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Holländer S, von Heesen M, Gäbelein G, Mercier J, Laschke MW, Menger MD, Glanemann M, Spiliotis AE. Perioperative treatment with cilostazol reverses steatosis and improves liver regeneration after major hepatectomy in a steatotic rat model. Sci Rep 2025; 15:2753. [PMID: 39843785 PMCID: PMC11754906 DOI: 10.1038/s41598-025-87135-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 01/16/2025] [Indexed: 01/24/2025] Open
Abstract
Cilostazol has previously been shown to reduce liver steatosis and enhance hepatic perfusion. We investigated the effects of cilostazol after major hepatectomy in a steatotic rat model. Six weeks prior to surgery, Sprague-Dawley rats were fed with a high-fructose diet. The treatment group received daily 5 mg/kg cilostazol. Seven days following the cilostazol treatment, all animals underwent 70% liver resection (PHX). Analysis of hepatic blood flow and microcirculation and immunohistochemical examinations were conducted 30 min after PHX (postoperative day [POD] 0) as well as on POD 1, POD 3 and POD 7. The weight of cilostazol-treated animals was significantly reduced compared to untreated controls after completion of the 6-week high-FRC diet. Furthermore, 41% macrovesicular steatosis was found in the control group compared to 8% in the cilostazol group. Hepatic arterial and portal venous perfusion were increased in the cilostazol group on POD 7. Lower liver enzyme release was found postoperatively in cilostazol-treated animals. Moreover, apoptosis and neutrophil infiltration were reduced after cilostazol treatment. Proliferation of hepatocytes and liver regeneration after PHX were significantly increased in the cilostazol group. Consequently, cilostazol should be evaluated as a novel strategy to reduce the rate of liver failure after PHX in steatotic liver.
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Affiliation(s)
- Sebastian Holländer
- Department of General Surgery, Vascular-, Visceral- and Pediatric Surgery, Saarland University Medical Center, 66421, Homburg, Germany
| | - Maximilian von Heesen
- Department of General- and Visceral Surgery, University Hospital Göttingen, 37075, Göttingen, Germany
| | - Gereon Gäbelein
- Department of General Surgery, Vascular-, Visceral- and Pediatric Surgery, Saarland University Medical Center, 66421, Homburg, Germany
| | - Julie Mercier
- Department of General Surgery, Vascular-, Visceral- and Pediatric Surgery, Saarland University Medical Center, 66421, Homburg, Germany
| | - Matthias W Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Germany
| | - Matthias Glanemann
- Department of General Surgery, Vascular-, Visceral- and Pediatric Surgery, Saarland University Medical Center, 66421, Homburg, Germany
| | - Antonios E Spiliotis
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Germany.
- Department of Surgery, Campus Charité Mitte, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, 13353, Berlin, Germany.
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Lopez-Lopez V, Martínez-Caceres C, Gomez-Valles P, Cruz J, Caballero-Illanes A, Brusadin R, López-Conesa A, Pérez M, Miura K, de la Peña-Moral J, Robles-Campos R. Impact of rapid hypertrophy of tourniquet associating liver partition and portal vein ligation in the tumor progression pathways compared to two stage hepatectomy in patients with colorectal liver metastases. HPB (Oxford) 2023; 25:1235-1246. [PMID: 37407399 DOI: 10.1016/j.hpb.2023.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 01/22/2023] [Accepted: 06/10/2023] [Indexed: 07/07/2023]
Abstract
BACKGROUND It is not known if the inflammatory phenomena related to highly accelerated regeneration activate any signaling pathways that are associated with a major stimulus to colorectal liver metastases (CRLM) disease in tourniquet associating liver partition and portal vein ligation for staged hepatectomy (T-ALPPS) compared to two stage hepatectomy (TSH). METHODS Between January 2012 and April 2018, we prospectively performed biopsies from future liver remnant and deportalized lobe in CRLM patients undergoing T-ALPPS in both stages. Immunohistopathological analysis was performed on the above tissue samples and compared to biopsy samples from patients who underwent TSH for CRLM at our center between September 2000 and August 2011. RESULTS A total of 42 patients (20 TSH and 22 T-ALPPS) were included. There were no differences in the rates of recurrence, overall survival or any of the factors analyzed relating to tumor progression between stages 1 and 2. Regarding the anti-tumor effect, there was a significant reduction in the number of T-CD8 infiltrates in the second stage of TSH (12.5 vs. 5.5, p = 0.02). CONCLUSION The results suggest that liver regeneration with T-ALPPS does not induce higher tumor progression or significant immunological changes in the tumor environment when compared to classical TSH.
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Affiliation(s)
- Victor Lopez-Lopez
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain
| | - Carlos Martínez-Caceres
- Investigation Support Platforms, IMIB-Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain
| | - Paula Gomez-Valles
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain
| | - Juan Cruz
- Group of Applied Mathematics in Science and Engineering, Faculty of Computer Science, University of Murcia, C. Campus Universitario, Edificio 32, 30100, Murcia, Spain
| | - Albert Caballero-Illanes
- Department of Pathology, Virgen de La Arrixaca University Hospital, IMIB-Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain
| | - Roberto Brusadin
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain
| | - Asuncion López-Conesa
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain
| | - María Pérez
- University of Lleida, Catalonia, Plaça de Víctor Siurana, 1, 25003, Lleida, Spain
| | - Kohei Miura
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata City, 951-8510, Niigata, Japan
| | - Jesús de la Peña-Moral
- Group of Applied Mathematics in Science and Engineering, Faculty of Computer Science, University of Murcia, C. Campus Universitario, Edificio 32, 30100, Murcia, Spain
| | - Ricardo Robles-Campos
- Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital Virgen de La Arrixaca, IMIB-Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain.
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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Kambakamba P, Linecker M, Schneider M, Reiner CS, Nguyen-Kim TDL, Limani P, Romic I, Figueras J, Petrowsky H, Clavien PA, Lesurtel M. Impact of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) on growth of colorectal liver metastases. Surgery 2018; 163:311-317. [PMID: 29248180 DOI: 10.1016/j.surg.2017.10.036] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 09/30/2017] [Accepted: 10/18/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy induces an unprecedented liver hypertrophy and enables resection of otherwise unresectable liver tumors. The effect of associating liver partition and portal vein ligation for staged hepatectomy on tumor proliferation, however, remains a concern. This study investigated the impact of associating liver partition and portal vein ligation for staged hepatectomy on growth of colorectal metastases in mice and in humans. METHODS The effect of associating liver partition and portal vein ligation for staged hepatectomy and 90% portal vein ligation on colorectal liver and lung metastases was investigated in mice. In vivo tumor progression was assessed by magnetic resonance imaging, histology, and survival experiments. The effects of associating liver partition and portal vein ligation for staged hepatectomy, portal vein ligation, and control sera on cultures of several colorectal cancer cell lines (MC38 and CT26) were tested in vitro. Additionally, the international associating liver partition and portal vein ligation for staged hepatectomy registry enabled us to identify patients with remaining tumor in the future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy stage 1. RESULTS Two and 3 weeks after associating liver partition and portal vein ligation for staged hepatectomy stage 1, portal vein ligation, or sham surgery, liver magnetic resonance images showed similar numbers (P=.14/0.82), sizes (P=.45/0.98), and growth kinetics (P=.58/0.68) of intrahepatic tumor. Tumor growth was not different between the associating liver partition and portal vein ligation for staged hepatectomy and portal vein ligation groups after completion of stage 2. Median survival after tumor cell injection was similar after sham surgery (36 days; 95% confidence interval; 27-57 days), completion of associating liver partition and portal vein ligation for staged hepatectomy (42 days; 95% confidence interval; 35-49 days), and portal vein ligation (39 days; 95% confidence interval; 34-43 days, P=.237). Progression of pulmonary metastases and in vitro cell proliferation were comparable among groups. Observations in humans failed to identify any accelerated tumor growth in the future liver remnant within the regenerative phase after associating liver partition and portal vein ligation for staged hepatectomy stage 1. CONCLUSION The accelerated regeneration process associated with associating liver partition and portal vein ligation for staged hepatectomy does not appear to enhance growth of colorectal metastases.
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Affiliation(s)
- Patryk Kambakamba
- Department of Visceral and Transplant Surgery, University and University Hospital Zurich, Zürich, Switzerland
| | - Michael Linecker
- Department of Visceral and Transplant Surgery, University and University Hospital Zurich, Zürich, Switzerland
| | - Marcel Schneider
- Department of Visceral and Transplant Surgery, University and University Hospital Zurich, Zürich, Switzerland
| | - Cäcilia S Reiner
- Department of Radiology, University Hospital Zurich, Zürich, Switzerland
| | | | - Perparim Limani
- Department of Visceral and Transplant Surgery, University and University Hospital Zurich, Zürich, Switzerland
| | - Ivan Romic
- Department of Surgery, University Hospital Zagreb, Zagreb, Croatia
| | - Joan Figueras
- Department of Surgery, University Hospital Dr. Josep Trueta Girona, Girona, Spain
| | - Henrik Petrowsky
- Department of Visceral and Transplant Surgery, University and University Hospital Zurich, Zürich, Switzerland
| | - Pierre-Alain Clavien
- Department of Visceral and Transplant Surgery, University and University Hospital Zurich, Zürich, Switzerland
| | - Mickaël Lesurtel
- Department of Visceral and Transplant Surgery, University and University Hospital Zurich, Zürich, Switzerland; Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.
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Senger S, Sperling J, Oberkircher B, Schilling MK, Kollmar O, Menger MD, Ziemann C. Portal branch ligation does not counteract the inhibiting effect of temsirolimus on extrahepatic colorectal metastatic growth. Clin Exp Metastasis 2017. [PMID: 28631253 DOI: 10.1007/s10585-017-9852-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The mTor-inhibitor temsirolimus (TEM) has potent anti-tumor activities on extrahepatic colorectal metastases. Treatment of patients with advanced disease may require portal branch ligation (PBL). While PBL can induce intrahepatic tumor growth, the effect of PBL on extrahepatic metastases under TEM treatment is unknown. Therefore, we analyzed the effects of TEM treatment on extrahepatic metastases during PBL-associated liver regeneration. GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chamber of BALB/c-mice. Mice were randomized to four groups (n = 8). One was treated daily with TEM (1.5 mg/kg), PBS-treated animals served as controls. Another group underwent PBL of the left liver lobe and received daily TEM treatment. Animals with PBL and PBS treatment served as controls. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied over 14 days. In non-PBL animals TEM treatment inhibited tumor cell proliferation as well as vascularization and growth of the extrahepatic metastases. PBL did not influence tumor cell engraftment, vascularization and metastatic growth. Of interest, TEM treatment significantly reduced tumor cell engraftment, neovascularization and metastatic groth also after PBL. PBL does not counteract the inhibiting effect of TEM on extrahepatic colorectal metastatic growth.
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Affiliation(s)
- Sebastian Senger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
- Department of Neurosurgery, Saarland University, Homburg/Saar, Germany
| | - Jens Sperling
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Barbara Oberkircher
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Martin K Schilling
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
- Klinik St. Anna Ärztehaus Lützelmatt, Lucerne, Switzerland
| | - Otto Kollmar
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
- Department of General and Visceral Surgery, Dr. Horst Schmidt Kliniken, Wiesbaden, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Christian Ziemann
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany.
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany.
- Department of Cardiovascular Surgery, University Heart Center, University Medical Center, University of Freiburg, Freiburg, Germany.
- Department of General, Visceral, Vascular and Pediatric Surgery and Institute for Clinical and Experimental Surgery, Saarland Medical School, Saarland University, Kirrberger Straße 1, 66424, Homburg/Saar, Germany.
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von Heesen M, Dold S, Müller S, Scheuer C, Kollmar O, Schilling MK, Menger MD, Moussavian MR. Cilostazol improves hepatic blood perfusion, microcirculation, and liver regeneration after major hepatectomy in rats. Liver Transpl 2015; 21:792-800. [PMID: 25772848 DOI: 10.1002/lt.24114] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 02/09/2015] [Accepted: 03/01/2015] [Indexed: 12/19/2022]
Abstract
Major hepatectomy or small-for-size liver transplantation may result in postoperative liver failure. So far, no treatment is available to improve liver regeneration. Herein, we studied whether cilostazol, a selective phosphodiesterase III inhibitor, is capable of improving liver regeneration after major hepatectomy. Sprague-Dawley rats (n = 74) were treated with cilostazol (5 mg/kg daily) or a glucose solution and underwent either 70% liver resection or a sham operation. Before and after surgery, hepatic arterial and portal venous blood flow and hepatic microvascular perfusion were analyzed. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, western blotting, and bile excretion analysis. Cilostazol significantly increased hepatic blood flow and microcirculation before and after hepatectomy in comparison with sham-operated controls. This was associated with an elevation of hepatic vascular endothelial growth factor expression, an increase of hepatocellular proliferation, and an acceleration of liver regeneration. Furthermore, cilostazol protected the tissue of the remnant liver as indicated by an attenuation of hepatocellular disintegration. In conclusion, cilostazol increases hepatic blood perfusion, microcirculation, and liver regeneration after a major hepatectomy. Thus, cilostazol may represent a novel strategy to reduce the rate of liver failure after both extended hepatectomy and small-for-size liver transplantation.
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Affiliation(s)
| | - Stefan Dold
- Department of General, Visceral, Vascular, and Paediatric Surgery
| | - Simon Müller
- Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany
| | - Claudia Scheuer
- Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany
| | - Otto Kollmar
- Department of General, Visceral, Vascular, and Paediatric Surgery
| | | | - Michael D Menger
- Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany
| | - Mohammed R Moussavian
- Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany
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Sperling J, Ziemann C, Gittler A, Benz-Weißer A, Menger MD, Kollmar O. Tumour growth of colorectal rat liver metastases is inhibited by hepatic arterial infusion of the mTOR-inhibitor temsirolimus after portal branch ligation. Clin Exp Metastasis 2015; 32:313-21. [PMID: 25693517 DOI: 10.1007/s10585-015-9707-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 02/10/2015] [Indexed: 02/08/2023]
Abstract
Portal branch ligation (PBL) can be performed before major hepatic resection of colorectal liver metastases (mCRC) to increase the remnant liver mass. However, PBL may also stimulate mCRC growth through hepatic arterial hyperperfusion and growth factor release. Herein, we studied whether hepatic arterial infusion (HAI) of the mTOR-inhibitor temsirolimus (Tem) is capable of inhibiting the growth of colorectal liver metastases after PBL. WAG/Rij rats were randomized to four groups (n=6 each) and underwent subcapsular implantation of 5×10(5) CC531 cells into the left liver lobe. The animals of two groups underwent simultaneous PBL of the tumour bearing liver lobe. Ten days later animals underwent a HAI either of temsirolimus (Tem and PBL Tem) or saline solution (Sham and PBL Sham). Tumour size was analyzed at days 10 and 13 using three-dimensional ultrasound. In Sham controls tumour volume increased by 43%. After PBL Sham tumour volume increased by 52%. In contrast, in animals undergoing HAI of temsirolimus the tumour growth was not only completely inhibited, but tumour volume was found decreased, irrespective of PBL. After HAI of temsirolimus immunohistochemistry revealed an increased cleaved caspase-3 activity, indicating stimulation of apoptotic cell death. In parallel temsirolimus treatment was associated with a significant reduction of PECAM-1 positive cells within the tumour tissue, implying a reduced tumour vascularisation. HAI of temsirolimus is capable of inhibiting the growth of CC531 colorectal rat liver metastases also after PBL.
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Affiliation(s)
- Jens Sperling
- Institute for Clinical and Experimental Surgery, University of Saarland, Homburg, Saarland, Germany,
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A review of animal models for portal vein embolization. J Surg Res 2014; 191:179-88. [PMID: 25017706 DOI: 10.1016/j.jss.2014.05.089] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 03/19/2014] [Accepted: 05/30/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Portal vein embolization (PVE) is a preoperative intervention to increase the future remnant liver (FRL) through regeneration of the non-embolized liver lobes. This review assesses all the relevant animal models of PVE available, to guide researchers who intend to study PVE. MATERIALS AND METHODS We performed a systematic literature search in Medline and Pubmed, from 1993-June 2013, using search headings "PVE" and "portal vein ligation". Articles were included when meeting the selection criteria: experimental animal study on PVE or portal vein ligation and experiments described in 5 animals or more. RESULTS Sixty-one articles were selected, describing six different animal models. Most articles reported experiments with rats, rabbits, and pigs. In rats, the increase in wet-weight ratio of the non-occluded liver or total liver weight is greatest in the first 7 d with values ranging from 75%-80.5% on day 7. The volume increase of FRL in the rabbit model is greatest in the first 7 d with values ranging from 33.6%-80% on day 7. In pigs, the largest gain in volume of the FRL was seen in the first 2 wk. CONCLUSIONS The choice of the model depends on the specific aim of the study. Evaluating the increase in liver volume and liver function after PVE, larger animals as the pig, rabbit, or the dog is useful because of the possibility to apply computed tomography volumetry. To evaluate mechanisms of regeneration after PVE, the rat model is useful, because of the variety of antibodies commercially available.
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Lim C, Cauchy F, Azoulay D, Farges O, Ronot M, Pocard M. Tumour progression and liver regeneration--insights from animal models. Nat Rev Gastroenterol Hepatol 2013; 10:452-62. [PMID: 23567217 DOI: 10.1038/nrgastro.2013.55] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Surgery remains the only curative treatment for colorectal liver metastases. For patients with multiple bilobar spread, extended hepatectomy might be required to achieve complete margin-free resection. In such cases, portal vein occlusion has been developed to induce preoperative hypertrophy of the future remnant liver and increase the resectability rate. Evidence now suggests that liver regeneration after hepatectomy and portal vein occlusion has a protumorigenic role, either through an upregulation of growth factors and cytokines or by haemodynamic changes in the blood supply to the liver. Experimental studies have reported a stimulatory effect of liver regeneration on the tumoral volume of liver metastases and on the metastatic potential of cells engrafted in the liver; this effect seems to depend on the timing of hepatectomy and portal vein occlusion. However, the variability of animal tumour models that are used for research in experimental colorectal liver metastases might account for some of the inconsistent and conflicting results. This Review presents clinical and experimental data pertaining to whether liver regeneration causes proliferation of tumour cells. We also analyse the different animal models of colorectal liver metastases in use and discuss current controversies in the field.
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Affiliation(s)
- Chetana Lim
- Unité INSERM U965 (Université Paris 7), Angiogénèse et Recherche Translationnelle, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75010 Paris, France
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10
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Lam VWT, Laurence JM, Johnston E, Hollands MJ, Pleass HCC, Richardson AJ. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB (Oxford) 2013; 15:483-91. [PMID: 23750490 PMCID: PMC3692017 DOI: 10.1111/j.1477-2574.2012.00607.x] [Citation(s) in RCA: 137] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 09/19/2012] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Selected patients with unresectable colorectal liver metastases (CLM) may be rendered resectable using the two-stage hepatectomy (TSH) approach. This review was conducted with the aim of collating and evaluating published evidence for TSH in patients with initially unresectable CLM. METHODS Searches of the MEDLINE and EMBASE databases were undertaken to identify studies of TSH in patients with initially unresectable CLM. Studies were required to focus on the perioperative treatment regimen, operative strategy, morbidity, technical success and survival outcomes. RESULTS Ten observational studies were reviewed. A total of 459 patients with initially unresectable CLM were selected for the first stage of TSH. Preoperative chemotherapy was used in 88% of patients and achieved partial and stable response rates of 59% and 39%, respectively. Postoperative morbidity and mortality after the first stage of TSH were 17% and 0.5%, respectively. Portal vein embolization (PVE) was used in 76% of patients. Ultimately, 352 of the initial 459 (77%) patients underwent the second stage of TSH. Major liver resection was undertaken in 84% of patients; the negative margin (R0) resection rate was 75%. Postoperative morbidity and mortality after the second stage of TSH were 40% and 3%, respectively. Median overall survival was 37 months (range: 24-44 months) in patients who completed both stages of TSH. In patients who did not complete both stages of TSH, median survival was 16 months (range: 10-29 months). The 3-year disease-free survival rate was 20% (range: 6-27%). CONCLUSIONS Two-stage hepatectomy is safe and effective in selected patients with initially unresectable CLM. Further studies are required to better define patient selection criteria for TSH and the exact roles of PVE and preoperative and interval chemotherapy.
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Affiliation(s)
- Vincent W T Lam
- Department of Surgery, Westmead HospitalWestmead, NSW, Australia,Discipline of Surgery, Sydney Medical SchoolSydney, NSW, Australia
| | | | - Emma Johnston
- Department of Surgery, Westmead HospitalWestmead, NSW, Australia,Discipline of Surgery, Sydney Medical SchoolSydney, NSW, Australia
| | - Michael J Hollands
- Department of Surgery, Westmead HospitalWestmead, NSW, Australia,Discipline of Surgery, Sydney Medical SchoolSydney, NSW, Australia
| | - Henry C C Pleass
- Department of Surgery, Westmead HospitalWestmead, NSW, Australia,Discipline of Surgery, Sydney Medical SchoolSydney, NSW, Australia
| | - Arthur J Richardson
- Department of Surgery, Westmead HospitalWestmead, NSW, Australia,Discipline of Surgery, Sydney Medical SchoolSydney, NSW, Australia
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Siriwardana RC, Lo CM, Chan SC, Fan ST. Role of portal vein embolization in hepatocellular carcinoma management and its effect on recurrence: a case-control study. World J Surg 2012; 36:1640-6. [PMID: 22411084 PMCID: PMC3368111 DOI: 10.1007/s00268-012-1522-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver regeneration that occurs after portal vein embolization (PVE) may have adverse effects on the microscopic tumor foci in the residual liver mass in patients with hepatocellular carcinoma (HCC). METHODS Fifty-four HCC patients with inadequate functional residual liver volume were offered PVE during a seven-year period. Among them, 34 (63%) patients underwent curative resection. They were compared with a matched control group (n = 102) who underwent surgery without PVE. Postoperative complications, pattern of recurrence, and survival were compared between groups. RESULTS In the PVE group, a pre-embolization functional residual liver volume of 23% (12-33.5%) improved to 34% (20-54%) (p = 0.005) at the time of surgery. When the two groups were compared, minor (PVE, 24%; control, 29%; p = 0.651) and major (PVE, 18%; control, 15%; p = 0.784) complications were similar. After a follow-up period of 35 months (standard deviation 25 months), extrahepatic recurrences were detected in 10 PVE patients (29%) and 41 control patients (40%) (p = 0.310). Intrahepatic recurrences were seen in 10 (29%) and 47 (46%) cases (p = 0.109) in the PVE and control groups, respectively. In the PVE group, 41% (n = 14) of the recurrences were detected before one year, compared with 42% (n = 43) in the control group (p = 1). Disease-free survival rates at 1, 3, and 5 years were 57, 29, and 26% in the control group and 60, 42, and 42% in the PVE group (log-rank, p = 0.335). On multivariate analysis, PVE was not a factor affecting survival (p = 0.821). CONCLUSIONS Portal vein embolization increases the resectability of initially unresectable HCC due to inadequate functional residual liver volume, and it has no deleterious oncological effect after major resection of HCC.
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Affiliation(s)
- Rohan C. Siriwardana
- Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, People’s Republic of China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, People’s Republic of China
- State Key Laboratory for Liver Research, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, People’s Republic of China
| | - See Ching Chan
- Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, People’s Republic of China
- State Key Laboratory for Liver Research, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, People’s Republic of China
| | - Sheung Tat Fan
- Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, People’s Republic of China
- State Key Laboratory for Liver Research, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, People’s Republic of China
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Muratore A, Zimmitti G, Ribero D, Mellano A, Viganò L, Capussotti L. Chemotherapy between the first and second stages of a two-stage hepatectomy for colorectal liver metastases: should we routinely recommend it? Ann Surg Oncol 2012; 19:1310-1315. [PMID: 21947627 DOI: 10.1245/s10434-011-2069-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Indexed: 01/12/2023]
Abstract
BACKGROUND The aim of the present study is to examine the effect of systemic chemotherapy after the 1st-stage hepatectomy (CT×2) on the progression of disease and dropout rates. A major pitfall of the 2-stage hepatectomy procedure is a high dropout rate after the 1st-stage hepatectomy due to progression of disease (PD). Routine use of CT×2 has been advocated. METHODS A total of 47 patients with multiple, bilateral unresectable liver metastases were selected for a 2-stage hepatectomy procedure (±portal vein occlusion). RESULTS Of the total, 37 patients (78.7%) underwent systemic chemotherapy before the 1st-stage hepatectomy (CT×1) and 25 patients (53.2%) underwent CT×2; PD was significantly more common during CT×2 than during CT×1 (P=.002). Of the 47 patients planned for the 2nd-stage hepatectomy, 36 (76.6%) completed the procedure. Of these 47 patients, 25 (53.2%) showed PD after the 1st-stage hepatectomy, 12 in the CT×2 group and 13 in the no-CT×2 group; administration of CT×2 did not significantly affect the PD rate (P=.561). The overall dropout rate was 23.4% (n=11 patients): 16% in the CT×2 group vs. 31.8% in the no-CT×2 group (P=.303). CONCLUSIONS The routine use of chemotherapy between the 1st- and 2nd-stage hepatectomy does not guarantee lower PD and dropout rates.
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Affiliation(s)
- Andrea Muratore
- Department of Surgical Oncology, Istituto per la Ricerca e la Cura del Cancro, Candiolo, Turin, Italy.
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