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Wehrle CJ, Panconesi R, Satish S, Maspero M, Jiao C, Sun K, Karakaya O, Allkushi E, Modaresi Esfeh J, Whitsett Linganna M, Ma WW, Fujiki M, Hashimoto K, Miller C, Kwon DCH, Aucejo F, Schlegel A. The Impact of Biliary Injury on the Recurrence of Biliary Cancer and Benign Disease after Liver Transplantation: Risk Factors and Mechanisms. Cancers (Basel) 2024; 16:2789. [PMID: 39199562 PMCID: PMC11352383 DOI: 10.3390/cancers16162789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/01/2024] Open
Abstract
Liver transplantation is known to generate significant inflammation in the entire organ based on the metabolic profile and the tissue's ability to recover from the ischemia-reperfusion injury (IRI). This cascade contributes to post-transplant complications, affecting both the synthetic liver function (immediate) and the scar development in the biliary tree. The new occurrence of biliary strictures, and the recurrence of malignant and benign liver diseases, such as cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC), are direct consequences linked to this inflammation. The accumulation of toxic metabolites, such as succinate, causes undirected electron flows, triggering the releases of reactive oxygen species (ROS) from a severely dysfunctional mitochondrial complex 1. This initiates the inflammatory IRI cascade, with subsequent ischemic biliary stricturing, and the upregulation of pro-tumorigenic signaling. Such inflammation is both local and systemic, promoting an immunocompromised status that can lead to the recurrence of underlying liver disease, both malignant and benign in nature. The traditional treatment for CCA was resection, when possible, followed by cytotoxic chemotherapy. Liver transplant oncology is increasingly recognized as a potentially curative approach for patients with intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma. The link between IRI and disease recurrence is increasingly recognized in transplant oncology for hepatocellular carcinoma. However, smaller numbers have prevented similar analyses for CCA. The mechanistic link may be even more critical in this disease, as IRI causes the most profound damage to the intrahepatic bile ducts. This article reviews the underlying mechanisms associated with biliary inflammation and biliary pathology after liver transplantation. One main focus is on the link between transplant-related IRI-associated inflammation and the recurrence of cholangiocarcinoma and benign liver diseases of the biliary tree. Risk factors and protective strategies are highlighted.
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Affiliation(s)
- Chase J. Wehrle
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - Rebecca Panconesi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (R.P.); (C.J.)
| | - Sangeeta Satish
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (R.P.); (C.J.)
| | - Marianna Maspero
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, 20133 Milan, Italy
| | - Chunbao Jiao
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (R.P.); (C.J.)
| | - Keyue Sun
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (R.P.); (C.J.)
| | - Omer Karakaya
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (R.P.); (C.J.)
| | - Erlind Allkushi
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - Jamak Modaresi Esfeh
- Department of Gastroenterology and Transplant Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Maureen Whitsett Linganna
- Department of Gastroenterology and Transplant Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Wen Wee Ma
- Novel Therapeutics Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Masato Fujiki
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - Koji Hashimoto
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - Charles Miller
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - David C. H. Kwon
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - Federico Aucejo
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
| | - Andrea Schlegel
- Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA; (C.J.W.); (F.A.)
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (R.P.); (C.J.)
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Downregulation of DNA repair proteins and increased DNA damage in hypoxic colon cancer cells is a therapeutically exploitable vulnerability. Oncotarget 2017; 8:86296-86311. [PMID: 29156796 PMCID: PMC5689686 DOI: 10.18632/oncotarget.21145] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 08/04/2017] [Indexed: 01/08/2023] Open
Abstract
Surgical removal of colorectal cancer (CRC) liver metastases generates areas of tissue hypoxia. Hypoxia imposes a stem-like phenotype on residual tumor cells and promotes tumor recurrence. Moreover, in primary CRC, gene expression signatures reflecting hypoxia and a stem-like phenotype are highly expressed in the aggressive Consensus Molecular Subtype 4 (CMS4). Therapeutic strategies eliminating hypoxic stem-like cells may limit recurrence following resection of primary tumors or metastases. Here we show that expression of DNA repair genes is strongly suppressed in CMS4 and inversely correlated with hypoxia-inducible factor-1 alpha (HIF1α) and HIF-2α co-expression signatures. Tumors with high expression of HIF signatures and low expression of repair proteins showed the worst survival. In human tumors, expression of the repair proteins RAD51, KU70 and RIF1 was strongly suppressed in hypoxic peri-necrotic tumor areas. Experimentally induced hypoxia in patient derived colonospheres in vitro or in vivo (through vascular clamping) was sufficient to downregulate repair protein expression and caused DNA damage. Hypoxia-induced DNA damage was prevented by expressing the hydroperoxide-scavenging enzyme glutathione peroxidase-2 (GPx2), indicating that reactive oxygen species mediate hypoxia-induced DNA damage. Finally, the hypoxia-activated prodrug Tirapazamine greatly augmented DNA damage and reduced the fraction of stem-like (Aldefluorbright) tumor cells in vitro, and in vivo following vascular clamping. We conclude that decreased expression of DNA repair proteins and increased DNA damage in hypoxic tumor areas may be therapeutically exploited with hypoxia-activated prodrugs, and that such drugs reduce the fraction of Aldefluorbright (stem-like) tumor cells.
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Olthof PB, Huiskens J, Schulte NR, Wicherts DA, Besselink MG, Busch ORC, Tanis PJ, van Gulik TM. Hepatic vascular inflow occlusion is associated with reduced disease free survival following resection of colorectal liver metastases. Eur J Surg Oncol 2016; 43:100-106. [PMID: 27692534 DOI: 10.1016/j.ejso.2016.09.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/19/2016] [Accepted: 09/02/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatic vascular inflow occlusion (VIO) can be applied during resection of colorectal liver metastases (CRLM) to control intra-operative blood loss, but has been linked to accelerated growth of micrometastases in experimental models. This study aimed to investigate the effects of hepatic VIO on disease-free and overall survival (DFS and OS) in patients following resection for CRLM. METHODS All patients who underwent liver resection for CRLM between January 2006 and September 2015 at our center were analyzed. Hepatic VIO was performed if deemed indicated by the operating surgeon and severe ischemia was defined as ≥20 min continuous or ≥45 min cumulative intermittent VIO. Cox regression analysis was performed to identify predictive factors for DFS and OS. RESULTS A total of 208 patients underwent liver resection for CRLM. VIO was performed in 64 procedures (31%), and fulfilled the definition of severe ischemia in 40 patients. Patients with severe ischemia had inferior DFS (5-year DFS 32% vs. 11%, P < 0.01), and inferior OS (5-year OS 37% vs. 64%, P < 0.01). At multivariate analysis, a high clinical risk score (Hazard ratio (HR) 1.60 (1.08-2.36)) and severe ischemia (HR 1.89 (1.21-2.97)) were independent predictors of worse DFS. Severe ischemia was not an independent predictor of OS. CONCLUSION The present cohort study suggests that prolonged hepatic VIO during liver resection for CRLM was associated with reduced DFS. A patient-tailored approach seems advisable although larger studies should confirm these findings.
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Affiliation(s)
- P B Olthof
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - J Huiskens
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - N R Schulte
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - D A Wicherts
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - M G Besselink
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - O R C Busch
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - P J Tanis
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - T M van Gulik
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands.
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Safety and Efficacy of a New Bipolar Energy Device for Parenchymal Dissection in Laparoscopic Liver Resection. Surg Laparosc Endosc Percutan Tech 2016; 26:21-4. [DOI: 10.1097/sle.0000000000000223] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Hypoxia After Liver Surgery Imposes an Aggressive Cancer Stem Cell Phenotype on Residual Tumor Cells. Ann Surg 2014; 259:750-9. [DOI: 10.1097/sla.0b013e318295c160] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Matsuda A, Miyashita M, Matsumoto S, Matsutani T, Sakurazawa N, Akagi I, Kishi T, Yokoi K, Uchida E. Hepatic pedicle clamping does not worsen survival after hepatic resection for colorectal liver metastasis: results from a systematic review and meta-analysis. Ann Surg Oncol 2013; 20:3771-8. [PMID: 23775409 DOI: 10.1245/s10434-013-3048-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Indexed: 11/18/2022]
Abstract
BACKGROUND Hepatic pedicle clamping (HPC) has been demonstrated to be effective for short-term outcomes during hepatic resection. However, HPC-induced hepatic ischemia/reperfusion injury can accelerate the outgrowth of hepatic micrometastases in experimental studies. The conclusive evidence regarding effects of HPC on long-term patient outcomes after hepatic resection for colorectal liver metastasis (CRLM) has not been determined. METHODS A comprehensive electronic literature search was performed to identify studies evaluating the oncological effects of HPC after hepatic resection for CRLM. The main outcome measures were intrahepatic recurrence (IHR), disease-free survival (DFS), and overall survival (OS). A meta-analysis was performed using the random-effects models to compute odds ratio (OR) along with 95% confidence intervals (CI). RESULTS Four studies, with a total of 2,114 patients (73.7% HPC, 26.3% non-HPC), matched the inclusion criteria. Meta-analyses revealed that IHR (OR 0.88; 95% CI 0.69-1.11; P = 0.27), DFS (OR 0.88; 95% CI 0.70-1.10; P = 0.27) and OS (OR 0.99; 95% CI 0.79-1.24; P = 0.90) did not differ significantly between the HPC and non-HPC groups. CONCLUSIONS This meta-analysis provides persuasive evidence that HPC during hepatic resection for CRLM has no significant adverse oncological outcomes. HPC should be considered an option during parenchymal liver resection from current available evidence.
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Affiliation(s)
- Akihisa Matsuda
- Department of Surgery, Chiba-Hokuso Hospital Nippon Medical School, Inzai, Chiba, Japan,
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Vibert E, Pittau G, Gelli M, Cunha AS, Jamot L, Faivre J, Castro Benitez C, Castaing D, Adam R. Actual incidence and long-term consequences of posthepatectomy liver failure after hepatectomy for colorectal liver metastases. Surgery 2013; 155:94-105. [PMID: 24694360 DOI: 10.1016/j.surg.2013.05.039] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 05/31/2013] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Posthepatectomy liver failure (PHLF) is a severe complication after hepatectomy for colorectal liver metastases. This study evaluated its actual incidence and its effects on short- and long-term overall survival (OS) in a specialized center. MATERIALS AND METHODS Between 2006 and 2008, 193 patients who underwent 232 hepatectomies (147 minor and 85 major) for colorectal liver metastasis were studied prospectively. Hepatectomy was performed if the remnant liver volume was >0.5% of body weight. Uni- and multivariate analyses on OS after all hepatectomies (n = 232) or major resection only (n = 85) were then performed on pre-, intra-, and postoperative (including pathological) data to determine the consequences of PHLF by comparison with those of other intra- and postoperative events. RESULTS The 3-month postoperative mortality rate was 0.8%. PHLF was observed in six patients (7%) after major hepatectomy and in one (0.6%) after minor hepatectomy. With a 25-month follow-up, the 2-year OS rate was 84%. Preoperatively, pulmonary metastasis was the only determinant of OS. Intra- and postoperatively, four factors were determinant of OS: PHLF (risk ratio [RR] = 3.84, P = .04), mental confusion (RR = 3.11, P = .006), fluid collection (RR = 2.9, P = .01) and transfusion (RR = 2.27, P = .009). After major hepatectomy, only PHLF (RR = 4.14, P = .01) and confusion (RR = 3.6, P = .02) were identified. CONCLUSION With improvements in postoperative management, PHLF was found to be less responsible for 3-month mortality but remains an event that exerts a major impact on 2-year survival.
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Affiliation(s)
- Eric Vibert
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Inserm, Unité 785, Villejuif, France; Université Paris-Sud, Villejuif, France.
| | - Gabriella Pittau
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Université Paris-Sud, Villejuif, France
| | | | - Antonio Sa Cunha
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Inserm, Unité 785, Villejuif, France; Université Paris-Sud, Villejuif, France
| | | | - Jamila Faivre
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Inserm, Unité 785, Villejuif, France; Université Paris-Sud, Villejuif, France
| | | | - Denis Castaing
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Inserm, Unité 785, Villejuif, France; Université Paris-Sud, Villejuif, France
| | - René Adam
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Université Paris-Sud, Villejuif, France
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Galun DA, Bulajic P, Zuvela M, Basaric D, Ille T, Milicevic MN. Is there any benefit from expanding the criteria for the resection of hepatocellular carcinoma in cirrhotic liver? Experience from a developing country. World J Surg 2012; 36:1657-65. [PMID: 22395347 DOI: 10.1007/s00268-012-1544-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Patients with large-size (>10 cm) hepatocellular carcinoma (HCC) in Child B cirrhosis are usually excluded from curative treatment, i.e., hepatic resection, because of marginal liver function and poor outcome. This study was designed to evaluate the feasibility of the radiofrequency (RF)-assisted sequential "coagulate-cut liver resection technique" in expanding the criteria for resection of large HCC in cirrhotic livers with impaired liver function. METHODS Forty patients with Child-Pugh A or B cirrhosis underwent liver resection from December 1, 2001 to December 31, 2008. Of these, 20 patients (13 Child-Pugh A and 7 Child-Pugh B) with advanced stage HCC (stage B and C according to Barcelona-Clinic Liver Cancer Group) underwent major liver resection. The two groups were comparable in terms of patient age, liver cirrhosis etiology, tumor number, and size. RESULTS All resections were performed without the Pringle maneuver. There was no significant difference found between the two groups regarding resection time, perioperative transfusion, postoperative complications, hospital stay, and day 7 values of hemoglobin and liver enzymes. Likewise, there was no significant difference found in the overall survival between Child A and Child B patients who underwent major liver resection CONCLUSIONS RF-assisted sequentional "coagulate-cut liver resection technique" may be a viable alternative for management of patients with advanced HCC in cirrhotic liver with impaired function.
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Affiliation(s)
- Danijel A Galun
- First Surgical Clinic, Clinical Center of Serbia, Koste Todorovica 6, 11 000, Belgrade, Serbia.
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Does Hepatic Pedicle Clamping Affect Disease-Free Survival Following Liver Resection for Colorectal Metastases? Ann Surg 2010; 252:1020-6. [DOI: 10.1097/sla.0b013e3181f66918] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Abstract
BACKGROUND Vascular occlusion to prevent haemorrhage during liver resection causes ischaemia-reperfusion (IR) injury. Insights into the mechanisms of IR injury gathered from experimental models have contributed to the development of therapeutic approaches, some of which have already been tested in randomized clinical trials. METHODS The review was based on a PubMed search using the terms 'ischemia AND hepatectomy', 'ischemia AND liver', 'hepatectomy AND drug treatment', 'liver AND intermittent clamping' and 'liver AND ischemic preconditioning'; only randomized controlled trials (RCTs) were included. RESULTS Twelve RCTs reported on ischaemic preconditioning and intermittent clamping. Both strategies seem to confer protection and allow extension of ischaemia time. Fourteen RCTs evaluating pharmacological interventions, including antioxidants, anti-inflammatory drugs, vasodilators, pharmacological preconditioning and glucose infusion, were identified. CONCLUSION Several strategies to prevent hepatic IR have been developed, but few have been incorporated into clinical practice. Although some pharmacological strategies showed promising results with improved clinical outcome there is not sufficient evidence to recommend them.
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Affiliation(s)
- R Bahde
- Surgical Research, Department of General and Visceral Surgery, Muenster University Hospital, Waldeyer Strasse 1, D-48149 Muenster, Germany
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Clinical features of hepatocellular carcinoma developing extrahepatic recurrences after curative resection. World J Surg 2009; 32:1738-47. [PMID: 18463920 DOI: 10.1007/s00268-008-9613-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Few details of the clinical features of hepatocellular carcinoma (HCC) developing extrahepatic recurrence after a curative resection have been published. The purpose of this study was to clarify the clinicopathologic findings of patients with HCC who experienced extrahepatic metastases. METHODS Clinicopathologic data were available for 119 patients who underwent an R0 resection for HCC. Twenty-three patients who developed extrahepatic metastases during the follow-up period were compared with the patients who remained free from recurrence for at least 5 years after resection (n = 21) or with only intrahepatic recurrences (n = 75). RESULTS Patients with extrahepatic recurrences were more likely to have their tumor macro- or microscopically invading the tumor capsule (P < 0.001) and hepatic vein (P = 0.003), a high AFP concentration (P = 0.014), and advanced TNM stage (P = 0.006) than the other patients. As for treatment-related variables, inflow vessel occlusion during hepatectomy was less frequently associated with extrahepatic recurrences than if it were not performed (P < 0.001). By multivariate analysis, absence of tumor invasion to the capsule (relative risk [RR] = 0.080; P = 0.023) or to the hepatic vein (RR = 0.108; P = 0.014) and a hepatectomy in which inflow vessel occlusions were performed (RR = 0.161; P = 0.004) were selected as independent factors for reducing extrahepatic recurrences after a hepatectomy. CONCLUSION In HCC patients, the control of intrahepatic recurrences and extrahepatic recurrences after a hepatectomy is important to improve the prognosis. Inflow occlusion during the hepatectomy may reduce HCC metastases to extrahepatic sites.
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van der Bilt JDW, Kranenburg O, Borren A, van Hillegersberg R, Borel Rinkes IHM. Ageing and hepatic steatosis exacerbate ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases. Ann Surg Oncol 2008; 15:1392-8. [PMID: 18335279 DOI: 10.1245/s10434-007-9758-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2007] [Revised: 10/14/2007] [Accepted: 10/15/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is frequently encountered during hepatic surgery. We recently showed that I/R accelerates the outgrowth of pre-established colorectal micrometastases. The aim of this study was to assess the influence of ischemia time, gender, age, and liver steatosis on the accelerated outgrowth of colorectal metastases following I/R. METHODS Five days after tumor cell inoculation, mice were subjected to 20, 30 or 45 min of left lobar I/R. To assess the influence of age, gender, and liver steatosis on I/R-accelerated tumor growth, we compared old with young mice, male with female mice, and mice with healthy livers with mice with steatotic livers. Endpoints were extent of tissue necrosis and tumor growth. RESULTS With increasing ischemia times, tissue necrosis and I/R-accelerated tumor growth increased, with a significant stimulatory effect at 30 and 45 min of ischemia. I/R-stimulated outgrowth of micrometastases was further increased by 33% in aged mice and by 42% in steatotic livers and was associated with increased tissue necrosis. In female mice tissue necrosis had decreased by 47% and tumor growth was reduced in both control and clamped liver lobes. The stimulatory effect of I/R on metastasis outgrowth was similar in male and female mice. CONCLUSIONS I/R-accelerated outgrowth of colorectal micrometastases largely depends on the duration of the ischemic period, with a safe upper limit of 20 min in mice. The stimulatory effects of I/R on tumor growth are exacerbated in aged mice and in steatotic livers.
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Duenschede F, Erbes K, Riegler N, Ewald P, Kircher A, Westermann S, Schad A, Miesmer I, Albrecht-Schöck S, Gockel I, Kiemer AK, Junginger T. Protective effects of ischemic preconditioning and application of lipoic acid prior to 90 min of hepatic ischemia in a rat model. World J Gastroenterol 2007; 13:3692-8. [PMID: 17659728 PMCID: PMC4250640 DOI: 10.3748/wjg.v13.i27.3692] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare different preconditioning strategies to protect the liver from ischemia/reperfusion injury focusing on the expression of pro- and anti-apoptotic proteins. Interventions comprised different modes of ischemic preconditioning (IP) as well as pharmacologic pretreatment by α-lipoic acid (LA).
METHODS: Several groups of rats were compared: sham operated animals, non-pretreated animals (nt), animals receiving IP (10 min of ischemia by clamping of the portal triad and 10 min of reperfusion) prior to sustained ischemia, animals receiving selective ischemic preconditioning (IPsel, 10 min of ischemia by selective clamping of the ischemic lobe and 10 min of reperfusion) prior to sustained ichemia, and animals receiving 500 μmol α-LA injected i.v. 15 min prior to the induction of 90 min of selective ischemia.
RESULTS: Cellular damage was decreased only in the LA group. TUNEL-positive hepatocytes as well as necrotic hepatocyte injury were also decreased only by LA (19 ± 2 vs 10 ± 1, P < 0.05 and 29 ± 5 vs 12 ± 1, P < 0.05). Whereas caspase 3- activities in liver tissue were unchanged, caspase 9- activity in liver tissue was decreased only by LA pretreatment (3.1 ± 0.3 vs 1.8 ± 0.2, P < 0.05). Survival rate as the endpoint of liver function was increased after IP and LA pretreatment but not after IPsel. Levels of lipid peroxidation (LPO) in liver tissue were decreased in the IP as well as in the LA group compared to the nt group. Determination of pro- and anti-apoptotic proteins showed a shift towards anti-apoptotic proteins by LA. In contrast, both our IP strategies failed to influence apototic cell death.
CONCLUSION: IP, consisting of 10 min of ischemia and 10 min of reperfusion, protects only partly against ischemia/reperfusion injury of the liver prior to 90 min of selective ischemia. IPsel did not influence ischemic tolerance of the liver. LA improved tolerance to ischemia, possibly by downregulation of pro-apoptotic Bax.
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Affiliation(s)
- Friedrich Duenschede
- University Hospital Mainz, Department of General and Abdominal Surgery, Langenbeckstrasse 1, 55131 Mainz, Germany.
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