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Boubaddi M, Marichez A, Adam JP, Lapuyade B, Debordeaux F, Tlili G, Chiche L, Laurent C. Comprehensive Review of Future Liver Remnant (FLR) Assessment and Hypertrophy Techniques Before Major Hepatectomy: How to Assess and Manage the FLR. Ann Surg Oncol 2024; 31:9205-9220. [PMID: 39230854 DOI: 10.1245/s10434-024-16108-9] [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: 05/24/2024] [Accepted: 08/16/2024] [Indexed: 09/05/2024]
Abstract
BACKGROUND The regenerative capacities of the liver and improvements in surgical techniques have expanded the possibilities of resectability. Liver resection is often the only curative treatment for primary and secondary malignancies, despite the risk of post-hepatectomy liver failure (PHLF). This serious complication (with a 50% mortality rate) can be avoided by better assessment of liver volume and function of the future liver remnant (FLR). OBJECTIVE The aim of this review was to understand and assess clinical, biological, and imaging predictors of PHLF risk, as well as the various hypertrophy techniques, to achieve an adequate FLR before hepatectomy. METHOD We reviewed the state of the art in liver regeneration and FLR hypertrophy techniques. RESULTS The use of new biological scores (such as the aspartate aminotransferase/platelet ratio index + albumin-bilirubin [APRI+ALBI] score), concurrent utilization of 99mTc-mebrofenin scintigraphy (HBS), or dynamic hepatocyte contrast-enhanced MRI (DHCE-MRI) for liver volumetry helps predict the risk of PHLF. Besides portal vein embolization, there are other FLR optimization techniques that have their indications in case of risk of failure (e.g., associating liver partition and portal vein ligation for staged hepatectomy, liver venous deprivation) or in specific situations (transarterial radioembolization). CONCLUSION There is a need to standardize volumetry and function measurement techniques, as well as FLR hypertrophy techniques, to limit the risk of PHLF.
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Affiliation(s)
- Mehdi Boubaddi
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France.
- Bordeaux Institute of Oncology, BRIC U1312, INSERM, Bordeaux University, Bordeaux, France.
| | - Arthur Marichez
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France
- Bordeaux Institute of Oncology, BRIC U1312, INSERM, Bordeaux University, Bordeaux, France
| | - Jean-Philippe Adam
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Bruno Lapuyade
- Radiology Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Frederic Debordeaux
- Nuclear Medicine Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Ghoufrane Tlili
- Nuclear Medicine Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Laurence Chiche
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Christophe Laurent
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France
- Bordeaux Institute of Oncology, BRIC U1312, INSERM, Bordeaux University, Bordeaux, France
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Chan SM, Cornman-Homonoff J, Lucatelli P, Madoff DC. Image-guided percutaneous strategies to improve the resectability of HCC: Portal vein embolization, liver venous deprivation, or radiation lobectomy? Clin Imaging 2024; 111:110185. [PMID: 38781614 DOI: 10.1016/j.clinimag.2024.110185] [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: 06/26/2023] [Revised: 04/20/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024]
Abstract
Despite considerable advances in surgical technique, many patients with hepatic malignancies are not operative candidates due to projected inadequate hepatic function following resection. Consequently, the size of the future liver remnant (FLR) is an essential consideration when predicting a patient's likelihood of liver insufficiency following hepatectomy. Since its initial description 30 years ago, portal vein embolization has become the standard of care for augmenting the size and function of the FLR preoperatively. However, new minimally invasive techniques have been developed to improve surgical candidacy, chief among them liver venous deprivation and radiation lobectomy. The purpose of this review is to discuss the status of preoperative liver augmentation prior to resection of hepatocellular carcinoma with a focus on these three techniques, highlighting the distinctions between them and suggesting directions for future investigation.
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Affiliation(s)
- Shin Mei Chan
- Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA; Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, CT, USA
| | - Joshua Cornman-Homonoff
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, CT, USA
| | - Pierleone Lucatelli
- Department of Radiological, Oncological, and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - David C Madoff
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, CT, USA; Department of Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, CT, USA; Department of Surgery, Section of Surgical Oncology, Yale School of Medicine, New Haven, CT, USA.
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Barcena AJR, Owens TC, Melancon S, Workeneh I, Tran Cao HS, Vauthey JN, Huang SY. Current Perspectives and Progress in Preoperative Portal Vein Embolization with Stem Cell Augmentation (PVESA). Stem Cell Rev Rep 2024; 20:1236-1251. [PMID: 38613627 PMCID: PMC11222268 DOI: 10.1007/s12015-024-10719-1] [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] [Accepted: 04/03/2024] [Indexed: 04/15/2024]
Abstract
Portal vein embolization with stem cell augmentation (PVESA) is an emerging approach for enhancing the growth of the liver segment that will remain after surgery (i.e., future liver remnant, FLR) in patients with liver cancer. Conventional portal vein embolization (PVE) aims to induce preoperative FLR growth, but it has a risk of failure in patients with underlying liver dysfunction and comorbid illnesses. PVESA combines PVE with stem cell therapy to potentially improve FLR size and function more effectively and efficiently. Various types of stem cells can help improve liver growth by secreting paracrine signals for hepatocyte growth or by transforming into hepatocytes. Mesenchymal stem cells (MSCs), unrestricted somatic stem cells, and small hepatocyte-like progenitor cells have been used to augment liver growth in preclinical animal models, while clinical studies have demonstrated the benefit of CD133 + bone marrow-derived MSCs and hematopoietic stem cells. These investigations have shown that PVESA is generally safe and enhances liver growth after PVE. However, optimizing the selection, collection, and application of stem cells remains crucial to maximize benefits and minimize risks. Additionally, advanced stem cell technologies, such as priming, genetic modification, and extracellular vesicle-based therapy, that could further enhance efficacy outcomes should be evaluated. Despite its potential, PVESA requires more investigations, particularly mechanistic studies that involve orthotopic animal models of liver cancer with concomitant liver injury as well as larger human trials.
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Affiliation(s)
- Allan John R Barcena
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States
- College of Medicine, University of the Philippines Manila, Manila, NCR, 1000, Philippines
| | - Tyler C Owens
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States
| | - Sophie Melancon
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States
| | - Isias Workeneh
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States
| | - Hop S Tran Cao
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States
| | - Steven Y Huang
- Department of Interventional Radiology, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit, Houston, TX, 1471, 77030, United States.
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Haddad A, Lendoire M, Maki H, Kang HC, Habibollahi P, Odisio BC, Huang SY, Vauthey JN. Liver volumetry and liver-regenerative interventions: history, rationale, and emerging tools. J Gastrointest Surg 2024; 28:766-775. [PMID: 38519362 DOI: 10.1016/j.gassur.2024.02.020] [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: 12/16/2023] [Revised: 01/26/2024] [Accepted: 02/08/2024] [Indexed: 03/24/2024]
Abstract
BACKGROUND Postoperative hepatic insufficiency (PHI) is the most feared complication after hepatectomy. Volume of the future liver remnant (FLR) is one objectively measurable indicator to identify patients at risk of PHI. In this review, we summarized the development and rationale for the use of liver volumetry and liver-regenerative interventions and highlighted emerging tools that could yield new advancements in liver volumetry. METHODS A review of MEDLINE/PubMed, Embase, and Cochrane Library databases was conducted to identify literature related to liver volumetry. The references of relevant articles were reviewed to identify additional publications. RESULTS Liver volumetry based on radiologic imaging was developed in the 1980s to identify patients at risk of PHI and later used in the 1990s to evaluate grafts for living donor living transplantation. The field evolved in the 2000s by the introduction of standardized FLR based on the hepatic metabolic demands and in the 2010s by the introduction of the degree of hypertrophy and kinetic growth rate as measures of the FLR regenerative and functional capacity. Several liver-regenerative interventions, most notably portal vein embolization, are used to increase resectability and reduce the risk of PHI. In parallel with the increase in automation and machine assistance to physicians, many semi- and fully automated tools are being developed to facilitate liver volumetry. CONCLUSION Liver volumetry is the most reliable tool to detect patients at risk of PHI. Advances in imaging analysis technologies, newly developed functional measures, and liver-regenerative interventions have been improving our ability to perform safe hepatectomy.
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Affiliation(s)
- Antony Haddad
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Mateo Lendoire
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Harufumi Maki
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Hyunseon Christine Kang
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Peiman Habibollahi
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Bruno C Odisio
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Steven Y Huang
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
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García-Botella A, Martín P, Méndez R, Ortega L, Méndez J, Sastre J, Diez-Valladares L, Torres AJ. Preoperative liver regeneration with CD133+ infusion in patients with colorectal liver metastases: proof-of concept trial. HPB (Oxford) 2024; 26:603-605. [PMID: 38310081 DOI: 10.1016/j.hpb.2024.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/04/2024] [Accepted: 01/15/2024] [Indexed: 02/05/2024]
Affiliation(s)
- Alejandra García-Botella
- Surgery Department (HepatoPancreatoBiliary Unit), Health Research Institute (IdISSC), Hospital Clínico San Carlos, Madrid, Spain; Department of Surgery, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain.
| | - Paz Martín
- Department of Hematology, Hospital Universitario Clínico San Carlos, Madrid, Spain
| | - Ramiro Méndez
- Department of Surgery, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain; Department of Radiology, Hospital Universitario Clínico San Carlos, Madrid, Spain
| | - Luis Ortega
- Department of Surgery, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain; Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain
| | - Jose Méndez
- Department of Radiology, Hospital Universitario Clínico San Carlos, Madrid, Spain
| | - Javier Sastre
- Department of Surgery, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain; Department of Oncology, Hospital Universitario Clínico San Carlos, Madrid, Spain
| | - Luis Diez-Valladares
- Surgery Department (HepatoPancreatoBiliary Unit), Health Research Institute (IdISSC), Hospital Clínico San Carlos, Madrid, Spain; Department of Surgery, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Antonio J Torres
- Surgery Department (HepatoPancreatoBiliary Unit), Health Research Institute (IdISSC), Hospital Clínico San Carlos, Madrid, Spain; Department of Surgery, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
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Moreau R, Tonon M, Krag A, Angeli P, Berenguer M, Berzigotti A, Fernandez J, Francoz C, Gustot T, Jalan R, Papp M, Trebicka J. EASL Clinical Practice Guidelines on acute-on-chronic liver failure. J Hepatol 2023; 79:461-491. [PMID: 37364789 DOI: 10.1016/j.jhep.2023.04.021] [Citation(s) in RCA: 105] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 04/19/2023] [Indexed: 06/28/2023]
Abstract
Acute-on-chronic liver failure (ACLF), which was described relatively recently (2013), is a severe form of acutely decompensated cirrhosis characterised by the existence of organ system failure(s) and a high risk of short-term mortality. ACLF is caused by an excessive systemic inflammatory response triggered by precipitants that are clinically apparent (e.g., proven microbial infection with sepsis, severe alcohol-related hepatitis) or not. Since the description of ACLF, some important studies have suggested that patients with ACLF may benefit from liver transplantation and because of this, should be urgently stabilised for transplantation by receiving appropriate treatment of identified precipitants, and full general management, including support of organ systems in the intensive care unit (ICU). The objective of the present Clinical Practice Guidelines is to provide recommendations to help clinicians recognise ACLF, make triage decisions (ICU vs. no ICU), identify and manage acute precipitants, identify organ systems that require support or replacement, define potential criteria for futility of intensive care, and identify potential indications for liver transplantation. Based on an in-depth review of the relevant literature, we provide recommendations to navigate clinical dilemmas followed by supporting text. The recommendations are graded according to the Oxford Centre for Evidence-Based Medicine system and categorised as 'weak' or 'strong'. We aim to provide the best available evidence to aid the clinical decision-making process in the management of patients with ACLF.
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Optimizing Growth of the Future Liver Remnant and Making In-Situ Liver Transsection Safe—A Standardized Approach to ISLT or ALPPS. Curr Oncol 2023; 30:3277-3288. [PMID: 36975462 PMCID: PMC10046923 DOI: 10.3390/curroncol30030249] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 03/14/2023] Open
Abstract
In-situ splitting of the liver before extended resection has gained broad attention. This two-step procedure requires several measures to make an effective and safe procedure. Although the procedure is performed in many institutions, there is no consensus on a uniform technique. The two steps can be divided into different parts and a standardized technique may render the procedure safer and the results will be easier to evaluate. In this paper, we describe a detailed approach to in-situ splitting that allows making both procedures safe, avoids liver necrosis, and is easily reproducible. In the first procedure the portal branches to segments I and IV to VIII are divided, the arterial branches and bile ducts to these segments are preserved and encircled and the parenchyma between segments II/III and IVa/b is divided. This avoids necrosis and bile leaks of segments I and IV and avoids urgent completion operations. In particular, the handling of vital structures close to the dissection line seems important to us. Complete splitting and securing the right and middle hepatic vein will make the second step of this procedure a minimal-risk procedure at a stage where the patient is still recovering from the more demanding first step.
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Portal Vein Embolization: Rationale, Techniques, and Outcomes to Maximize Remnant Liver Hypertrophy with a Focus on Contemporary Strategies. Life (Basel) 2023; 13:life13020279. [PMID: 36836638 PMCID: PMC9959051 DOI: 10.3390/life13020279] [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: 11/30/2022] [Revised: 01/11/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Hepatectomy remains the gold standard for curative therapy for patients with limited primary or metastatic hepatic tumors as it offers the best survival rates. In recent years, the indication for partial hepatectomy has evolved away from what will be removed from the patient to the volume and function of the future liver remnant (FLR), i.e., what will remain. With this regard, liver regeneration strategies have become paramount in transforming patients who previously had poor prognoses into ones who, after major hepatic resection with negative margins, have had their risk of post-hepatectomy liver failure minimized. Preoperative portal vein embolization (PVE) via the purposeful occlusion of select portal vein branches to promote contralateral hepatic lobar hypertrophy has become the accepted standard for liver regeneration. Advances in embolic materials, selection of treatment approaches, and PVE with hepatic venous deprivation or concurrent transcatheter arterial embolization/radioembolization are all active areas of research. To date, the optimal combination of embolic material to maximize FLR growth is not yet known. Knowledge of hepatic segmentation and portal venous anatomy is essential before performing PVE. In addition, the indications for PVE, the methods for assessing hepatic lobar hypertrophy, and the possible complications of PVE need to be fully understood before undertaking the procedure. The goal of this article is to discuss the rationale, indications, techniques, and outcomes of PVE before major hepatectomy.
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Cassese G, Han HS, Lee B, Cho JY, Lee HW, Guiu B, Panaro F, Troisi RI. Portal vein embolization failure: Current strategies and future perspectives to improve liver hypertrophy before major oncological liver resection. World J Gastrointest Oncol 2022; 14:2088-2096. [PMID: 36438704 PMCID: PMC9694272 DOI: 10.4251/wjgo.v14.i11.2088] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/01/2022] [Accepted: 10/31/2022] [Indexed: 11/15/2022] Open
Abstract
Portal vein embolization (PVE) is currently considered the standard of care to improve the volume of an inadequate future remnant liver (FRL) and decrease the risk of post-hepatectomy liver failure (PHLF). PHLF remains a significant limitation in performing major liver surgery and is the main cause of mortality after resection. The degree of hypertrophy obtained after PVE is variable and depends on multiple factors. Up to 20% of patients fail to undergo the planned surgery because of either an inadequate FRL growth or tumor progression after the PVE procedure (usually 6-8 wk are needed before surgery). The management of PVE failure is still debated, with a lack of consensus regarding the best clinical strategy. Different additional techniques have been proposed, such as sequential transarterial chemoembolization followed by PVE, segment 4 PVE, intra-portal administration of stem cells, dietary supplementation, and hepatic vein embolization. The aim of this review is to summarize the up-to-date strategies to overcome such difficult situations and discuss future perspectives on improving FRL hypertrophy.
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Affiliation(s)
- Gianluca Cassese
- Clinical Medicine and Surgery, Federico II University, Naples 80131, Italy
| | - Ho-Seong Han
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, South Korea
| | - Boram Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Jai Young Cho
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, South Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
| | - Boris Guiu
- Department of Medical Imaging and Interventional Radiology, St-Eloi University Hospital, Montpellier 34295, France
| | - Fabrizio Panaro
- Digestive Surgery and Transplantation, CHU de Montpellier, Montpellier 34295, France
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Papamichail M, Pizanias M, Heaton ND, M P, M P, Nd H. Minimizing the risk of small-for-size syndrome after liver surgery. Hepatobiliary Pancreat Dis Int 2022; 21:113-133. [PMID: 34961675 DOI: 10.1016/j.hbpd.2021.12.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 12/06/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Primary and secondary liver tumors are not always amenable to resection due to location and size. Inadequate future liver remnant (FLR) may prevent patients from having a curative resection or may result in increased postoperative morbidity and mortality from complications related to small-for-size syndrome (SFSS). DATA SOURCES This comprehensive review analyzed the principles, mechanism and risk factors associated with SFSS and presented current available options in the evaluation of FLR when planning liver surgery. In addition, it provided a detailed description of specific modalities that can be used before, during or after surgery, in order to optimize the conditions for a safe resection and minimize the risk of SFSS. RESULTS Several methods which aim to reduce tumor burden, preserve healthy liver parenchyma, induce hypertrophy of FLR or prevent postoperative complications help minimize the risk of SFSS. CONCLUSIONS With those techniques the indications of radical treatment for patients with liver tumors have significantly expanded. The successful outcome depends on appropriate patient selection, the individualization and modification of interventions and the right timing of surgery.
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Affiliation(s)
- Michail Papamichail
- Department of Hepato-Pancreato-Biliary Surgery, Royal Blackburn Hospital, Blackburn BB2 3HH, UK.
| | - Michail Pizanias
- Department of General Surgery, Whittington Hospital, London N19 5NF, UK
| | - Nigel D Heaton
- Department of Liver Transplant and Hepato-Pancreato-Biliary Surgery, Institute of Liver Studies, Kings Health Partners at King's College Hospital NHS Trust, London SE5 9RS, UK
| | - Papamichail M
- Department of Hepato-Pancreato-Biliary Surgery, Royal Blackburn Hospital, Blackburn BB2 3HH, UK; Department of General Surgery, Whittington Hospital, London N19 5NF, UK; Department of Liver Transplant and Hepato-Pancreato-Biliary Surgery, Institute of Liver Studies, Kings Health Partners at King's College Hospital NHS Trust, London SE5 9RS, UK
| | - Pizanias M
- Department of Hepato-Pancreato-Biliary Surgery, Royal Blackburn Hospital, Blackburn BB2 3HH, UK; Department of General Surgery, Whittington Hospital, London N19 5NF, UK; Department of Liver Transplant and Hepato-Pancreato-Biliary Surgery, Institute of Liver Studies, Kings Health Partners at King's College Hospital NHS Trust, London SE5 9RS, UK
| | - Heaton Nd
- Department of Hepato-Pancreato-Biliary Surgery, Royal Blackburn Hospital, Blackburn BB2 3HH, UK; Department of General Surgery, Whittington Hospital, London N19 5NF, UK; Department of Liver Transplant and Hepato-Pancreato-Biliary Surgery, Institute of Liver Studies, Kings Health Partners at King's College Hospital NHS Trust, London SE5 9RS, UK
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11
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Engelmann C, Herber A, Franke A, Bruns T, Reuken P, Schiefke I, Zipprich A, Zeuzem S, Goeser T, Canbay A, Berg C, Trebicka J, Uschner FE, Chang J, Mueller T, Aehling N, Schmelzle M, Splith K, Lammert F, Lange CM, Sarrazin C, Trautwein C, Manns M, Häussinger D, Pfeiffenberger J, Galle PR, Schmiedeknecht A, Berg T. Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study). J Hepatol 2021; 75:1346-1354. [PMID: 34364917 DOI: 10.1016/j.jhep.2021.07.033] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/08/2021] [Accepted: 07/20/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 μg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. RESULTS Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. GOV NUMBER NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.
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Affiliation(s)
- Cornelius Engelmann
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany; Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany
| | - Adam Herber
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Annegret Franke
- Clinical Trial Centre (ZKS) Leipzig, Faculty of Medicine, University Leipzig, Leipzig, Germany
| | - Tony Bruns
- Department of Medicine III, Aachen University Hospital, Aachen, Germany; Clinic for Internal Medicine IV, University Hospital Jena, Jena, Germany
| | - Philipp Reuken
- Clinic for Internal Medicine IV, University Hospital Jena, Jena, Germany
| | - Ingolf Schiefke
- Clinic for Gastroenterology, Hepatology and Endocrinology, St. Georg Hospital, Leipzig, Germany
| | - Alexander Zipprich
- University Hospital for Internal Medicine 1, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany
| | - Tobias Goeser
- Clinic for Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany
| | - Ali Canbay
- Medical Department, University Hospital Ruhr-University Bochum, Bochum, Germany
| | - Christoph Berg
- Department of Internal Medicine I, University Hospital Tuebingen, Tuebingen, Germany
| | - Jonel Trebicka
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Frank E Uschner
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Johannes Chang
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Tobias Mueller
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Niklas Aehling
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Katrin Splith
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Christian M Lange
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Clinic for Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Christoph Sarrazin
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Medical Clinic 2, St. Josefs Hospital Wiesbaden, Wiesbaden, Germany
| | | | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Dieter Häussinger
- Clinic and Policlinic of Gastroenterology, Hepatology and Infectious Disease, Heinrich Heine University Duesseldorf, Düsseldorf, Germany
| | - Jan Pfeiffenberger
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter R Galle
- Department of Internal Medicine, University Medical Center Mainz, Mainz, Germany
| | - Anett Schmiedeknecht
- Clinical Trial Centre (ZKS) Leipzig, Faculty of Medicine, University Leipzig, Leipzig, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
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12
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Huang W, Han N, Du L, Wang M, Chen L, Tang H. A narrative review of liver regeneration-from models to molecular basis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1705. [PMID: 34988214 PMCID: PMC8667151 DOI: 10.21037/atm-21-5234] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/04/2021] [Indexed: 12/11/2022]
Abstract
Objective To elucidate the characteristics of different liver regeneration animal models, understand the activation signals and mechanisms related to liver regeneration, and obtain a more comprehensive conception of the entire liver regeneration process. Background Liver regeneration is one of the most enigmatic and fascinating phenomena of the human organism. Despite suffering significant injuries, the liver still can continue to perform its complex functions through the regeneration system. Although advanced topics on liver regeneration have been proposed; unfortunately, complete regeneration of the liver has not been achieved until now. Therefore, increasing understanding of the liver regenerative process can help improve our treatment of liver failure. It will provide a new sight for the treatment of patients with liver injury in the clinic. Methods Literatures on liver regeneration animal models and involved basic research on molecular mechanisms were retrieved to analyze the characteristics of different models and those related to molecular basis. Conclusions The process of liver regeneration is complex and intricate, consisting of various and interactive pathways. There is sufficient evidence to demonstrate that liver regeneration is similar between humans and rodents. At the same time, many of the same cytokines, growth factors, and signaling pathways are relevant. There are many gaps in our current knowledge. Understanding of this knowledge will provide more supportive clinical treatment strategies, including small-scale liver transplantation and high-quality regenerative process after surgical resection, and offer possible targets to treat the dysregulation of regeneration that occurs in chronic hepatic diseases and tumors. Current research work, such as the use of animal models as in vivo vectors for high-quality human hepatocytes, represents a unique and significant cutting edge in the field of liver regeneration.
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Affiliation(s)
- Wei Huang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ning Han
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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13
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Engelmann C, Martino VD, Kerbert AJC, Weil-Verhoeven D, Aehling NF, Herber A, Thévenot T, Berg T. The Current Status of Granulocyte-Colony Stimulating Factor to Treat Acute-on-Chronic Liver Failure. Semin Liver Dis 2021; 41:298-307. [PMID: 33992029 DOI: 10.1055/s-0041-1723034] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modulatory and proregenerative capacities. In this review, we aim to define the current evidence for the treatment with G-CSF in end-stage liver disease. Several smaller clinical trials in patients with different severity grades of end-stage liver disease have shown that G-CSF improves survival and reduces the rate of complications. Adequately powered multicenter European trials could not confirm these beneficial effects. In mouse models of ACLF, G-CSF increased the toll-like receptor (TLR)-mediated inflammatory response which led to an increase in mortality. Adding a TLR4 signaling inhibitor allowed G-CSF to unfold its proregenerative properties in these ACLF models. These data suggest that G-CSF requires a noninflammatory environment to exert its protective properties.
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Affiliation(s)
- Cornelius Engelmann
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.,Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.,Division of Hepatology and Gastroenterology, Department of Medical, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Vincent Di Martino
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Annarein J C Kerbert
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - Delphine Weil-Verhoeven
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Niklas Friedemann Aehling
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Adam Herber
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Thierry Thévenot
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
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14
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Soykan EA, Aarts BM, Lopez-Yurda M, Kuhlmann KFD, Erdmann JI, Kok N, van Lienden KP, Wilthagen EA, Beets-Tan RGH, van Delden OM, Gomez FM, Klompenhouwer EG. Predictive Factors for Hypertrophy of the Future Liver Remnant After Portal Vein Embolization: A Systematic Review. Cardiovasc Intervent Radiol 2021; 44:1355-1366. [PMID: 34142192 PMCID: PMC8382618 DOI: 10.1007/s00270-021-02877-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 05/18/2021] [Indexed: 12/15/2022]
Abstract
This systematic review was conducted to determine factors that are associated with the degree of hypertrophy of the future liver remnant following portal vein embolization. An extensive search on September 15, 2020, and subsequent literature screening resulted in the inclusion of forty-eight articles with 3368 patients in qualitative analysis, of which 18 studies were included in quantitative synthesis. Meta-analyses based on a limited number of studies showed an increase in hypertrophy response when additional embolization of segment 4 was performed (pooled difference of medians = − 3.47, 95% CI − 5.51 to − 1.43) and the use of N-butyl cyanoacrylate for portal vein embolization induced more hypertrophy than polyvinyl alcohol (pooled standardized mean difference (SMD) = 0.60, 95% CI 0.30 to 0.91). There was no indication of a difference in degree of hypertrophy between patients who received neo-adjuvant chemotherapy and those who did not receive pre-procedural systemic therapy (pooled SMD = − 0.37, 95% CI − 1.35 to 0.61), or between male and female patients (pooled SMD = 0.19, 95% CI − 0.12 to 0.50). The study was registered in the International Prospective Register of Systematic Reviews on April 28, 2020 (CRD42020175708).
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Affiliation(s)
- E. A. Soykan
- Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - B. M. Aarts
- Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - M. Lopez-Yurda
- Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - K. F. D. Kuhlmann
- Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - J. I. Erdmann
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - N. Kok
- Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - K. P. van Lienden
- Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - E. A. Wilthagen
- Scientific Information Service, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - R. G. H. Beets-Tan
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - O. M. van Delden
- Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - F. M. Gomez
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Interventional Radiology, Hospital Clinic Universitari de Barcelona, Barcelona, Spain
| | - E. G. Klompenhouwer
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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15
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Platelets Boost Recruitment of CD133 + Bone Marrow Stem Cells to Endothelium and the Rodent Liver-The Role of P-Selectin/PSGL-1 Interactions. Int J Mol Sci 2020; 21:ijms21176431. [PMID: 32899390 PMCID: PMC7504029 DOI: 10.3390/ijms21176431] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023] Open
Abstract
We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133+BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133+BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133+BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133+BMSC homing to the injured liver with heightened transmigration towards the extra sinusoidal space when compared to perfusion conditions without platelets. Extravascular co-localization of CD133+BMSC with hepatocytes was confirmed by confocal microscopy. We demonstrated an enhancing effect of platelets on CD133+BMSC homing to and transmigrating along hepatic EC putatively depending on PSGL-1 and P-selectin. Our insights suggest a new mechanism of platelets to augment stem cell dependent hepatic repair.
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16
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Madoff DC, Odisio BC, Schadde E, Gaba RC, Bennink RJ, van Gulik TM, Guiu B. Improving the Safety of Major Resection for Hepatobiliary Malignancy: Portal Vein Embolization and Recent Innovations in Liver Regeneration Strategies. Curr Oncol Rep 2020; 22:59. [PMID: 32415401 DOI: 10.1007/s11912-020-00922-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW For three decades, portal vein embolization (PVE) has been the "gold-standard" strategy to hypertrophy the anticipated future liver remnant (FLR) in advance of major hepatectomy. During this time, CT volumetry was the most common method to preoperatively assess FLR quality and function and used to determine which patients are appropriate surgical candidates. This review provides the most up-to-date methods for preoperatively assessing the anticipated FLR and summarizes data from the currently available strategies used to induce FLR hypertrophy before surgery for hepatobiliary malignancy. RECENT FINDINGS Functional and physiological imaging is increasingly replacing standard CT volumetry as the method of choice for preoperative FLR assessment. PVE, associating liver partition and portal vein ligation, radiation lobectomy, and liver venous deprivation are all currently available techniques to hypertrophy the FLR. Each strategy has pros and cons based on tumor type, extent of resection, presence or absence of underlying liver disease, age, performance status, complication rates, and other factors. Numerous strategies can lead to FLR hypertrophy and improve the safety of major hepatectomy. Which is best has yet to be determined.
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Affiliation(s)
- David C Madoff
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, CT, USA.
| | - Bruno C Odisio
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Erik Schadde
- Department of Surgery, Rush University Medical Center, Chicago, IL, USA
- Department of Surgery, Cantonal Hospital Winterthur, Zurich, Switzerland
- Institute of Physiology, Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Ron C Gaba
- Department of Radiology, Interventional Radiology Section, University of Illinois Hospital, Chicago, IL, USA
| | - Roelof J Bennink
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Thomas M van Gulik
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Boris Guiu
- Department of Radiology, St-Eloi University Hospital-Montpellier, Montpellier, France
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17
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Lehwald-Tywuschik N, Vaghiri S, Schulte Am Esch J, Alaghmand S, Klosterkemper Y, Schimmöller L, Lachenmayer A, Ashmawy H, Krieg A, Topp SA, Rehders A, Knoefel WT. In situ split plus portal vein ligation (ISLT) - a salvage procedure following inefficient portal vein embolization to gain adequate future liver remnant volume prior to extended liver resection. BMC Surg 2020; 20:63. [PMID: 32252737 PMCID: PMC7333278 DOI: 10.1186/s12893-020-00721-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 03/23/2020] [Indexed: 02/07/2023] Open
Abstract
Background Right extended liver resection is frequently required to achieve tumor-free margins. Portal venous embolization (PVE) of the prospective resected hepatic segments for conditioning segments II/III does not always induce adequate hypertrophy in segments II and III (future liver remnant volume (FLRV)) for extended right-resection. Here, we present the technique of in situ split dissection along segments II/III plus portal disruption to segments IV-VIII (ISLT) as a salvage procedure to overcome inadequate gain of FLRV after PVE. Methods In eight patients, FLRV was further pre-conditioned following failed PVE prior to hepatectomy (ISLT-group). We compared FLRV changes in the ISLT group with patients receiving extended right hepatectomy following sufficient PVE (PVEres-group). Survival of the ISLT-group was compared to PVEres patients and PVE patients with insufficient FLRV gain or tumor progress who did not receive further surgery (PVEnores-group). Results Patient characteristics and surgical outcome were comparable in both groups. The mean FLRV-to-body-weight ratio in the ISLT group was smaller than in the PVEres-group pre- and post-PVE. One intraoperative mortality due to a coronary infarction was observed for an ISLT patient. ISLT was successfully completed in the remaining seven ISLT patients. Liver function and 2-year survival of ~ 50% was comparable to patients with extended right hepatectomy after efficient PVE. Patients who received a PVE but who were not subsequently resected (PVEnores) demonstrated no survival beyond 4 months. Conclusion Despite extended embolization of segments I and IV-VIII, ISLT should be considered if hypertrophy was not adequate. Liver function and overall survival after ISLT was comparable to patients with trisectionectomy after efficient PVE.
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Affiliation(s)
- Nadja Lehwald-Tywuschik
- Department of Surgery A, University Hospital Duesseldorf, Duesseldorf, Germany.,Department of General, Visceral, Thorax and Pediatric Surgery,Heinrich-Heine-University Hospital, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Sascha Vaghiri
- Department of Surgery A, University Hospital Duesseldorf, Duesseldorf, Germany.,Department of General, Visceral, Thorax and Pediatric Surgery,Heinrich-Heine-University Hospital, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Jan Schulte Am Esch
- Present address: Center of Visceral Medicine, Department of Visceral Surgery, Protestant Hospital of Bethel Foundation, Bielefeld, Germany
| | - Salman Alaghmand
- Department of Surgery A, University Hospital Duesseldorf, Duesseldorf, Germany
| | - Yan Klosterkemper
- Department of Diagnostic and Interventional Radiology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - Lars Schimmöller
- Department of Diagnostic and Interventional Radiology, University Hospital Duesseldorf, Duesseldorf, Germany
| | - Anja Lachenmayer
- Present ccaddress: Department of Visceral Surgery and Medicine, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Hany Ashmawy
- Department of Surgery A, University Hospital Duesseldorf, Duesseldorf, Germany.,Department of General, Visceral, Thorax and Pediatric Surgery,Heinrich-Heine-University Hospital, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Andreas Krieg
- Department of Surgery A, University Hospital Duesseldorf, Duesseldorf, Germany.,Department of General, Visceral, Thorax and Pediatric Surgery,Heinrich-Heine-University Hospital, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Stefan A Topp
- Present address: Department of Surgery, Ameos Hospital, Bremerhaven, Germany
| | - Alexander Rehders
- Department of Surgery A, University Hospital Duesseldorf, Duesseldorf, Germany.,Department of General, Visceral, Thorax and Pediatric Surgery,Heinrich-Heine-University Hospital, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Wolfram Trudo Knoefel
- Department of Surgery A, University Hospital Duesseldorf, Duesseldorf, Germany. .,Department of General, Visceral, Thorax and Pediatric Surgery,Heinrich-Heine-University Hospital, Moorenstr. 5, 40225, Duesseldorf, Germany.
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18
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Garcia-Botella A, Sáez-Carlin P, Méndez R, Martin MP, Ortega L, Méndez JV, García-Paredes B, Diez-Valladares L, Torres AJ. CD133 + cell infusion in patients with colorectal liver metastases going to be submitted to a major liver resection (CELLCOL): A randomized open label clinical trial. Surg Oncol 2019; 33:224-230. [PMID: 32561087 DOI: 10.1016/j.suronc.2019.10.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/04/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Treatment of liver metastases of colorectal carcinoma is surgical resection. However, only 10-15% of the patients in this context will be candidate for curative resection arising other 10-13% after response to neoadyuvant chemotherapy. In order to perform the liver metastases surgery, it is necessary to have a sufficient remnant liver volume (RLV) which allows maintaining an optimal liver function after resection. Studies on liver regeneration have determined that CD133 + stem cells are involved in liver hypertrophy developed after an hepatectomy with encouraging results. As presented in previous studies, CD133 + stem cells can be selected from peripheral blood after stimulation with G-CSF, being able to obtain a large number of them. We propose to treat patients who do not meet criteria for liver metastases surgery because of insufficient RLV (<40%) with CD133 + cells together with portal embolization, in order to achieve enough liver volume which avoids liver failure. METHODS /Design: The aim of this study is to evaluate the effectiveness of preoperative PVE plus the administration of CD133 + mobilized from peripheral blood with G-CSF compared to PVE only. SECONDARY AIMS ARE: to compare the grade of hypertrophy, speed and changes in liver function, anatomopathological study of hypertrophied liver, to determine the safety of the treatment and analysis of postoperative morbidity and surveillance. STUDY DESIGN Prospective randomized longitudinal phase IIb clinical trial, open, to evaluate the efficacy of portal embolization (PVE) together with the administration of CD133 + cells obtained from peripheral blood versus PVE alone, in patients with hepatic metastasis of colorectal carcinoma (CCRHM). DISCUSSION The number of CD133 + obtained from peripheral blood after G -CSF stimulation will be far greater than the number obtained with direct puncture of bone marrow. This will allow a greater intrahepatic infusion, which could have a direct impact on achieving a larger and quicker hypertrophy. Consequently, it will permit the treatment of a larger number of patients with an increase on their survival. TRIAL REGISTRATION ClinicalTrials.gov, ID NCT03803241.
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Affiliation(s)
| | - Patricia Sáez-Carlin
- Surgery (HepatoPancreatoBiliary Unit), Hospital Clínico San Carlos Madrid, Spain.
| | - Ramiro Méndez
- Department of Radiology, Hospital Universitario Clínico San Carlos, Madrid, Spain.
| | - Maria Paz Martin
- Department o Hematology, Hospital Universitario Clínico San Carlos, Madrid, Spain.
| | - Luis Ortega
- Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain.
| | - Jose Vicente Méndez
- Department of Radiology, Hospital Universitario Clínico San Carlos, Madrid, Spain.
| | | | - L Diez-Valladares
- Surgery (HepatoPancreatoBiliary Unit), Hospital Clínico San Carlos Madrid, Spain.
| | - Antonio Jose Torres
- Surgery (HepatoPancreatoBiliary Unit), Hospital Clínico San Carlos Madrid, Spain.
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19
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Chen B, Pang L, Cao H, Wu D, Wang Y, Tao Y, Wang M, Chen E. Autologous stem cell transplantation for patients with viral hepatitis-induced liver cirrhosis: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2019; 31:1283-1291. [PMID: 31206409 DOI: 10.1097/meg.0000000000001455] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Recently, stem cells have been used in the treatment of viral hepatitis-induced liver cirrhosis (LC), and stem cell therapy is showing potential therapeutic effects on liver function improvement. The consensus on effects and safety of stem cell therapy has not been reached, thus it is essential for us to conduct a systematic review and meat-analysis to investigate the efficacy and safety of stem cell therapy for viral hepatitis-induced LC. MATERIALS AND METHODS Medline, Embase, SinoMed and Cochrane Library databases were searched with appropriate keywords through 5 August 2018. We included eight trials involving 467 patients. The pooled weight mean difference (WMD) and 95% confidence interval (CI) were calculated using a fixed or random effects model. Quality assessment and publication bias were also performed. The selected studies were considered for meta-analysis using RevMan V5.3. RESULTS Compared with traditional therapy group, autologous stem cell transplantation increased the level of albumin (WMD: 2.47, 95% CI: 1.05-3.90, P < 0.001), but decreased the level of total bilirubin (WMD: -2.26, 95% CI: -3.61 to -0.90, P = 0.001), alanine aminotransferase (WMD: -9.16, 95% CI: -16.47 to -1.85, P = 0.01) and prothrombin time (WMD: -3.02, 95% CI: -4.83 to -1.22, P = 0.001). Clinical symptoms such as edema, fatigue, anorexia and abdominal distention were alleviated. Model for End-Stage Liver Disease and Child-Pugh scores were decreased after stem cell therapy. Whereas, there was no statistically significant difference between two groups regarding aspartate aminotransferase, prothrombin time activity, ascites and pleural fluid. No procedure-related complications were found. CONCLUSION Autologous stem cell transplantation might have beneficial effects on patients with viral hepatitis-induced LC and is relatively safe for these patients. Further high-quality randomized controlled trials are needed.
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Affiliation(s)
- Bin Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Long Pang
- West China School of Medicine, Sichuan University, Chengdu, People's Republic of China
| | - Hongxin Cao
- West China School of Medicine, Sichuan University, Chengdu, People's Republic of China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Yonghong Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Yachao Tao
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Menglan Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University
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20
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Abstract
Posthepatectomy liver failure (PHLF) still represents a severe complication after major liver resection associated with a high mortality. In addition to an insufficient residual liver volume various factors play an important role in the pathophysiology of PHLF. These include the quality of the parenchyma, liver function, perfusion, i.e. maintenance of adequate inflow and outflow, as well as the condition of the patient and comorbidities. While the liver volume is relatively easy to evaluate using modern imaging techniques, the evaluation of liver function and liver quality require a differentiated approach. Both factors can be influenced by the constitutional status of the patient, medical history and previous treatment and must be given sufficient consideration in the risk evaluation. An adequate perfusion, e.g. portal and arterial circulation and adequate outflow by at least one hepatic vein as well an adequate biliary drainage should be always guaranteed in order to allow regeneration of the residual liver tissue. Only the understanding of all these aspects will support the surgeon in a correct and safe evaluation of the resectability. Additionally, the liver surgeon should be aware of all available perioperative and postoperative options to treat and to prevent PHLF. In this review article the most important questions regarding the risk factors related to PHLF are presented and the potential therapeutic and prophylactic management is described. The main goal is to ensure functional operability of the patient if oncological resectability is possible. In other words: in the case of correct oncological indication, the liver surgeon should be able to resect what is resectable or, alternatively, make resectable what primarily was not resectable.
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Affiliation(s)
- I Capobianco
- Universitätsklinik für Allgemeine, Viszeral- und Transplantationschirurgie Tübingen, Hoppe-Seylerstraße 3, 72076, Tübingen, Deutschland
| | - J Strohäker
- Universitätsklinik für Allgemeine, Viszeral- und Transplantationschirurgie Tübingen, Hoppe-Seylerstraße 3, 72076, Tübingen, Deutschland
| | - A Della Penna
- Universitätsklinik für Allgemeine, Viszeral- und Transplantationschirurgie Tübingen, Hoppe-Seylerstraße 3, 72076, Tübingen, Deutschland
| | - S Nadalin
- Universitätsklinik für Allgemeine, Viszeral- und Transplantationschirurgie Tübingen, Hoppe-Seylerstraße 3, 72076, Tübingen, Deutschland
| | - A Königsrainer
- Universitätsklinik für Allgemeine, Viszeral- und Transplantationschirurgie Tübingen, Hoppe-Seylerstraße 3, 72076, Tübingen, Deutschland.
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21
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Yasen A, Tuxun T, Apaer S, Li W, Maimaitinijiati Y, Wang H, Aisan M, Aji T, Shao Y, Hao W. Fetal liver stem cell transplantation for liver diseases. Regen Med 2019; 14:703-714. [PMID: 31393226 DOI: 10.2217/rme-2018-0160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Stem cell transplantation exhibited a promising lifesaving therapy for various end-stage liver diseases and could serve as a salvaging bridge until curative methods can be performed. In past decades, mature hepatocytes, liver progenitor cells, mesenchymal stem cells and induced pluripotent stem cells have been practiced in above settings. However, long-term survival rates and continuous proliferation ability of these cells in vivo are unsatisfactory, whereas, fetal liver stem cells (FLSCs), given their unique superiority, may be the best candidate for stem cell transplantation technique. Recent studies have revealed that FLSCs could be used as an attractive genetic therapy or regenerative treatments for inherited metabolic or other hepatic disorders. In this study, we reviewed current status and advancements of FLSCs-based treatment.
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Affiliation(s)
- Aimaiti Yasen
- Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Tuerhongjiang Tuxun
- Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Shadike Apaer
- State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Wending Li
- Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Liver & Laparoscopic Surgery, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Yusufukadier Maimaitinijiati
- Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Hui Wang
- State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Meiheriayi Aisan
- Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Tuerganaili Aji
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Yingmei Shao
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
| | - Wen Hao
- State Key Laboratory on Pathogenesis, Prevention & Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, 393 Xin Yi Road, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China.,Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang Uyghur Autonomous Region, PR China
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22
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Duhme C, Lehwald N, Kehrel BE, Bauchrowitz E, Ngepi A, Schmelzle M, Kolokotronis T, Benhidjeb T, Krüger M, Jurk K, Knoefel WT, Robson SC, Schulte Am Esch J. CD133 + bone marrow stem cells (BMSC) control platelet activation - Role of ectoNTPDase-1 (CD39). Blood Cells Mol Dis 2019; 77:142-148. [PMID: 31075617 DOI: 10.1016/j.bcmd.2019.04.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/25/2019] [Accepted: 04/26/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND We previously demonstrated CD133+ bone marrow stem cells (BMSC) to promote hepatic proliferation for liver regeneration. Here, we evaluated the capacity of CD133+BMSC to utilize platelets for homing to vasculature and concomitant controlling their aggregability upon ADP stimulation. METHODS CD133+BMSC and platelets were co-cultured along micro endothelial cells under variable flow conditions and tested for homing levels along vasculature. Aggregometry and FACS analysis were utilized to evaluate platelet reactivity following co-incubation ± CD133+BMSC. RT-PCR and FACS analyses served to characterize ADP degrading ectonucleoside triphosphate diphosphohydrolase-1 (ectoNTPDase-1/CD39) expression on various cell types. RESULTS Platelets attracted human CD133+BMSC to autologous micro endothelium under shear stress unaffected by ADP stimulation. However, CD133+BMSC inhibited ADP-mediated platelet activation and aggregation. Latter was dependent on ectoNTPDase-1 expression levels. Platelet aggregatory control was increased with CD133+BMSC compared to CD133+PHSC. Different effects of those stem cell subtypes positively correlated with their FACS-detected expression levels of ectoNTPDase-1. CONCLUSION We provide evidence that CD133+BMSC are capable of controlling ADP-dependent platelet aggregation and activation by direct interaction dependent on cellular expression of ectoNTPDase-1. Whether different capacities of BMSC modulate platelet-depending thrombogenicity at sites of regeneration impact effectiveness and adverse event profiles of regenerative treatment requires further evaluation.
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Affiliation(s)
- Constanze Duhme
- Department of Surgery A, University Hospital Duesseldorf, Germany
| | - Nadja Lehwald
- Department of Surgery A, University Hospital Duesseldorf, Germany
| | - Beate E Kehrel
- Department of Anesthesiology Intensive Care and Pain Medicine, Experimental and Clinical Hemostasis, University of Muenster, Muenster, Germany
| | | | - Arlette Ngepi
- Department of Surgery A, University Hospital Duesseldorf, Germany
| | | | - Theodoros Kolokotronis
- Center of Visceral Medicine, Department of General and Visceral Surgery, Protestant Hospital of Bethel Foundation, Bielefeld, Germany
| | - Tahar Benhidjeb
- Center of Visceral Medicine, Department of General and Visceral Surgery, Protestant Hospital of Bethel Foundation, Bielefeld, Germany
| | - Martin Krüger
- Center of Visceral Medicine, Department of Gastroenterology and Internal Medicine, Protestant Hospital of Bethel Foundation, Bielefeld, Germany
| | - Kerstin Jurk
- Department of Anesthesiology Intensive Care and Pain Medicine, Experimental and Clinical Hemostasis, University of Muenster, Muenster, Germany; Center for Thrombosis and Hemostasis, Johannes Gutenberg-University, Mainz, Germany
| | | | - Simon C Robson
- The Transplant Institute and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA
| | - Jan Schulte Am Esch
- Center of Visceral Medicine, Department of General and Visceral Surgery, Protestant Hospital of Bethel Foundation, Bielefeld, Germany.
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23
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Wabitsch S, Benzing C, Krenzien F, Splith K, Haber PK, Arnold A, Nösser M, Kamali C, Hermann F, Günther C, Hirsch D, Sauer IM, Pratschke J, Schmelzle M. Human Stem Cells Promote Liver Regeneration After Partial Hepatectomy in BALB/C Nude Mice. J Surg Res 2019; 239:191-200. [PMID: 30844633 DOI: 10.1016/j.jss.2019.02.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 01/16/2019] [Accepted: 02/05/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been suggested to augment liver regeneration after surgically and pharmacologically induced liver failure. To further investigate this we processed human bone marrow-derived MSC according to good manufacturing practice (GMP) and tested those cells for their modulatory capacities of metabolic alterations and liver regeneration after partial hepatectomy in BALB/c nude mice. METHODS Human MSCs were obtained by bone marrow aspiration of healthy donors as in a previously described GMP process. Transgenic GFP-MSCs were administered i.p. 24 h after 70% hepatectomy in BALB/c nude mice, whereas control mice received phosphate-buffered saline. Mice were sacrificed 2, 3, and 5 d after partial hepatectomy. Blood and organs were harvested and metabolic alterations as well as liver regeneration subsequently assessed by liver function tests, multianalyte profiling immunoassays, histology, and immunostaining. RESULTS Hepatocyte and sinusoidal endothelial cell proliferation were significantly increased after partial hepatectomy in mice receiving MSC compared to control mice (Hepatocyte postoperative day 3, P < 0.01; endothelial cell postoperative day 5, P < 0.05). Hepatocyte fat accumulation correlated inversely with hepatocyte proliferation (r2 = 0.4064, P < 0.01) 2 d after partial hepatectomy, with mice receiving MSC being protected from severe fat accumulation. No GFP-positive cells could be detected in the samples. Serum levels of IL-6, HGF, and IL-10 were significantly decreased at day 3 in mice receiving MSC when compared to control mice (P < 0.05). Relative body weight loss was significantly attenuated after partial hepatectomy in mice receiving MSC (2 d and 3 d, both P < 0.001) with a trend toward a faster relative restoration of liver weight, when compared to control mice. CONCLUSIONS Human bone marrow-derived MSC attenuate metabolic alterations and improve liver regeneration after partial hepatectomy in BALB/c nude mice. Obtained results using GMP-processed human MSC suggest functional links between fat accumulation and hepatocyte proliferation, without any evidence for cellular homing. This study using GMP-proceeded MSC has important regulatory implications for an urgently needed translation into a clinical trial.
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Affiliation(s)
- Simon Wabitsch
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany.
| | - Christian Benzing
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Katrin Splith
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Philipp Konstantin Haber
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Alexander Arnold
- Departement of Pathology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Maximilian Nösser
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Can Kamali
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | | | | | | | - Igor M Sauer
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
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24
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Mononuclear-cell-derived microparticles attenuate endothelial inflammation by transfer of miR-142-3p in a CD39 dependent manner. Purinergic Signal 2018; 14:423-432. [PMID: 30244433 DOI: 10.1007/s11302-018-9624-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 08/29/2018] [Indexed: 12/22/2022] Open
Abstract
Plasma microparticles (MP) bear functional active ectonucleotidases of the CD39 family with implications in vascular inflammation. MP appear to be able to fuse with cells and transfer genetic information. Here, we tested whether levels of different immunomodulatory microRNAs (miRs) in plasma MP are modulated by CD39 after experimental hepatectomy. We further investigated whether horizontal transfer of miR-142-3p between mononuclear (MNC) and endothelial cells via MP is regulated by purinergic signaling. Partial hepatectomy was performed in C57BL/6 wild type and Cd39 null mice. MP were collected via ultracentrifugation. MNC were stimulated with nucleotides and nucleosides, in vitro, and tested for miR-142-3p levels. Fusion of MNC-derived MP and endothelial cells with subsequent transfer of miR-142-3p was imaged by flow cytometry and confocal microscopy. Endothelial inflammation and apoptosis were quantified after transfection with miR-142-3p. Significantly lower miR-142-3p levels were observed in plasma MP of Cd39 null mice after partial hepatectomy, when compared to C57BL/6 wild types (p < 0.05). In contrast to extracellular nucleotides, anti-inflammatory adenosine significantly increased miR-142-3p levels in MNC-derived MP, in vitro (p < 0.05). MNC-derived MP are able to transfer miR-142-3p to endothelial cells by fusion. Transfection of endothelial cells with miR-142-3p decreased TNF-α levels (p < 0.05) and endothelial apoptosis (p < 0.05). MiR-142-3p levels in MNC-derived MP are modulated by nucleoside signaling and might reflect compensatory responses in vascular inflammation. Our data suggest the transfer of genetic information via shed MP as a putative mechanism of intercellular communication-with implications in organ regeneration.
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25
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Chia DKA, Yeo Z, Loh SEK, Iyer SG, Madhavan K, Kow AWC. ALPPS for Hepatocellular Carcinoma Is Associated with Decreased Liver Remnant Growth. J Gastrointest Surg 2018; 22:973-980. [PMID: 29380118 DOI: 10.1007/s11605-018-3697-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 01/15/2018] [Indexed: 01/31/2023]
Abstract
BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been widely described for colorectal liver metastases with insufficient future liver remnant (FLR). However, its role in hepatocellular carcinoma (HCC) remains poorly defined and not widely accepted. METHODS A retrospective comparison of clinical data, liver volumetry, histological characteristics, and surgical outcomes between nine HCC and four non-HCC patients who underwent ALPPS was performed. RESULTS Patients with HCC were more likely to have histological evidence of hepatic fibrosis (HCC vs. non-HCC, 66.7 vs. 0%, p = 0.049). Baseline demographic and disease characteristics were otherwise comparable between both groups. FLR growth after ALPPS-Stage 1 was significantly less in HCC patients (HCC vs. non-HCC, 154.5 vs. 251.0 ml, p = 0.012). FLR growth was also significantly decreased in patients with hepatic fibrosis (fibrosis vs. non-fibrosis, 157.5 vs. 247.5 ml, p = 0.033). There was no difference in post-hepatectomy liver failure (HCC vs. non-HCC, 28.6 vs. 25%, p = 0.721) or 90-day mortality (HCC vs. non-HCC, 11.1 vs. 0%, p = NS). DISCUSSION In our study, HCC patients demonstrated significantly less FLR growth after ALPPS-Stage 1 compared to non-HCC patients. Hepatic fibrosis was also found to negatively impact FLR growth. When considering suitability for ALPPS, patients with HCC may benefit from additional pre-operative assessment of fibrosis.
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Affiliation(s)
- Daryl Kai Ann Chia
- Division of Hepatopancreaticobiliary Surgery and Liver Transplantation, Department of Surgery, National University Health System Singapore, Singapore, Singapore
| | - Zachery Yeo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Stanley Eu Kuang Loh
- Department of Diagnostic Imaging, National University Health System, Singapore, Singapore
| | - Shridhar Ganpathi Iyer
- Division of Hepatopancreaticobiliary Surgery and Liver Transplantation, Department of Surgery, National University Health System Singapore, Singapore, Singapore
| | - Krishnakumar Madhavan
- Division of Hepatopancreaticobiliary Surgery and Liver Transplantation, Department of Surgery, National University Health System Singapore, Singapore, Singapore
| | - Alfred Wei Chieh Kow
- Division of Hepatopancreaticobiliary Surgery and Liver Transplantation, Department of Surgery, National University Health System Singapore, Singapore, Singapore.
- Division of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, University Surgical Cluster, National University Hospital, 1E, Kent Ridge Road, NUHS Tower Block, Level 8, Singapore, 119228, Singapore.
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26
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Hung ML, McWilliams JP. Portal vein embolization prior to hepatectomy: Techniques, outcomes and novel therapeutic approaches. INTERNATIONAL JOURNAL OF GASTROINTESTINAL INTERVENTION 2018. [DOI: 10.18528/gii180010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Matthew L. Hung
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Justin P. McWilliams
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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27
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Jonas S, Krenzien F, Atanasov G, Hau HM, Gawlitza M, Moche M, Wiltberger G, Pratschke J, Schmelzle M. Hilar en bloc resection for hilar cholangiocarcinoma in patients with limited liver capacities-preserving parts of liver segment 4. Eur Surg 2018; 50:22-29. [PMID: 30459814 PMCID: PMC6223732 DOI: 10.1007/s10353-017-0507-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 12/12/2017] [Indexed: 01/15/2023]
Abstract
Background A right trisectionectomy with portal vein resection represents the conventional approach for hilar cholangiocarcinoma. Here, we present a technical modification of hilar en bloc resection in order to increase the remnant volume by partially preserving liver segment 4. Methods The caudal parenchymal dissection line starts centrally between the left lateral and left medial segments. Cranially, the resection line switches to the right towards Cantlie's line and turns again upwards perpendicularly. Hence, segment 4a and subtotal segment 4b are partially preserved by this novel technique. The left hepatic duct is dissected at the segmental ramification and reconstruction is performed as a single hepaticojejunostomy. The feasibility of the novel parenchyma-sparing approach for hilar cholangiocarcinoma was proven in a case series and medical records were reviewed retrospectively. Results Ten patients (6 male, 4 female) underwent segment 4 partially preserving right trisectionectomy for hilar cholangiocarcinoma. Estimated future liver remnant volume was significantly increased (FLRV 38.3%), when compared to standard right trisectionectomy (FLRV 23.9%; p < 0.01). Three of 10 liver resections were associated with major surgical complications (≥IIIb; n = 3); categorized according to the Dindo-Clavien classification. No patient died due to complications associated with postoperatively impaired liver function. Tumor-free margins could be achieved in 8 patients while median overall survival and disease-free survival were 547 and 367 days, respectively. Conclusion This novel parenchyma-sparing modification of hilar en bloc resection by partially preserving segment 4 allows to safely increase the remnant liver volume without neglecting principles of local radicality.
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Affiliation(s)
- Sven Jonas
- Department of Surgery, 310Klinik, Nürnberg, Germany
| | - Felix Krenzien
- 2Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Georgi Atanasov
- 2Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Hans-Michael Hau
- 3Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Matthias Gawlitza
- Department of Diagnostic and Interventional Radiology, 310Klinik, Nürnberg, Germany
| | - Michael Moche
- Department of Diagnostic and Interventional Radiology, 310Klinik, Nürnberg, Germany
| | - Georg Wiltberger
- 3Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Johann Pratschke
- 2Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Moritz Schmelzle
- 2Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
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Ha S, Alshahrani AA, Hwang S. ALPPS in a patient with periductal infiltrating intrahepatic cholangiocarcinoma. Ann Hepatobiliary Pancreat Surg 2017; 21:223-227. [PMID: 29264586 PMCID: PMC5736743 DOI: 10.14701/ahbps.2017.21.4.223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 09/05/2017] [Accepted: 09/05/2017] [Indexed: 12/22/2022] Open
Abstract
Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) is a novel method to prevent post-hepatectomy hepatic failure. We present a case of periductal infiltrating intrahepatic cholangiocarcinoma undergone ALPPS, that was conducted as intraoperative choice instead of conducting preoperative portal vein embolization (PVE). A 65-year-old male patient was to undergo extended right posterior sectionectomy, but the operation plan was changed to conduct right hepatectomy with/without bile duct resection due to invasion of the right hepatic duct. After deciding to conduct ALPPS, we stopped further perihilar dissection and liver was transected. The right portal vein was ligated and Surgicel was densely packed between the transected hemilivers. There was rapid regeneration of the left liver on computed tomography follow-up, thus the second-stage right hepatectomy was conducted 10 days after the first-stage operation. Bile duct resection (BDR) was not performed due to heavy perihilar adhesion and inflammation, but fortunately tumor-negative bile duct resection margin was achieved after meticulous dissection. This patient recovered uneventfully and discharged nine days after the second-stage right hepatectomy. Thereafter he underwent concurrent chemoradiation therapy. He is doing well so far without evidence of tumor recurrence for 20 months after operation. In conclusion, this case suggests that ALPPS may be applied to an unexpected situation requiring PVE, but ALPPS is not recommend for treatment of perihilar malignancy requiring BDR.
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Affiliation(s)
- Sumin Ha
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Abdulwahab A Alshahrani
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Multi Organ Transplant Center, King Fahad Specialist University Hospital, Dammam, Saudi Arabia
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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29
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Huang SY, Aloia TA. Portal Vein Embolization: State-of-the-Art Technique and Options to Improve Liver Hypertrophy. Visc Med 2017; 33:419-425. [PMID: 29344515 DOI: 10.1159/000480034] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Portal vein embolization (PVE) is associated with a high technical and clinical success rate for induction of future liver remnant hypertrophy prior to surgical resection. The degree of hypertrophy is variable and depends on multiple factors, including technical aspects of the procedure and underlying chronic liver disease. For patients with insufficient liver volume following PVE, adjunctive techniques, such as intra-portal administration of stem cells, dietary supplementation, transarterial embolization, and hepatic vein embolization, are available. Our purpose is to review the state-of-the-art technique associated with high-quality PVE and to discuss options to improve hypertrophy of the future liver remnant.
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Affiliation(s)
- Steven Y Huang
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Thomas A Aloia
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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30
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Greater hypertrophy can be achieved with associating liver partition with portal vein ligation for staged hepatectomy compared to conventional staged hepatectomy, but with a higher price to pay? Am J Surg 2017; 215:131-137. [PMID: 28859921 DOI: 10.1016/j.amjsurg.2017.08.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 08/12/2017] [Accepted: 08/21/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) and conventional staged hepatectomy (CSH) are options for patients with unresectable liver tumors due to insufficient future liver remnant (FLR). METHODS A retrospective comparison of clinical data, liver volumetry and surgical outcomes between 10 ALPPS and 29 CSH patients was performed. RESULTS Patient demographics and disease characteristics were similar between both groups. ALPPS induced superior FLR growth (ALPPS vs. CSH, 48.1% (IQR 39.4-96.9%) vs. 11.8% (IQR 4.3-41.9%), p = 0.013). However, post-operative day 5 international normalized ratio (INR) (ALPPS vs. CSH, 1.6 (IQR 1.5-1.8) vs. 1.4 (IQR 1.3-1.6), p = 0.015) and rate of post-hepatectomy liver failure (ALPPS vs. CSH, 25 vs. 0%, p = 0.032) was higher in the ALPPS group. 90-day mortality (ALPPS vs. CSH, 12.5% vs. 0%, p = 0.320) was similar in both groups. CONCLUSION ALPPS was superior in inducing FLR growth but associated with increased post-hepatectomy liver failure compared to CSH.
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31
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Liver Cells Proliferation and Apoptosis in Patients with Alcoholic Liver Disease After Autologous Hematopoietic Stem Cell Transplantation. BIONANOSCIENCE 2017. [DOI: 10.1007/s12668-016-0354-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Ludvík J, Duras P, Třeška V, Matoušková T, Brůha J, Fichtl J, Lysák D, Ferda J, Baxa J. Portal Vein Embolization with Contralateral Application of Stem Cells Facilitates Increase of Future Liver Remnant Volume in Patients with Liver Metastases. Cardiovasc Intervent Radiol 2017; 40:690-696. [PMID: 28091729 DOI: 10.1007/s00270-017-1566-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Accepted: 01/02/2017] [Indexed: 02/08/2023]
Abstract
OBJECTIVES This study aimed to evaluate the progress of future liver remnant volume (FLRV) in patients with liver metastases after portal vein embolization (PVE) with the application of hematopoietic stem cells (HSCs) and compare it with a patients control group after PVE only. METHODS Twenty patients (group 1) underwent PVE with contralateral HSC application. Subsequently, CT volumetry with the determination of FLRV was performed at weekly intervals, in total three weeks. A sample of twenty patients (group 2) who underwent PVE without HSC application was used as a control group. RESULTS The mean of FLRV increased by 173.2 mL during three weeks after the PVE/HSC procedure, whereas by 98.9 mL after PVE only (p = 0.015). Furthermore, the mean daily growth of FLRV by 7.6 mL in group 1 was significantly higher in comparison with 4.1 mL in group 2 (p = 0.007). CONCLUSIONS PVE with the application of HSC significantly facilitates growth of FLRV in comparison with PVE only. This method could be one of the new suitable approaches to increase the resectability of liver tumours.
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Affiliation(s)
- Jaroslav Ludvík
- Department of Imaging Methods, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic. .,, alej Svobody 80, 30460, Plzeň, Czech Republic.
| | - Petr Duras
- Department of Imaging Methods, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | - Vladislav Třeška
- Department of Surgery, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | - Táňa Matoušková
- Department of Imaging Methods, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | - Jan Brůha
- Department of Surgery, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | - Jakub Fichtl
- Department of Surgery, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | - Daniel Lysák
- Department of Haemato-Oncology, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | - Jiří Ferda
- Department of Imaging Methods, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
| | - Jan Baxa
- Department of Imaging Methods, University Hospital and Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic
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Engelmann C, Splith K, Berg T, Schmelzle M. Effects of granulocyte-colony stimulating factor (G-CSF) on stem cell mobilization in patients with liver failure. Eur J Intern Med 2016; 36:e37-e39. [PMID: 27745994 DOI: 10.1016/j.ejim.2016.09.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 09/07/2016] [Indexed: 12/23/2022]
Affiliation(s)
- Cornelius Engelmann
- University Hospital Leipzig, Section of Hepatology, Department of Internal Medicine, Neurology, Dermatology, Liebigstraße 20, 04103 Leipzig, Germany.
| | - Katrin Splith
- Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Surgery, Augustenburger Platz 1, 13353 Berlin, Germany.
| | - Thomas Berg
- University Hospital Leipzig, Section of Hepatology, Department of Internal Medicine, Neurology, Dermatology, Liebigstraße 20, 04103 Leipzig, Germany.
| | - Moritz Schmelzle
- Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Surgery, Augustenburger Platz 1, 13353 Berlin, Germany.
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Eshmuminov D, Raptis DA, Linecker M, Wirsching A, Lesurtel M, Clavien PA. Meta-analysis of associating liver partition with portal vein ligation and portal vein occlusion for two-stage hepatectomy. Br J Surg 2016; 103:1768-1782. [PMID: 27633328 DOI: 10.1002/bjs.10290] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 07/04/2016] [Accepted: 07/06/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Discussion is ongoing regarding whether associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) or portal vein occlusion is better in staged hepatectomy. The aim of this study was to compare available strategies using a two-stage approach in extended hepatectomy. METHODS A literature search was performed in MEDLINE, Scopus, the Cochrane Library and Embase, and additional articles were identified by hand searching. Data from the international ALPPS registry were extracted. Clinical studies reporting volumetric changes, mortality, morbidity, feasibility of the second stage and tumour-free resection margins (R0) in two-stage hepatectomy were included. RESULTS Ninety studies involving 4352 patients, including 320 from the ALPPS registry, met the inclusion criteria. Among these, nine studies (357 patients) reported on comparisons with other strategies. In the comparison of ALPPS versus portal vein embolization (PVE), ALPPS was associated with a greater increase in the future liver remnant (76 versus 37 per cent; P < 0·001) and more frequent completion of stage 2 (100 versus 77 per cent; P < 0·001). Compared with PVE, ALPPS had a trend towards higher morbidity (73 versus 59 per cent; P = 0·16) and mortality (14 versus 7 per cent; P = 0·19) after stage 2. In the non-comparative studies, complication rates were 39 per cent in the PVE group, 47 per cent in the portal vein ligation (PVL) group and 70 per cent in the ALPPS group. After stage 2, mortality rates were 5, 7 and 12 per cent respectively. CONCLUSION ALPPS is associated with greater future liver remnant hypertrophy and a higher rate of completion of stage 2, but this may be at the price of greater morbidity and mortality.
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Affiliation(s)
- D Eshmuminov
- Department of Surgery, Swiss HPB and Transplantation Centre, University Hospital Zurich, Zurich, Switzerland
| | - D A Raptis
- Department of Surgery, Swiss HPB and Transplantation Centre, University Hospital Zurich, Zurich, Switzerland
| | - M Linecker
- Department of Surgery, Swiss HPB and Transplantation Centre, University Hospital Zurich, Zurich, Switzerland
| | - A Wirsching
- Department of Surgery, Swiss HPB and Transplantation Centre, University Hospital Zurich, Zurich, Switzerland
| | - M Lesurtel
- Department of Surgery, Swiss HPB and Transplantation Centre, University Hospital Zurich, Zurich, Switzerland.,Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France
| | - P-A Clavien
- Department of Surgery, Swiss HPB and Transplantation Centre, University Hospital Zurich, Zurich, Switzerland
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Diener Y, Bosio A, Bissels U. Delivery of RNA-based molecules to human hematopoietic stem and progenitor cells for modulation of gene expression. Exp Hematol 2016; 44:991-1001. [PMID: 27576131 DOI: 10.1016/j.exphem.2016.08.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 08/01/2016] [Accepted: 08/18/2016] [Indexed: 12/26/2022]
Abstract
Gene modulation of human hematopoietic stem and progenitor cells (HSPCs) harbors great potential for therapeutic application of these cells and presents a versatile tool in basic research to enhance our understanding of HSPC biology. However, stable genetic modification might be adverse, particularly in clinical settings. Here, we review a broad range of approaches to transient, nonviral modulation of protein expression with a focus on RNA-based methods. We compare different delivery methods and describe the usefulness of RNA molecules for overexpression as well as downregulation of proteins in HSPCs.
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Affiliation(s)
| | | | - Ute Bissels
- Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
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36
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Hau HM, Tautenhahn HM, Schmelzle M, Morgul HM, Moche M, Bartels M, Uhlmann D. Current strategies for preoperative conditioning of the liver to expand criteria for resectability of hepatic metastases. Eur Surg 2016; 48:180-190. [DOI: 10.1007/s10353-015-0381-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Madoff DC, Gaba RC, Weber CN, Clark TWI, Saad WE. Portal Venous Interventions: State of the Art. Radiology 2016; 278:333-53. [PMID: 26789601 DOI: 10.1148/radiol.2015141858] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In recent decades, there have been numerous advances in the management of liver cancer, cirrhosis, and diabetes mellitus. Although these diseases are wide ranging in their clinical manifestations, each can potentially be treated by exploiting the blood flow dynamics within the portal venous system, and in some cases, adding cellular therapies. To aid in the management of these disease states, minimally invasive transcatheter portal venous interventions have been developed to improve the safety of major hepatic resection, to reduce the untoward effects of sequelae from end-stage liver disease, and to minimize the requirement of exogenously administered insulin for patients with diabetes mellitus. This state of the art review therefore provides an overview of the most recent data and strategies for utilization of preoperative portal vein embolization, transjugular intrahepatic portosystemic shunt placement, balloon retrograde transvenous obliteration, and islet cell transplantation.
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Affiliation(s)
- David C Madoff
- From the Department of Radiology, Division of Interventional Radiology, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th St, P-518, New York, NY 10065 (D.C.M.); Department of Radiology, Interventional Radiology Section, University of Illinois Hospital, Chicago, Ill (R.C.G.); Department of Radiology, University of Pennsylvania School of Medicine, Penn Presbyterian Medical Center, Philadelphia, Pa (C.N.W., T.W.I.C.); and Department of Radiology, Division of Vascular and Interventional Radiology, University of Michigan Medical Center, Ann Arbor, Mich (W.E.S.)
| | - Ron C Gaba
- From the Department of Radiology, Division of Interventional Radiology, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th St, P-518, New York, NY 10065 (D.C.M.); Department of Radiology, Interventional Radiology Section, University of Illinois Hospital, Chicago, Ill (R.C.G.); Department of Radiology, University of Pennsylvania School of Medicine, Penn Presbyterian Medical Center, Philadelphia, Pa (C.N.W., T.W.I.C.); and Department of Radiology, Division of Vascular and Interventional Radiology, University of Michigan Medical Center, Ann Arbor, Mich (W.E.S.)
| | - Charles N Weber
- From the Department of Radiology, Division of Interventional Radiology, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th St, P-518, New York, NY 10065 (D.C.M.); Department of Radiology, Interventional Radiology Section, University of Illinois Hospital, Chicago, Ill (R.C.G.); Department of Radiology, University of Pennsylvania School of Medicine, Penn Presbyterian Medical Center, Philadelphia, Pa (C.N.W., T.W.I.C.); and Department of Radiology, Division of Vascular and Interventional Radiology, University of Michigan Medical Center, Ann Arbor, Mich (W.E.S.)
| | - Timothy W I Clark
- From the Department of Radiology, Division of Interventional Radiology, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th St, P-518, New York, NY 10065 (D.C.M.); Department of Radiology, Interventional Radiology Section, University of Illinois Hospital, Chicago, Ill (R.C.G.); Department of Radiology, University of Pennsylvania School of Medicine, Penn Presbyterian Medical Center, Philadelphia, Pa (C.N.W., T.W.I.C.); and Department of Radiology, Division of Vascular and Interventional Radiology, University of Michigan Medical Center, Ann Arbor, Mich (W.E.S.)
| | - Wael E Saad
- From the Department of Radiology, Division of Interventional Radiology, New York-Presbyterian Hospital/Weill Cornell Medical Center, 525 E 68th St, P-518, New York, NY 10065 (D.C.M.); Department of Radiology, Interventional Radiology Section, University of Illinois Hospital, Chicago, Ill (R.C.G.); Department of Radiology, University of Pennsylvania School of Medicine, Penn Presbyterian Medical Center, Philadelphia, Pa (C.N.W., T.W.I.C.); and Department of Radiology, Division of Vascular and Interventional Radiology, University of Michigan Medical Center, Ann Arbor, Mich (W.E.S.)
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Simultaneous trans-hepatic portal and hepatic vein embolization before major hepatectomy: the liver venous deprivation technique. Eur Radiol 2016; 26:4259-4267. [DOI: 10.1007/s00330-016-4291-9] [Citation(s) in RCA: 139] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 02/14/2016] [Accepted: 02/17/2016] [Indexed: 02/06/2023]
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Infusion of CD133+ Bone Marrow–derived Stem Cell After Selective Portal Vein Embolization Enhances Functional Hepatic Reserves After Extended Right Hepatectomy. Ann Surg 2016; 263:e44-5. [DOI: 10.1097/sla.0000000000000404] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Li D, Madoff DC. Portal vein embolization for induction of selective hepatic hypertrophy prior to major hepatectomy: rationale, techniques, outcomes and future directions. Cancer Biol Med 2016; 13:426-442. [PMID: 28154774 PMCID: PMC5250600 DOI: 10.20892/j.issn.2095-3941.2016.0083] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The ability to modulate the future liver remnant (FLR) is a key component of modern oncologic hepatobiliary surgery practice and has extended surgical candidacy for patients who may have been previously thought unable to survive liver resection. Multiple techniques have been developed to augment the FLR including portal vein embolization (PVE), associating liver partition and portal vein ligation (ALPPS), and the recently reported transhepatic liver venous deprivation (LVD). PVE is a well-established means to improve the safety of liver resection by redirecting blood flow to the FLR in an effort to selectively hypertrophy and ultimately improve functional reserve of the FLR. This article discusses the current practice of PVE with focus on summarizing the large number of published reports from which outcomes based practices have been developed. Both technical aspects of PVE including volumetry, approaches, and embolization agents; and clinical aspects of PVE including data supporting indications, and its role in conjunction with chemotherapy and transarterial embolization will be highlighted. PVE remains an important aspect of oncologic care; in large part due to the substantial foundation of information available demonstrating its clear clinical benefit for hepatic resection candidates with small anticipated FLRs.
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Affiliation(s)
- David Li
- Department of Radiology, Division of Interventional Radiology, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York 10065, NY, USA
| | - David C Madoff
- Department of Radiology, Division of Interventional Radiology, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York 10065, NY, USA
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41
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Diener Y, Jurk M, Kandil B, Choi YH, Wild S, Bissels U, Bosio A. RNA-based, transient modulation of gene expression in human haematopoietic stem and progenitor cells. Sci Rep 2015; 5:17184. [PMID: 26599627 PMCID: PMC4657003 DOI: 10.1038/srep17184] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 10/20/2015] [Indexed: 12/13/2022] Open
Abstract
Modulation of gene expression is a useful tool to study the biology of haematopoietic stem and progenitor cells (HSPCs) and might also be instrumental to expand these cells for therapeutic approaches. Most of the studies so far have employed stable gene modification by viral vectors that are burdensome when translating protocols into clinical settings. Our study aimed at exploring new ways to transiently modify HSPC gene expression using non-integrating, RNA-based molecules. First, we tested different methods to deliver these molecules into HSPCs. The delivery of siRNAs with chemical transfection methods such as lipofection or cationic polymers did not lead to target knockdown, although we observed more than 90% fluorescent cells using a fluorochrome-coupled siRNA. Confocal microscopic analysis revealed that despite extensive washing, siRNA stuck to or in the cell surface, thereby mimicking a transfection event. In contrast, electroporation resulted in efficient, siRNA-mediated protein knockdown. For transient overexpression of proteins, we used optimised mRNA molecules with modified 5'- and 3'-UTRs. Electroporation of mRNA encoding GFP resulted in fast, efficient and persistent protein expression for at least seven days. Our data provide a broad-ranging comparison of transfection methods for hard-to-transfect cells and offer new opportunities for DNA-free, non-integrating gene modulation in HSPCs.
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Affiliation(s)
| | - Marion Jurk
- Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | | | - Yeong-Hoon Choi
- Heart Center of the University of Cologne, Department of Cardiothoracic Surgery, Center of Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Stefan Wild
- Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Ute Bissels
- Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
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Wang K, Chen X, Ren J. Autologous bone marrow stem cell transplantation in patients with liver failure: a meta-analytic review. Stem Cells Dev 2015; 24:147-59. [PMID: 25356526 DOI: 10.1089/scd.2014.0337] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Autologous bone marrow stem cell (ABMSC) transplantation has been utilized in clinical practice to treat patients with liver failure, but the therapeutic effect remains to be defined. A meta-analysis is essential to assess clinical advantages of ABMSC transplantation in patients with liver failure. A systematic search of published works [eg, PubMed, Medline, Embase, Chin J Clinicians (Electronic edition), and Science Citation Index] was conducted to compare clinical outcomes of ABMSC transplantation in patients with liver failure. Meta-analytic results were tested by fixed-effects model or random-effects model, dependent on the characteristics of variables. A total of 534 patients from seven studies were included in final meta-analysis. Subsequent to ABMSC transplantation, there was no significant improvement in general symptom and signs such as loss of appetite, fatigue, and ascites. Activities of serum ALT were not significantly decreased with weighted mean difference (WMD) of -19.36 and 95% confidence interval (CI) -57.53 to 18.80 (P=0.32). Postoperative level of albumin (ALB) was expectedly enhanced by stem cell transplantation (WMD 2.97, 95% CI 0.52 to 5.43, P<0.05, I(2)=84%). Coagulation function was improved as demonstrated by a short prothrombin time (PT) (WMD -1.18, 95% CI -2.32 to -0.03, P<0.05, I(2)=6%), but was not reflected by prothrombin activity (PTA) (P=0.39). Total bilirubin (TBIL) was drastically diminished after ABMSC therapy (WMD -14.85, 95% CI -20.39 to -9.32, P<0.01, I(2)=73%). Model for end-stage liver disease (MELD) scores were dramatically reduced (WMD -2.27, 95% CI -3.53 to -1.02, P<0.01, I(2)=0%). The advantage of ABMSC transplantation could be maintained more than 24 weeks as displayed by time-courses of ALB, TBIL, and MELD score. ABMSC transplantation does provide beneficial effects for patients with liver failure. Therapeutic effects can last for 6 months. However, long-term effects need to be determined.
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Affiliation(s)
- Kewei Wang
- 1 Department of Surgery, University of Illinois College of Medicine , Peoria, Illinois
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Reply to Letter: "Infusion of CD133+ Bone Marrow-Derived Stem Cell After Selective Portal Vein Embolization Enhances Functional Hepatic Reserves After Extended Right Hepatectomy". Ann Surg 2015; 263:e44-5. [PMID: 25894409 DOI: 10.1097/sla.0000000000000849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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King A, Barton D, Beard HA, Than N, Moore J, Corbett C, Thomas J, Guo K, Guha I, Hollyman D, Stocken D, Yap C, Fox R, Forbes SJ, Newsome PN. REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC): a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial. BMJ Open 2015; 5:e007700. [PMID: 25795699 PMCID: PMC4368910 DOI: 10.1136/bmjopen-2015-007700] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Liver disease mortality and morbidity are rapidly rising and liver transplantation is limited by organ availability. Small scale human studies have shown that stem cell therapy is safe and feasible and has suggested clinical benefit. No published studies have yet examined the effect of stem cell therapy in a randomised controlled trial and evaluated the effect of repeated therapy. METHODS AND ANALYSIS Patients with liver cirrhosis will be randomised to one of three trial groups: group 1: Control group, Standard conservative management; group 2 treatment: granulocyte colony-stimulating factor (G-CSF; lenograstim) 15 µg/kg body weight daily on days 1-5; group 3 treatment: G-CSF 15 µg/kg body weight daily on days 1-5 followed by leukapheresis, isolation and aliquoting of CD133+ cells. Patients will receive an infusion of freshly isolated CD133+ cells immediately and frozen doses at days 30 and 60 via peripheral vein (0.2×10(6) cells/kg for each of the three doses). Primary objective is to demonstrate an improvement in the severity of liver disease over 3 months using either G-CSF alone or G-CSF followed by repeated infusions of haematopoietic stem cells compared with standard conservative management. The trial is powered to answer two hypotheses of each treatment compared to control but not powered to detect smaller expected differences between the two treatment groups. As such, the overall α=0.05 for the trial is split equally between the two hypotheses. Conventionally, to detect a relevant standardised effect size of 0.8 point reduction in Model for End-stage Liver Disease score using two-sided α=0.05(overall α=0.1 split equally between the two hypotheses) and 80% power requires 27 participants to be randomised per group (81 participants in total). ETHICS AND DISSEMINATION The trial is registered at Current Controlled Trials on 18 November 2009 (ISRCTN number 91288089, EuDRACT number 2009-010335-41). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.
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Affiliation(s)
- A King
- NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Birmingham, UK Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
| | - D Barton
- NIHR Liver BRU Clinical trials group (EDD), CRUK clinical trials unit, University of Birmingham, Birmingham, UK
| | - H A Beard
- NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Birmingham, UK Cellular and Molecular Therapies, NHS Blood and Transplant, Birmingham, UK
| | - N Than
- NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - J Moore
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - C Corbett
- NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - J Thomas
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - K Guo
- NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - I Guha
- National Institute for Health Research Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - D Hollyman
- Cellular and Molecular Therapies, NHS Blood and Transplant, Birmingham, UK
| | - D Stocken
- Newcastle Clinical Trial Unit, Institute of Health and Society, Newcastle University, Newcastle, UK
| | - C Yap
- NIHR Liver BRU Clinical trials group (EDD), CRUK clinical trials unit, University of Birmingham, Birmingham, UK
| | - R Fox
- NIHR Liver BRU Clinical trials group (EDD), CRUK clinical trials unit, University of Birmingham, Birmingham, UK
| | - S J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - P N Newsome
- NIHR Centre for Liver Research and Biomedical Research Unit, University of Birmingham, Birmingham, UK Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
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Bone marrow cell therapy and liver regeneration: the potential clinical caveat. Dig Dis Sci 2015; 60:280-2. [PMID: 25480406 DOI: 10.1007/s10620-014-3479-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 11/30/2014] [Indexed: 12/09/2022]
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Atanasov G, Schmelzle M, Thelen A, Wiltberger G, Hau HM, Krenzien F, Petersen TO, Moche M, Jonas S. Selective hypertrophy of the lobus caudatus as a novel approach enabling extended right hepatectomy in the presence of a non-perfused left lateral liver lobe. Clin J Gastroenterol 2014; 7:370-5. [PMID: 25285175 PMCID: PMC4176950 DOI: 10.1007/s12328-014-0511-5] [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: 12/27/2013] [Accepted: 06/23/2014] [Indexed: 11/29/2022]
Abstract
Introduction Portal vein embolization (PVE) is a well-established technique to enhance functional hepatic reserves of segments II and III before curative extended right hepatectomy for tumors of the right liver lobe. However, an adequate hepatopetal flow of the left lateral portal vein branches is required for a sufficient PVE-associated hypertrophy. Case report Here, we report a 65-year old patient suffering from a locally advanced intrahepatic cholangiocarcinoma in the right liver lobe and segment IV. A curative extended right hepatectomy after preoperative PVE of liver segments IV–VIII was initially impossible because of partial thrombosis of the left lateral portal vein branches resulting in an ischemic-type atrophy of segments II and III. However, due to a massive hypertrophy of the caudate lobe following PVE of liver segments IV–VIII, subsequent extended right hepatectomy with intraoperative thrombectomy of segments II and III was made possible. Conclusions To our knowledge this is the first case in which an extended right hepatectomy for a liver malignancy, in the presence of atrophic left lateral section, was made possible by a massive PVE-associated hypertrophy of the caudate lobe.
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Affiliation(s)
- Georgi Atanasov
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany
| | - Moritz Schmelzle
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany ; Translational Centre for Regenerative Medicine, Leipzig University, Leipzig, Germany
| | - Armin Thelen
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany
| | - Georg Wiltberger
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany
| | - Hans-Michael Hau
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany
| | - Felix Krenzien
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany
| | - Tim-Ole Petersen
- Department of Diagnostic and Interventional Radiology, University Hospital Leipzig, Leipzig, Germany
| | - Michael Moche
- Department of Diagnostic and Interventional Radiology, University Hospital Leipzig, Leipzig, Germany
| | - Sven Jonas
- Department of Visceral-, Transplantation-, Thoracic- and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany ; Translational Centre for Regenerative Medicine, Leipzig University, Leipzig, Germany
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Behbahan IS, Keating A, Gale RP. Concise review: bone marrow autotransplants for liver disease? Stem Cells 2014; 31:2313-29. [PMID: 23939914 DOI: 10.1002/stem.1510] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Revised: 07/08/2013] [Accepted: 07/15/2013] [Indexed: 12/11/2022]
Abstract
There are increasing reports of using bone marrow-derived stem cells to treat advanced liver disease. We consider several critical issues that underlie this approach. For example, are there multipotent stem cell populations in human adult bone marrow? Can they develop into liver cells or supporting cell types? What are stromal stem/progenitor cells, and can they promote tissue repair without replacing hepatocytes? Does reversal of end-stage liver disease require new hepatocytes, a new liver microenvironment, both, neither or something else? Although many of these questions are unanswered, we consider the conceptual and experimental bases underlying these issues and critically analyze results of clinical trials of stem cell therapy of end-stage liver disease.
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Affiliation(s)
- Iman Saramipoor Behbahan
- Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
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Abstract
Liver disease is a rising cause of mortality and morbidity, and treatment options remain limited. Liver transplantation is curative but limited by donor organ availability, operative risk and long-term complications. The contribution of bone marrow (BM)-derived stem cells to tissue regeneration has been recognised and there is considerable interest in the potential benefits of BM stem cells in patients with liver disease. In chronic liver disease, deposition of fibrous scar tissue inhibits hepatocyte proliferation and leads to portal hypertension. Although initial reports had suggested transdifferentiation of stem cells into hepatocytes, the beneficial effects of BM stem cells are more likely derived from the ability to breakdown scar tissue and stimulate hepatocyte proliferation. Studies in animal models have yielded promising results, although the exact mechanisms and cell type responsible have yet to be determined. Small-scale clinical studies have quickly followed and, although primarily designed to examine safety and feasibility of this approach, have reported improvements in liver function in treated patients. Well-designed, controlled studies are required to fully determine the benefits of BM stem cell therapy.
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Affiliation(s)
- Andrew King
- NIHR Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK
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Moore JK, Stutchfield BM, Forbes SJ. Systematic review: the effects of autologous stem cell therapy for patients with liver disease. Aliment Pharmacol Ther 2014; 39:673-85. [PMID: 24528093 DOI: 10.1111/apt.12645] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 11/24/2013] [Accepted: 01/12/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND As morbidity and mortality from liver disease continues to rise, new strategies are necessary. Liver transplantation is not only an expensive resource committing the patient to lifelong immunosuppression but also suitable donor organs are in short supply. Against this background, autologous stem cell therapy has emerged as a potential treatment option. AIM To evaluate if it is possible to make a judgement on the safety, feasibility and effect of autologous stem cell therapy for patients with liver disease. METHODS MEDLINE and EMBASE were searched up until July 2013 to identify studies where autologous stem cell therapy was administered to patients with liver disease. RESULTS Of 1668 studies identified, 33 were eligible for inclusion evaluating a median sample size of 10 patients for a median follow-up of 6 months. Although there was marked heterogeneity between studies with regards to type, dose and route of delivery of stem cell, the treatment was shown to be safe and feasible largely when a peripheral route of administration was used. Of the studies which also looked at biochemical outcome, statistically significant improvement in liver function tests was seen in 16 studies post-treatment. CONCLUSION Although autologous stem cell therapy is a much needed possibility in the treatment of liver disease, further robust clinical trials and collaborative protocols are required.
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Affiliation(s)
- J K Moore
- MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK
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Lehwald N, Duhme C, Wildner M, Kuhn S, Fürst G, Forbes SJ, Jonas S, Robson SC, Knoefel WT, Schmelzle M, Schulte Am Esch J. HGF and SDF-1-mediated mobilization of CD133+ BMSC for hepatic regeneration following extensive liver resection. Liver Int 2014; 34:89-101. [PMID: 23701640 DOI: 10.1111/liv.12195] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Accepted: 04/04/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND The molecular mechanisms of haematopoietic stem cells (HSC) mobilization and homing to the liver after partial hepatectomy (PH) remain largely unexplored. METHODS Functional liver volume loss and regain was determined by computerized tomography (CT) volumetry in 30 patients following PH. Peripheral HSC mobilization was investigated by fluorescence-activated cell sorting (FACS) analyses and cytokine enzyme-linked immunosorbent assay assays. Migration of purified HSC towards hepatic growth factor (HGF) and stroma-derived factor-1 (SDF-1) gradients was tested in vitro. Mice after 70% PH were examined for HSC mobilization by FACS and cytokine mRNA expression in the liver. FACS-sorted HSC were administered after PH and hepatocyte proliferation was evaluated by immunohistochemical staining for Ki67. RESULTS Impaired liver function was noted after extended hepatic resection when compared to smaller resections. Patients with large liver resections were characterized by significantly higher levels of peripheral HSC which were positively correlated with the extent of resected liver volume and its regain after 3 weeks. Increased plasma levels of HGF, SDF-1 and insulin like growth factor (IGF-1) were evident within the first 6 hours post resection. Migration assays of human HSC in vitro showed a specific target-demonstrated migration towards recombinant HGF and SDF-1 gradients in a concentration and specific receptor (c-Met and CXCR4) dependent manner. The evaluation of peripheral human alpha foetoprotein expression demonstrated pronounced stemness following increased CD133(+) HSC in the course of liver regeneration following PH. Our human data were further validated in a murine model of PH and furthermore demonstrated increased hepatocyte proliferation subsequent to CD133(+) HSC treatment. CONCLUSION HGF and SDF-1 are required for effective HSC mobilization and homing to the liver after hepatic resection. These findings have significant implications for potential therapeutic strategies targeting chemotactant modulation and stem cell mobilization for liver protection and regeneration.
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Affiliation(s)
- Nadja Lehwald
- Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
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