - Linman Li
- Shanghai Engineering Research Centre of Transplantation and Immunology
| | - Yuanhao Wang
- Shanghai Engineering Research Centre of Transplantation and Immunology
| | - Zijie Zhang
- Shanghai Engineering Research Centre of Transplantation and Immunology
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital (Punan Branch), School of Medicine, Shanghai Jiao Tong University
- Shanghai Engineering Research Centre of Transplantation and Immunology
| | - Hao Feng
- Department of Liver Surgery, Renji Hospital (Punan Branch), School of Medicine, Shanghai Jiao Tong University
- Clinical Research Unit, Renji Hospital, School of Medicine, Shanghai Jiao Tong University
- Shanghai Engineering Research Centre of Transplantation and Immunology
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Kulkarni AV, Kumaraswamy P, Menon B, Sekaran A, Rambhatla A, Iyengar S, Alla M, Venishetty S, Ramachandra SK, Premkumar GV, Sharma M, Rao PN, Reddy DN, Singal AG. Downstaging with atezolizumab-bevacizumab: a case series. JOURNAL OF LIVER CANCER 2024; 24:224-233. [PMID: 38797993 PMCID: PMC11449572 DOI: 10.17998/jlc.2024.05.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/10/2024] [Accepted: 05/12/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUNDS/AIMS Hepatocellular carcinoma (HCC) is generally diagnosed at an advanced stage, which limits curative treatment options for these patients. Locoregional therapy (LRT) is the standard approach to bridge and downstage unresectable HCC for liver transplantation (LT). Atezolizumab-bevacizumab (atezo-bev) can induce objective responses in nearly one-third of patients; however, the role and outcomes of downstaging using atezo-bev remains unknown. METHODS In this retrospective single-center study, we included consecutive patients between November 2020 and August 2023, who received atezo-bev with or without LRT and were subsequently considered for resection/LT after downstaging. RESULTS Of the 115 patients who received atezo-bev, 12 patients (10.4%) achieved complete or partial response and were willing to undergo LT; they (age, 58.5 years; women, 17%; Barcelona Clinic Liver Cancer stage system B/C, 5/7) had received 3-12 cycles of atezo- bev, and four of them had received prior LRT. Three patients died before LT, while three were awaiting LT. Six patients underwent curative therapies: four underwent living donor LT after a median of 79.5 days (range, 54-114) following the last atezo-bev dose, one underwent deceased donor LT 38 days after the last dose, and one underwent resection. All but one patient had complete pathologic response with no viable HCC. Three patients experienced wound healing complications, and one required re-exploration and succumbed to sepsis. After a median follow-up of 10 months (range, 4-30), none of the alive patients developed HCC recurrence or graft rejection. CONCLUSIONS Surgical therapy, including LT, is possible after atezo-bev therapy in well-selected patients after downstaging.
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Affiliation(s)
| | | | | | | | - Anuhya Rambhatla
- Department of Liver Transplant Anaesthesia, AIG Hospitals, Hyderabad, India
| | - Sowmya Iyengar
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Manasa Alla
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | | | | | - Giri V. Premkumar
- Department of Liver Transplant Anaesthesia, AIG Hospitals, Hyderabad, India
| | - Mithun Sharma
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | | | | | - Amit G. Singal
- Department of Medicine, UT Southwestern Medical Centre, Dallas, TX, USA
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Testa U. Recent developments in molecular targeted therapies for hepatocellular carcinoma in the genomic era. Expert Rev Mol Diagn 2024; 24:803-827. [PMID: 39194003 DOI: 10.1080/14737159.2024.2392278] [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: 04/03/2024] [Accepted: 08/11/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION Primary liver cancer is a major health problem being the sixth most frequent cancer in the world and the third cause of cancer-related death in the world. The most common histological type of liver cancer is hepatocellular carcinoma (HCC, 75-80%). AREAS COVERED Based on primary literature, this review provides an updated analysis of studies of genetic characterization of HCC at the level of gene mutation profiling, copy number alterations, and gene expression, with the definition of molecular subgroups and the identification of some molecular biomarkers and therapeutic targets. Recent therapeutic developments are also highlighted. EXPERT OPINION Deepening the understanding of the molecular complexity of HCC is progressively paving the way for the development of more personalized treatment approaches. Two important strategies involve the definition and validation of molecularly defined therapeutic targets in a subset of HCC patients and the identification of suitable biomarkers for approved systematic therapies (multikinase inhibitors and immunotherapies). The extensive molecular characterization of patients at the genomic and transcriptomic levels and the inclusion of detailed and relevant translational studies in clinical trials will represent a fundamental tool for improving the benefit of systemic therapies in HCC.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore di Sanità, Rome, Italy
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34
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Hou G, Zhang F, Feng X, Chen Y, Zhang J, Wang H. Neoadjuvant-Based Triple Therapy for Hepatocellular Carcinoma with Type I/II Portal Vein Tumor Thrombosis. J Hepatocell Carcinoma 2024; 11:1581-1595. [PMID: 39184154 PMCID: PMC11344545 DOI: 10.2147/jhc.s479810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/14/2024] [Indexed: 08/27/2024] Open
Abstract
Purpose Hepatectomy could provide better survival benefit for hepatocellular carcinoma (HCC) with type I/II portal vein tumor thrombosis (PVTT). However, the postoperative recurrence remains high. We discussed whether neoadjuvant therapy could reduce HCC recurrence for these patients. Patients and Methods One hundred and thirty-eight resectable HCC with type I-II PVTT were retrospectively included. The neoadjuvant therapy regimens included tyrosine kinase inhibitor (TKI), programmed death 1(PD-1) antibodies and transarterial chemoembolization (TACE). Short-term and long-term outcomes were compared. Propensity score matching (PSM) was performed to minimize the influence of potential confounders. Results Thirty-three patients underwent neoadjuvant therapy and 105 patients underwent surgery alone. In the neoadjuvant group, 7 (21.2%) patients achieved stable disease, 13 (39.4%) achieved partial response and 13 (39.4%) achieved complete response based on the modified Response Evaluation Criteria in Solid Tumors criterion. By PSM, the neoadjuvant therapy resulted in less microvascular invasion (24.1% vs 50.0%, P=0.021), satellite nodule (6.9% vs 24.1%, P=0.036) and less patients with alpha-fetoprotein>20(ng/mL) (37.9% vs 69.0%, P=0.006). The neoadjuvant therapy reduced tumor recurrence and prolonged survival. Multivariate analysis found that neoadjuvant therapy was an independent protective factor for overall survival and recurrence free survival. Conclusion Neoadjuvant treatment presents a promising treatment option for HCC patients with type I/II PVTT.
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Affiliation(s)
- Guimin Hou
- Department of Hepatopancreatobiliary Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Feng Zhang
- Department of Hepatopancreatobiliary Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Xielin Feng
- Department of Hepatopancreatobiliary Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Yan Chen
- Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Jinliang Zhang
- Department of Hepatopancreatobiliary Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
| | - Haiqing Wang
- Department of Hepatopancreatobiliary Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China
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Nakazawa M, Fang M, Vong T, Zorzi J, Griffith P, Anders RA, Oshima K, Kim AK, Laurin J, Lafaro KJ, Shubert CR, Burns WR, He J, Burkhart RA, Philosophe B, Meyer J, Liddell RP, Georgiades C, Hong K, Ho WJ, Baretti M, Strauss AT, Yarchoan M. Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC. CANCER RESEARCH COMMUNICATIONS 2024; 4:2123-2132. [PMID: 39142659 PMCID: PMC11324369 DOI: 10.1158/2767-9764.crc-24-0151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/22/2024] [Accepted: 08/01/2024] [Indexed: 08/16/2024]
Abstract
Surgical resection for localized hepatocellular carcinoma (HCC) is typically reserved for a minority of patients with favorable tumor features and anatomy. Neoadjuvant immunotherapy can expand the number of patients who are candidates for surgical resection and potentially reduce the chance for recurrence, but its role in HCC not defined. We retrospectively examined the outcomes of patients who underwent surgical resection for HCC at the Johns Hopkins Hospital and compared the clinical outcomes of patients who received neoadjuvant immunotherapy with those who underwent upfront resection. The clinical cohort included a total of 92 patients, 36 of whom received neoadjuvant immune checkpoint inhibitor (ICI)-based treatment. A majority of patients (61.1%) who received neoadjuvant ICI-based therapy were outside of standard resectability criteria and were more likely to have features known to confer risk of disease recurrence, including α-fetoprotein ≥ 400 ng/mL (P = 0.02), tumor diameter ≥ 5 cm (P = 0.001), portal vein invasion (P < 0.001), and multifocality (P < 0.001). Patients who received neoadjuvant immunotherapy had similar rates of margin-negative resection (P = 0.47) and recurrence-free survival (RFS) as those who underwent upfront surgical resection (median RFS 44.8 months compared with 49.3 months, respectively, log-rank P = 0.66). There was a nonsignificant trend toward superior RFS in the subset of patients with a pathologic response (tumor necrosis ≥ 70%) with neoadjuvant immunotherapy. Neoadjuvant ICI-based therapy may allow high-risk patients, including those who are outside traditional resectability criteria, to achieve comparable clinical outcomes with those who undergo upfront resection. SIGNIFICANCE Surgical resection for localized HCC is typically only reserved for those with solitary tumors without vascular invasion. In this retrospective analysis, we show that neoadjuvant immunotherapy may allow high-risk patients, including those who are outside of standard resection criteria, to undergo successful margin-negative resection and achieve comparable long-term clinical outcomes compared with upfront resection. These findings highlight need for prospective studies on neoadjuvant immunotherapy in HCC.
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Affiliation(s)
- Mari Nakazawa
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Mike Fang
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Tyrus Vong
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Jane Zorzi
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Paige Griffith
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Robert A. Anders
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Kiyoko Oshima
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Amy K. Kim
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Jacqueline Laurin
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Kelly J. Lafaro
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Christopher R. Shubert
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - William R. Burns
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Jin He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Richard A. Burkhart
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Benjamin Philosophe
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Jeffrey Meyer
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Robert P. Liddell
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
- Department of Interventional Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Christos Georgiades
- Department of Interventional Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Kelvin Hong
- Department of Interventional Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Marina Baretti
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Alexandra T. Strauss
- Department of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Wang F, Zhu L, Xiong F, Chai B, Wang J, Zhou G, Cao Y, Zheng C. Relaxin combined with transarterial chemoembolization achieved synergistic effects and inhibited liver cancer metastasis in a rabbit VX2 model. J Cancer Res Clin Oncol 2024; 150:333. [PMID: 38955827 PMCID: PMC11219380 DOI: 10.1007/s00432-024-05864-6] [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: 02/07/2024] [Accepted: 06/21/2024] [Indexed: 07/04/2024]
Abstract
OBJECTIVE To explore the effect and mechanism of relaxin (RLX) in the growth and metastasis of livercancer after combination treatment with transarterial chemoembolization (TACE). MATERIALS AND METHODS HCCLM3 and Huh-7 cells were adopted to evaluate the effect of tumor proliferation, migration, and invasion after RLX administration in vitro. The rabbit VX2 model was used to evaluate the biosafety, doxorubicin penetration, local tumor response, tumor metastasis, and survival benefit of RLX combined with TACE treatment. RESULTS RLX did not affect the proliferation, migration, or invasion of HCCLM3 and Huh-7 cells, and the expression of E-cadherin and HIF-1α also remained unchanged while the MMP-9 protein was upregulated in vitro. In the rabbit VX2 model, compared to the normal saline group (NS), RLX group (RLX) and TACE mono-therapy group (TACE), the group that received TACE combined with RLX (TACE + RLX) showed an improved local tumor response and survival benefit. Furthermore, TACE combined with RLX was found to reduce tumor metastasis. This combination therapy reduced the fibrotic extracellular matrix in the tumor microenvironment, allowing for better penetration of doxorubicin, improved infiltration of CD8+ T cells and affected the secretion of cytokines. Additionally, RLX combined with TACE was able to decrease the expression of HIF-1α and PD-L1. The biosafety of TACE combined with RLX was also confirmed. CONCLUSION RLX synergized with TACE by mitigating the fibrotic extracellular matrix and tumor hypoxic microenvironment, improving the therapeutic effect and inhibiting metastasis during the treatment of liver cancer.
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Affiliation(s)
- Fuquan Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, Hubei, China
| | - Licheng Zhu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, Hubei, China
| | - Fu Xiong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, Hubei, China
| | - Bin Chai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, Hubei, China
| | - Jihua Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, Hubei, China
| | - Guofeng Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, Hubei, China
| | - Yanyan Cao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, Hubei, China.
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, Hubei, China.
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Wang C, Wei F, Sun X, Qiu W, Yu Y, Sun D, Zhi Y, Li J, Fan Z, Lv G, Wang G. Exploring potential predictive biomarkers through historical perspectives on the evolution of systemic therapies into the emergence of neoadjuvant therapy for the treatment of hepatocellular carcinoma. Front Oncol 2024; 14:1429919. [PMID: 38993637 PMCID: PMC11236692 DOI: 10.3389/fonc.2024.1429919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 06/13/2024] [Indexed: 07/13/2024] Open
Abstract
Hepatocellular carcinoma (HCC), a type of liver cancer, ranks as the sixth most prevalent cancer globally and represents the third leading cause of cancer-related deaths. Approximately half of HCC patients miss the opportunity for curative treatment and are then limited to undergoing systemic therapies. Currently, systemic therapy has entered the era of immunotherapy, particularly with the advent of immune-checkpoint inhibitors (ICIs), which have significantly enhanced outcomes for patients with advanced HCC. Neoadjuvant treatment for HCC has become a possibility-findings from the IMbrave 050 trial indicated that ICIs offer the benefit of recurrence-free survival for high-risk HCC patients post-resection or local ablation. However, only a small fraction of individuals benefit from systemic therapy. Consequently, there is an urgent need to identify predictive biomarkers for treatment response and outcome assessment. This study reviewed the historical progression of systemic therapy for HCC, highlighting notable therapeutic advancements. This study examined the development of systemic therapies involving conventional drugs and clinical trials utilized in HCC treatment, as well as potential predictive biomarkers for advanced and/or locally advanced HCC. Various studies have revealed potential biomarkers in the context of HCC treatment. These include the association of dendritic cells (DCs) with a favorable response to neoadjuvant therapy, the presence of enriched T effector cells and tertiary lymphoid structures, the identification of CD138+ plasma cells, and distinct spatial arrangements of B cells in close proximity to T cells among responders with locally advanced HCC receiving neoadjuvant cabozantinib and nivolumab treatment. Furthermore, pathological response has been associated with intratumoral cellular triads consisting of progenitor CD8+ T cells and CXCL13+ CD4+ T helper cells surrounding mature DCs in patients receiving neoadjuvant cemiplimab for resectable HCC. Despite no widely recognized predictive biomarkers for HCC individualized treatment, we believe neoadjuvant trials hold the most promise in identifying and validating them. This is because they can collect multiple samples from resectable HCC patients across stages, especially with multi-omics, bridging preclinical and clinical gaps.
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Affiliation(s)
- Chuanlei Wang
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Feng Wei
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Xiaodong Sun
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Wei Qiu
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Ying Yu
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Dawei Sun
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Yao Zhi
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Jing Li
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Zhongqi Fan
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Guoyue Lv
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
| | - Guangyi Wang
- Department of Hepatobiliary and Pancreatic Surgery I, General Surgery Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of the General Surgery Health Department of Jilin Province, Changchun, China
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Zarlashat Y, Mushtaq H, Pham L, Abbas W, Sato K. Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies. Int J Mol Sci 2024; 25:6830. [PMID: 38999940 PMCID: PMC11241106 DOI: 10.3390/ijms25136830] [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: 05/25/2024] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 07/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.
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Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Hassan Mushtaq
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Linh Pham
- Department of Science and Mathematics, Texas A&M University-Central Texas, Killeen, TX 76549, USA
| | - Wasim Abbas
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan
- Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan
| | - Keisaku Sato
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Singal AG, Yarchoan M, Yopp A, Sapisochin G, Pinato DJ, Pillai A. Neoadjuvant and adjuvant systemic therapy in HCC: Current status and the future. Hepatol Commun 2024; 8:e0430. [PMID: 38829199 PMCID: PMC11150030 DOI: 10.1097/hc9.0000000000000430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 01/13/2024] [Indexed: 06/05/2024] Open
Abstract
Surgical therapies in patients with early-stage HCC can afford long-term survival but are often limited by the continued risk of recurrence, underscoring an interest in (neo)adjuvant strategies. Prior attempts at adjuvant therapy using tyrosine kinase inhibitors failed to yield significant improvements in recurrence-free survival or overall survival. Advances in the efficacy of systemic therapy options, including the introduction of immune checkpoint inhibitors, have fueled renewed interest in this area. Indeed, the IMBrave050 trial recently demonstrated significant improvements in recurrence-free survival with 1 year of adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing surgical resection or ablation, with several other ongoing trials in this space. There is a strong rationale for consideration of the administration of these therapies in the neoadjuvant setting, supported by early clinical data demonstrating high rates of objective responses, although larger trials examining downstream outcomes are necessary, particularly considering the possible risks of this strategy. In parallel, there has been increased interest in using systemic therapies as a bridging or downstaging strategy for liver transplantation. Current data suggest the short-term safety of this approach, with acceptable rates of rejection, so immunotherapy is not considered a contraindication to transplant; however, larger studies are needed to evaluate the incremental value of this approach over locoregional therapy. Conversely, the use of immunotherapy is currently discouraged after liver transplantation, given the high risk of graft rejection and death. The increasing complexity of HCC management and increased consideration of (neo)adjuvant strategies highlight the critical role of multidisciplinary care when making these decisions.
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Affiliation(s)
- Amit G. Singal
- Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Adam Yopp
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Gonzalo Sapisochin
- Department of Surgery, University of Toronto and University Health Network, Toronto, Ontario, Canada
| | - David J. Pinato
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
- Department of Translational Medicine, Division of Oncology, University of Piemonte Orientale, Novara, Italy
| | - Anjana Pillai
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
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Wang H, Qian YW, Dong H, Cong WM. Pathologic assessment of hepatocellular carcinoma in the era of immunotherapy: a narrative review. Hepatobiliary Surg Nutr 2024; 13:472-493. [PMID: 38911201 PMCID: PMC11190517 DOI: 10.21037/hbsn-22-527] [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: 11/05/2022] [Accepted: 02/23/2023] [Indexed: 06/25/2024]
Abstract
Background and Objective Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma (HCC) in recent decade. Meanwhile, numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival, respectively. In this review, we aim to summarize some pragmatic histomorphologic, immunohistochemical, and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC. Methods We searched PubMed using the terms hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitor, immune checkpoint blockade, conversion therapy, neoadjuvant therapy, adjuvant therapy, biomarker, pathologic evaluation, pathologic assessment till February 2023. Key Content and Findings Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens, it is encouraging that a few of studies have concentrated on this field, and moreover, the methods and parameters noted on other cancer types are also worthy of reference. For the pathologic assessment of HCC specimens underwent immunotherapy, a suitable sampling scheme, identifying immunotherapy-related pathologic response, and quantification of pathologic response rate should be emphasized. For the patients of HCC who are scheduled to receive immunotherapy, tumor-infiltrating lymphocyte, intratumoral tertiary lymphoid structure, programmed cell death ligand 1, Wnt/β-catenin, microsatellite instability and mismatch repair, tumor mutational burden and tumor neoantigen, as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI. Conclusions The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report. Albeit many related researches are preclinical or insufficient, they may tremendously alter the immunotherapy strategy of HCC in future.
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Affiliation(s)
- Han Wang
- Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - You-Wen Qian
- Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hui Dong
- Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Wen-Ming Cong
- Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
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Wang DX, Liu H, Tian JC, Zhang DL, Yan LJ, Ding ZN, Li H, Yan YC, Dong ZR, Li T. Neoadjuvant immunotherapy based on PD-1/L1 inhibitors for gastrointestinal tumors: a review of the rationale and clinical advances. Int J Surg 2024; 110:3707-3722. [PMID: 38518083 PMCID: PMC11175801 DOI: 10.1097/js9.0000000000001357] [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: 10/25/2023] [Accepted: 03/03/2024] [Indexed: 03/24/2024]
Abstract
The landscape of current tumor treatment has been revolutionized by the advent of immunotherapy based on PD-1/PD-L1 inhibitors. Leveraging its capacity to mobilize systemic antitumor immunity, which is primarily mediated by T cells, there is growing exploration and expansion of its potential value in various stages of clinical tumor treatment. Neoadjuvant immunotherapy induces a robust immune response against tumors prior to surgery, effectively facilitating tumor volume reduction, early eradication or suppression of tumor cell activity, and control of potential metastatic spread, to improve curative surgical resection rates, and prevent tumor recurrence. This review delineates the theoretical basis of neoadjuvant immunotherapy from preclinical research evidence, discusses specific challenges in clinical application, and provides a comprehensive overview of clinical research progress in neoadjuvant immunotherapy for gastrointestinal tumors. These findings suggest that neoadjuvant immunotherapy has the potential to ameliorate immunosuppressive states and enhance cytotoxic T cell function while preserving lymphatic drainage in the preoperative period. However, further investigations are needed on specific treatment regimens, suitable patient populations, and measurable endpoints. Despite numerous studies demonstrating the promising efficacy and manageable adverse events of neoadjuvant immunotherapy in gastrointestinal tumors, the availability of high-quality randomized controlled trials is limited, which highlights the necessity for further research.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, People’s Republic of China
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Zarlashat Y, Abbas S, Ghaffar A. Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy. Cancers (Basel) 2024; 16:2034. [PMID: 38893154 PMCID: PMC11171154 DOI: 10.3390/cancers16112034] [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: 03/31/2024] [Revised: 04/27/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.
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Affiliation(s)
- Yusra Zarlashat
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
| | - Shakil Abbas
- Gomal Center of Biotechnology and Biochemistry (GCBB), Gomal University, Dera Ismail Khan 29050, Pakistan;
| | - Abdul Ghaffar
- Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
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Urquijo-Ponce JJ, Alventosa-Mateu C, Latorre-Sánchez M, Castelló-Miralles I, Diago M. Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma. World J Gastroenterol 2024; 30:2512-2522. [PMID: 38817666 PMCID: PMC11135412 DOI: 10.3748/wjg.v30.i19.2512] [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: 02/22/2024] [Revised: 04/08/2024] [Accepted: 04/26/2024] [Indexed: 05/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a high mortality neoplasm which usually appears on a cirrhotic liver. The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis. Notwithstanding the current deployment of treatments with curative intent (liver resection/local ablation and liver transplantation) in early and intermediate stages, a high rate of HCC recurrence persists, underscoring a pivotal clinical challenge. Emergent systemic therapies (ST), particularly immunotherapy, have demonstrate promising outcomes in terms of increase overall survival, but they are currently bound to the advanced stage of HCC. This review provides a comprehensive analysis of the literature, encompassing studies up to March 10, 2024, evaluating the impact of novel ST in the early and intermediate HCC stages, specially focusing on the findings of neoadjuvant and adjuvant regimens, aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent. We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent. Finally, we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.
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Affiliation(s)
- Juan Jose Urquijo-Ponce
- Hepatology Unit, Department of Digestive Diseases, Consorcio Hospital General Universitario of Valencia, Valencia 46014, Spain
| | - Carlos Alventosa-Mateu
- Hepatology Unit, Department of Digestive Diseases, Consorcio Hospital General Universitario of Valencia, Valencia 46014, Spain
| | - Mercedes Latorre-Sánchez
- Hepatology Unit, Department of Digestive Diseases, Consorcio Hospital General Universitario of Valencia, Valencia 46014, Spain
| | - Inmaculada Castelló-Miralles
- Hepatology Unit, Department of Digestive Diseases, Consorcio Hospital General Universitario of Valencia, Valencia 46014, Spain
| | - Moisés Diago
- Hepatology Unit, Department of Digestive Diseases, Consorcio Hospital General Universitario of Valencia, Valencia 46014, Spain
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44
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Wu TKH, Hui RWH, Mak LY, Fung J, Seto WK, Yuen MF. Hepatocellular carcinoma: Advances in systemic therapies. F1000Res 2024; 13:104. [PMID: 38766497 PMCID: PMC11099512 DOI: 10.12688/f1000research.145493.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/23/2024] [Indexed: 05/22/2024] Open
Abstract
Advanced hepatocellular carcinoma (HCC) is traditionally associated with limited treatment options and a poor prognosis. Sorafenib, a multiple tyrosine kinase inhibitor, was introduced in 2007 as a first-in-class systemic agent for advanced HCC. After sorafenib, a range of targeted therapies and immunotherapies have demonstrated survival benefits in the past 5 years, revolutionizing the treatment landscape of advanced HCC. More recently, evidence of novel combinations of systemic agents with distinct mechanisms has emerged. In particular, combination trials on atezolizumab plus bevacizumab and durvalumab plus tremelimumab have shown encouraging efficacy. Hence, international societies have revamped their guidelines to incorporate new recommendations for these novel systemic agents. Aside from treatment in advanced HCC, the indications for systemic therapy are expanding. For example, the combination of systemic therapeutics with locoregional therapy (trans-arterial chemoembolization or stereotactic body radiation therapy) has demonstrated promising early results in downstaging HCC. Recent trials have also explored the role of systemic therapy as neoadjuvant treatment for borderline-resectable HCC or as adjuvant treatment to reduce recurrence risk after curative resection. Despite encouraging results from clinical trials, the real-world efficacy of systemic agents in specific patient subgroups (such as patients with advanced cirrhosis, high bleeding risk, renal impairment, or cardiometabolic diseases) remains uncertain. The effect of liver disease etiology on systemic treatment efficacy warrants further research. With an increased understanding of the pathophysiological pathways and accumulation of clinical data, personalized treatment decisions will be possible, and the field of systemic treatment for HCC will continue to evolve.
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Affiliation(s)
- Trevor Kwan-Hung Wu
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
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Tabrizian P, Abdelrahim M, Schwartz M. Immunotherapy and transplantation for hepatocellular carcinoma. J Hepatol 2024; 80:822-825. [PMID: 38253289 DOI: 10.1016/j.jhep.2024.01.011] [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: 08/14/2023] [Revised: 12/22/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as the primary treatment for advanced hepatocellular carcinoma (HCC) and have shown promise in the neoadjuvant setting prior to resection. Liver transplantation (LT) is the preferred treatment for unresectable early HCC or locally advanced disease post locoregional therapy, but the need for immunosuppression after LT conflicts with ICIs' immune augmenting effects. Neoadjuvant ICI may benefit select LT candidates, but challenges arise in understanding response indicators and managing post-LT risks. Reports of severe rejection after LT have raised concerns, though liver-specific factors may mitigate rejection risks, prompting exploration of pre-LT ICI usage. While focus has been on PD-1/PD-L1 inhibitors, the optimal pre-LT ICI regimen remains uncertain, and trials must emphasize careful patient selection and management. Living donor LT is advantageous because ICIs can be withheld for a predefined washout period. In the post-LT setting, use of ICIs is generally avoided, though a few reports suggest that PD-L1 expression in the transplanted liver may be a safety biomarker and that, despite the risk, ICI therapy may be better than supportive care for patients with otherwise-untreatable HCC recurrence. This expert opinion highlights the complexities in the management of HCC vis-à-vis LT. Prospective studies and biomarkers are needed to define safe and effective pre- and post-LT immunotherapy protocols.
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Affiliation(s)
- Parissa Tabrizian
- Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, United States
| | - Maen Abdelrahim
- Medical Oncology, Houston Methodist Texas Medical Center, Texas, United States
| | - Myron Schwartz
- Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, United States.
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Li Z, Liu J, Zhang B, Yue J, Shi X, Cui K, Liu Z, Chang Z, Sun Z, Li M, Yang Y, Ma Z, Li L, Zhang C, Sun P, Zhong J, Zhao L. Neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial. Nat Commun 2024; 15:3260. [PMID: 38627377 PMCID: PMC11021407 DOI: 10.1038/s41467-024-47420-3] [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: 12/29/2023] [Accepted: 03/29/2024] [Indexed: 04/19/2024] Open
Abstract
Notable-HCC (NCT05185531) is a phase 1b trial, aiming to evaluate the safety and preliminary effectiveness of neoadjuvant PD-1 blockade plus stereotactic body radiotherapy (SBRT) in early-stage resectable hepatocellular carcinoma (HCC). Twenty patients with HCC of BCLC stage 0-A received 3 × Gy SBRT and two cycles of tislelizumab, an anti-PD-1 monoclonal antibody before the curative HCC resection. Primary endpoints were the surgery delay, radiographic and pathological tumor response after the neoadjuvant therapy, safety and tolerability. During the neoadjuvant therapy, treatment-related adverse events (TRAEs) of grade 1-2 occurred in all 20 patients (100%), eight patients (40%) had grade 3 TRAEs, no grade 4 to 5 TRAE occurred, and all resolved without corticosteroids treatment. Per mRECIST, the objective response rate was 63.2% (12/19), with 3 complete response; the disease control rate was 100%. Two (10.5%) patients achieved complete pathological response. No surgery delay occurred. The neoadjuvant therapy did not increase the surgical difficulty or the incidence of complications. Secondary endpoints of disease-free survival and overall survival were not mature at the time of the analysis. Our pilot trial shows that neoadjuvant therapy with anti-PD-1 + SBRT is safe and promotes tumor responses in early-stage resectable HCC.
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Affiliation(s)
- Zhongchao Li
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Jing Liu
- Department of Abdominal Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Bo Zhang
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Jinbo Yue
- Department of Abdominal Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Xuetao Shi
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Kai Cui
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Zhaogang Liu
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Zhibin Chang
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
- Shandong First Medical University and Shandong Academy of Medical Sciences, 6699 Qingdao Road, Huaiyin District, Jinan, China
| | - Zhicheng Sun
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
- Shandong First Medical University and Shandong Academy of Medical Sciences, 6699 Qingdao Road, Huaiyin District, Jinan, China
| | - Mingming Li
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
- Shandong First Medical University and Shandong Academy of Medical Sciences, 6699 Qingdao Road, Huaiyin District, Jinan, China
| | - Yue Yang
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
- Shandong First Medical University and Shandong Academy of Medical Sciences, 6699 Qingdao Road, Huaiyin District, Jinan, China
| | - Zhao Ma
- The Fourth People's Hospital of Jinan, Jinan, China
| | - Lei Li
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Chengsheng Zhang
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Pengfei Sun
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Jingtao Zhong
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China
| | - Lei Zhao
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital Affiliated to Shandong First Medical University, 440 Jiyan Road, Huaiyin District, Jinan, China.
- Shandong First Medical University and Shandong Academy of Medical Sciences, 6699 Qingdao Road, Huaiyin District, Jinan, China.
- The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China.
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Akbulut Z, Aru B, Aydın F, Yanıkkaya Demirel G. Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. Front Immunol 2024; 15:1379622. [PMID: 38638433 PMCID: PMC11024234 DOI: 10.3389/fimmu.2024.1379622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/18/2024] [Indexed: 04/20/2024] Open
Abstract
Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.
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Affiliation(s)
- Zeynep Akbulut
- Cancer and Stem Cell Research Center, Maltepe University, Istanbul, Türkiye
- Department of Medical Biology and Genetics, Faculty of Medicine, Maltepe University, Istanbul, Türkiye
| | - Başak Aru
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Furkan Aydın
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
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48
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Tabrizian P, Zeitlhoefler M, Hassan AT, Marino R. Immunotherapy for transplantation of hepatocellular carcinoma: the next frontier in adjunctive therapy. Curr Opin Organ Transplant 2024; 29:144-154. [PMID: 38164882 DOI: 10.1097/mot.0000000000001133] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
PURPOSE OF REVIEW The increasing success of liver transplantation in hepatocellular carcinoma (HCC) drives an ever-evolving search for innovative strategies to broaden eligible patients' pools. Recent advances in immuno-oncology have turned the spotlight on immune checkpoint inhibitors (ICIs). This review offers an updated overview of ICIs in liver transplantation for HCC, exploring neoadjuvant and adjuvant approaches and addressing unanswered questions on safety, patients' selection, and response predictors. RECENT FINDINGS ICIs have transitioned from being a last-chance therapeutic hope to becoming an integral cornerstone in the treatment of advanced HCC, holding great promise as a compelling option not only to downstage patients for transplantation but also as an alternative strategy in addressing posttransplantation disease recurrence. Despite ongoing refinements in immunotherapeutic agents, the complex molecular pathways involved emphasize the need for a comprehensive approach to integrate immunotherapy in liver transplantation. SUMMARY Initial concerns about graft rejection, with ICIs as a bridging therapy to liver transplantation, were successfully addressed using adequate immunosuppressants strategies and minimized with a sufficient washout period. Post-liver transplantation disease recurrence remains challenging, requiring a balance between effective therapy and preserving graft function. Emphasis should be placed on clinical trials validating the risk-benefit ratio of ICIs for liver transplantation, guiding appropriate patients' selection, and establishing clear management pathways.
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Affiliation(s)
- Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Nishizaki D, Eskander RN. Targeted Therapies, Biologics, and Immunotherapy in the Neoadjuvant and Adjuvant Settings: Perioperative Risks. Surg Oncol Clin N Am 2024; 33:279-291. [PMID: 38401910 DOI: 10.1016/j.soc.2023.12.002] [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: 02/26/2024]
Abstract
Cancer therapeutics has been revolutionized by the introduction of molecularly targeted therapies and immune checkpoint inhibitors (ICIs). The paradigm of neoadjuvant therapy is commonly employed across multiple solid tumors, exhibiting significant clinical benefit as exemplified with ICIs in melanoma and non-small-cell lung cancer. However, neoadjuvant therapy can be associated with treatment-related adverse events. As the incorporation of these novel therapies in the preoperative space expands, it is crucial for surgical oncologists to understand the potential perioperative implications of these treatments. This article focuses on surgical considerations tied to these treatments, highlighting potential drug-surgery interactions and complications.
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Affiliation(s)
- Daisuke Nishizaki
- Division of Hematology and Oncology, Department of Medicine, Center for Personalized Cancer Therapy, University of California San Diego, Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92037, USA.
| | - Ramez N Eskander
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Personalized Cancer Therapy, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
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50
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Newhook TE, Tsai S, Meric-Bernstam F. Precision Oncology in Hepatopancreatobiliary Cancer Surgery. Surg Oncol Clin N Am 2024; 33:343-367. [PMID: 38401914 DOI: 10.1016/j.soc.2023.12.016] [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: 02/26/2024]
Abstract
Advances in technology have allowed for the characterization of tumors at the genomic, transcriptomic, and proteomic levels. There are well-established targets for biliary tract cancers, with exciting new targets emerging in pancreatic ductal adenocarcinoma and potential targets in hepatocellular carcinoma. Taken together, these data suggest an important role for molecular profiling for personalizing cancer therapy in advanced disease and need for design of novel neoadjuvant studies to leverage these novel therapeutics perioperatively in the surgical patient.
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Affiliation(s)
- Timothy E Newhook
- Department of Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Susan Tsai
- Division of Surgical Oncology, Department of Surgery, Ohio State University Comprehensive Cancer Center, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, FC8.3044, Houston, TX 77030, USA.
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