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1
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Jeong A, Pastor CM, Brouwer KLR. Application of Pharmacokinetic Modeling to Characterize Hepatobiliary Disposition of Imaging Agents and Alterations due to Liver Injury in Isolated Perfused Rat Livers. Pharm Res 2023; 40:2513-2523. [PMID: 37349653 PMCID: PMC10739561 DOI: 10.1007/s11095-023-03549-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 06/05/2023] [Indexed: 06/24/2023]
Abstract
BACKGROUND Understanding the impact of altered hepatic uptake and/or efflux on the hepatobiliary disposition of the imaging agents [99mTc]Mebrofenin (MEB) and [153Gd]Gadobenate dimeglumine (BOPTA) is important for proper estimation of liver function. METHODS A multi-compartmental pharmacokinetic (PK) model describing MEB and BOPTA disposition in isolated perfused rat livers (IPRLs) was developed. The PK model was simultaneously fit to MEB and BOPTA concentration-time data in the extracellular space, hepatocytes, bile canaliculi, and sinusoidal efflux in livers from healthy rats, and to BOPTA concentration-time data in rats pretreated with monocrotaline (MCT). RESULTS The model adequately described MEB and BOPTA disposition in each compartment. The hepatocyte uptake clearance was much higher for MEB (55.3 mL/min) than BOPTA (6.67 mL/min), whereas the sinusoidal efflux clearance for MEB (0.000831 mL/min) was lower than BOPTA (0.0127 mL/min). The clearance from hepatocytes to bile (CLbc) for MEB (0.658 mL/min) was similar to BOPTA (0.642 mL/min) in healthy rat livers. The BOPTA CLbc was reduced in livers from MCT-pretreated rats (0.496 mL/min), while the sinusoidal efflux clearance was increased (0.0644 mL/min). CONCLUSION A PK model developed to characterize MEB and BOPTA disposition in IPRLs was used to quantify changes in the hepatobiliary disposition of BOPTA caused by MCT pretreatment of rats to induce liver toxicity. This PK model could be applied to simulate changes in the hepatobiliary disposition of these imaging agents in rats in response to altered hepatocyte uptake or efflux associated with disease, toxicity, or drug-drug interactions.
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Affiliation(s)
- Angela Jeong
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 100 L Beard Hall, CB# 7569, Chapel Hill, NC, 27599-7569, USA
| | - Catherine M Pastor
- Centre de recherche sur l'inflammation, Université de Paris, Inserm, U1149, CNRS, ERL8252, F-75006, Paris, France
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 100 L Beard Hall, CB# 7569, Chapel Hill, NC, 27599-7569, USA.
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Inhibition of Vascular Endothelial Growth Factor Protects against the Development of Oxaliplatin-Induced Sinusoidal Obstruction Syndrome in Wild-Type but Not in CD39-Null Mice. Cancers (Basel) 2022; 14:cancers14235992. [PMID: 36497474 PMCID: PMC9739893 DOI: 10.3390/cancers14235992] [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: 09/18/2022] [Revised: 11/19/2022] [Accepted: 11/20/2022] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy is associated with unfavorable outcomes after partial hepatectomy for colorectal liver metastases (CLM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), may prevent SOS development. We investigated the impact of VEGF-inhibition on the development of SOS in a murine model. (2) Methods: Male wild-type and CD39-null mice received oxaliplatin, additional anti-VEGF (OxAV), or controls, and were sacrificed or subjected to major partial hepatectomy (MH). Specimen were used for histological analysis of SOS. Liver damage was assessed by plasma transaminases. The VEGF pathway was elucidated by quantitative PCR of liver tissue and protein analysis of plasma. (3) Results: Mice treated with oxaliplatin developed SOS. Concomitant anti-VEGF facilitated a reduced incidence of SOS, but not in CD39-null mice. SOS was associated with increased plasma VEGF-A and decreased hepatocyte growth factor (HGF). After OxAV treatment, VEGF-R2 was upregulated in wild-type but downregulated in CD39-null mice. Oxaliplatin alone was associated with higher liver damage after MH than in mice with concomitant VEGF-inhibition. (4) Conclusions: We established a murine model of oxaliplatin-induced SOS and provided novel evidence on the protective effect of VEGF-inhibition against the development of SOS that may be associated with changes in the pathway of VEGF and its receptor VEGF-R2.
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3
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Tan YB, Teh JGX, Gwee YY, Ng YK. A Review and Case Discussion on a Rare Cause of Non-cirrhotic Portal Hypertension. Cureus 2022; 14:e30252. [DOI: 10.7759/cureus.30252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2022] [Indexed: 11/07/2022] Open
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Monocrotaline Toxicity Alters the Function of Hepatocyte Membrane Transporters in Rats. Int J Mol Sci 2022; 23:ijms23147928. [PMID: 35887275 PMCID: PMC9323134 DOI: 10.3390/ijms23147928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/13/2022] [Accepted: 07/16/2022] [Indexed: 12/10/2022] Open
Abstract
Pyrrolizidine alkaloid monocrotaline (MCT) induces sinusoidal obstruction syndrome (SOS) in rats characterised by a sinusoidal congestive obstruction. Additionally, MCT administration decreases the biliary excretion of gadobenate dimeglumine (BOPTA), a hepatobiliary substrate used in clinical imaging. BOPTA crosses hepatocyte membranes through organic anion transporting polypeptides, multidrug-resistance-associated protein 2, and Mrp3/4 transporters, and a modified function of these transporters is likely to explain the decreased biliary excretion. This study compared BOPTA transport across hepatocytes in livers isolated from normal (Nl) rats and rats with intragastric administration of MCT. BOPTA hepatocyte influx clearance was similar in both groups, while biliary clearance and bile concentrations were much lower in MCT than in Nl livers. BOPTA efflux clearance back to the sinusoids compensated for the low biliary excretion, and hepatocyte concentrations remained similar in both groups. This SOS-associated changes of transporter functions might impact the pharmacokinetics of numerous drugs that use similar transporters to cross hepatocytes.
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Does Chemotherapy-Induced Liver Injury Impair Postoperative Outcomes After Laparoscopic Liver Resection for Colorectal Metastases? J Gastrointest Surg 2021; 25:1203-1211. [PMID: 32410180 DOI: 10.1007/s11605-020-04636-0] [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: 01/20/2020] [Accepted: 04/25/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND Chemotherapy-associated liver injuries (CALI) have been associated with poor postoperative outcome after open liver resection. To date, no data concerning any correlation of CALI and laparoscopic liver resection (LLR) are available. In the present study, we evaluated the impact of CALI on short-term outcomes in patients undergoing LLR. MATERIALS AND METHODS All patients who underwent in our department LLR for colorectal liver metastases (CRLM) from 2000 to 2016 were retrospectively reviewed. Patients were divided in 4 groups according to their pathological histology. In group 1 patients had normal liver parenchyma. Group 2 included patients with steatosis and steatohepatitis. Patients with sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH) were allocated to group 3, whereas the remaining with fibrosis and cirrhosis, were assigned to group 4. RESULTS A total of 490 LLR for CRLM were included in the study. Perioperative details and morbidity did not differ significantly between the four groups. Subgroup analysis showed that NRH was associated with higher amount of blood loss (p = 0.043), overall (p = 0.021) and liver-specific morbidity (p = 0.039). CONCLUSION NRH is a severe form of CALI that may worsen the short-term outcomes of patients undergoing LLR for CRLM. However, the remaining forms of CALI do not have a significant impact on perioperative outcomes after LLR.
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6
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Truant S, Baillet C, Gnemmi V, Fulbert M, Turpin A, Dardenne S, Leteurtre E, El Amrani M, Dharancy S, Dubuquoy L, Huglo D, Chesné C, Pruvot FR. The Impact of Modern Chemotherapy and Chemotherapy-Associated Liver Injuries (CALI) on Liver Function: Value of 99mTc-Labelled-Mebrofenin SPECT-Hepatobiliary Scintigraphy. Ann Surg Oncol 2020; 28:1959-1969. [PMID: 32833150 DOI: 10.1245/s10434-020-08988-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 04/16/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Chemotherapy is increasingly used before hepatic resection, with controversial impact regarding liver function. This study aimed to assess the capacity of 99mTc-labelled-mebrofenin SPECT-hepatobiliary scintigraphy (HBS) to predict liver dysfunction due to chemotherapy and/or chemotherapeutic-associated liver injuries (CALI), such as sinusoidal obstruction syndrome (SOS) and nonalcoholic steatohepatitis (NASH) activity score (NAS). METHODS From 2011 to 2015, all consecutive noncirrhotic patients scheduled for a major hepatectomy (≥ 3 segments) gave informed consent for preoperative SPECT-HBS allowing measurements of segmental liver function. As primary endpoint, HBS results were compared between patients with versus without (1) preoperative chemotherapy (≤ 3 months); and (2) CALI, mainly steatosis, NAS (Kleiner), or SOS (Rubbia-Brandt). Secondary endpoints were (1) other factors impairing function; and (2) impact of chemotherapy, and/or CALI on hepatocyte isolation outcome via liver tissues. RESULTS Among 115 patients, 55 (47.8%) received chemotherapy. Sixteen developed SOS and 35 NAS, with worse postoperative outcome. Overall, chemotherapy had no impact on liver function, except above 12 cycles. In patients with CALI, a steatosis ≥ 30% significantly compromised function, as well as NAS, especially grades 2-5. Conversely, SOS had no impact, although subjected to very low patients number with severe SOS. Other factors impairing function were diabetes, overweight/obesity, or fibrosis. Similarly, chemotherapy in 73 of 164 patients had no effect on hepatocytes isolation outcome; regarding CALI, steatosis ≥ 30% and NAS impaired the yield and/or viability of hepatocytes, but not SOS. CONCLUSIONS In this first large, prospective study, HBS appeared to be a valuable tool to select heavily treated patients at risk of liver dysfunction through steatosis or NAS.
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Affiliation(s)
- Stéphanie Truant
- Department of Digestive Surgery and Transplantation, Univ. Lille, CHRU Lille, Lille, France. .,CANTHER laboratory Cancer Heterogeneity, Plasticity and Resistance to Therapies UMR-S1277 INSERM, Team Mucins, Cancer and Drug Resistance, 59000, Lille, France.
| | - Clio Baillet
- Department of Nuclear Medicine, Univ. Lille, Lille, France
| | | | - Maxence Fulbert
- Department of Digestive Surgery and Transplantation, Univ. Lille, CHRU Lille, Lille, France
| | - Anthony Turpin
- Department of Medical Oncology, Univ. Lille, Lille, France
| | - Sabrina Dardenne
- Department of Digestive Surgery and Transplantation, Univ. Lille, CHRU Lille, Lille, France
| | | | - Mehdi El Amrani
- Department of Digestive Surgery and Transplantation, Univ. Lille, CHRU Lille, Lille, France.,CANTHER laboratory Cancer Heterogeneity, Plasticity and Resistance to Therapies UMR-S1277 INSERM, Team Mucins, Cancer and Drug Resistance, 59000, Lille, France
| | - Sébastien Dharancy
- Hepatology Unit, Univ. Lille, Lille, France.,LIRIC-Lille Inflammation Research International Center-U995, Univ. Lille, Inserm, CHU Lille, Lille, France
| | - Laurent Dubuquoy
- Hepatology Unit, Univ. Lille, Lille, France.,LIRIC-Lille Inflammation Research International Center-U995, Univ. Lille, Inserm, CHU Lille, Lille, France
| | - Damien Huglo
- Department of Nuclear Medicine, Univ. Lille, Lille, France
| | | | - François-René Pruvot
- Department of Digestive Surgery and Transplantation, Univ. Lille, CHRU Lille, Lille, France
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Konishi T, Yoshidome H, Shimizu H, Yoshitomi H, Furukawa K, Takayashiki T, Kuboki S, Takano S, Miyazaki M, Ohtsuka M. Splenic enlargement induced by preoperative chemotherapy is a useful indicator for predicting liver regeneration after resection for colorectal liver metastases. World J Surg Oncol 2020; 18:139. [PMID: 32576191 PMCID: PMC7313099 DOI: 10.1186/s12957-020-01918-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/15/2020] [Indexed: 11/13/2022] Open
Abstract
Background Conversion chemotherapy may downsize unresectable colorectal liver metastases (CRLMs), but may cause liver injury and splenic enlargement. The effect of preoperative chemotherapy on liver regeneration after liver resection remains undetermined. The aim of this study was to examine whether splenic enlargement induced by preoperative chemotherapy is an indicator to identify high-risk patients for impaired liver regeneration and liver dysfunction after resection. Methods We retrospectively reviewed 118 Japanese patients with CRLMs. Fifty-one patients had conversion chemotherapy. The other 67 patients underwent up-front liver resection. We clarified effects of conversion chemotherapy on splenic volume, liver function, and postoperative liver regeneration. Perioperative outcome was also analyzed. Results A ratio of the splenic volume before and after chemotherapy (SP index) in the oxaliplatin-based chemotherapy group was significantly greater than other chemotherapy groups after 9 or more chemotherapy cycles. Patients whose SP index was 1.2 or more had significantly higher indocyanine green retention rate at 15 min (ICG-R15) than patients without chemotherapy. Analyses of covariance showed liver regeneration rate after resection was decreased in patients whose SP index was 1.2 or more. The incidence of postoperative liver dysfunction in patients whose SP index was 1.2 or more was significantly greater than patients without chemotherapy. Multivariate analysis showed SP index was a significant predictive factor of impaired liver regeneration. Conclusions Splenic enlargement induced by preoperative chemotherapy was a useful indicator for impaired liver regeneration after resection and a decision-making tool of treatment strategy for unresectable CRLMs.
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Affiliation(s)
- Takanori Konishi
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hiroyuki Yoshidome
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan. .,Department of Surgery, Oami Municipal Hospital, 884-1 Tomida, Oami-Shirasato-shi, Chiba, 299-3221, Japan.
| | - Hiroaki Shimizu
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hideyuki Yoshitomi
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan.,Surgery and Digestive Disease Center, International University of Health and Welfare, Mita Hospital, 1-4-3 Mita, Minato-Ku, Tokyo, 108-8329, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
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Kumar A, Palek R, Liska V. A Critical Analysis of Experimental Animal Models of Sinusoidal Obstruction Syndrome. J Clin Exp Hepatol 2019; 9:345-353. [PMID: 31360027 PMCID: PMC6637067 DOI: 10.1016/j.jceh.2018.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/07/2018] [Indexed: 02/08/2023] Open
Abstract
Given the high mortality rate and clinical impact associated with sinusoidal obstruction syndrome (SOS), many studies have attempted to better characterize the disease and potential treatment strategies. However, the unpredictability of SOS onset represents a major obstacle when developing reproducible and controlled clinical trials in humans. Similarly, although in vitro studies have elucidated many of the molecular and cellular mechanisms of SOS, they often lack clinical relevance and translatability, highlighting the importance of experimental in vivo research. Animal models have greatly varied in the approach used to induce SOS in accordance with the numerous causes of human disease. Thus far, the most common and prevalent model is the monocrotaline-induced model in rats, which has served as the basis for both new diagnostic and treatment studies and has been revised over the last 20 years to optimize its use. Furthermore, radiotherapy, oxaliplatin-based chemotherapy, and even hematopoietic stem cell transplantation have been recently used to better replicate human SOS in animals. Nevertheless, because of the novelty of such research, further studies should be conducted to better understand the reproducibility and applicability of these newer models. Thus, this review seeks to summarize the methods and results of experimental in vivo models of SOS and compare the efficacy of these various adaptations.
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Key Words
- BM SPC, Bone Marrow Endothelial Progenitor Cell
- CRLM, Colorectal Liver Metastases
- CV, Central Vein
- HSCT, Hematopoietic Stem Cell Transplantation
- HVOD, Hepatic Veno-Occlusive Disease
- MCT, Monocrotaline
- MMP-9, Matrix Metalloproteinase-9
- NO, Nitric Oxide
- PA, Pyrrolizidine Alkaloid
- RILD, Radiation-Induced Liver Disease
- SEC, Sinusoidal Endothelial Cell
- SOS, Sinusoidal Obstruction Syndrome
- blue liver disease
- in vivo
- monocrotaline
- oxaliplatin
- veno-occlusive disease
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Affiliation(s)
- Arvind Kumar
- Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Pilsen, Czech Republic,Department of Surgery, Charles University, Faculty of Medicine in Pilsen, Teaching Hospital Pilsen, Pilsen, Czech Republic
| | - Richard Palek
- Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Pilsen, Czech Republic,Department of Surgery, Charles University, Faculty of Medicine in Pilsen, Teaching Hospital Pilsen, Pilsen, Czech Republic
| | - Vaclav Liska
- Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Pilsen, Czech Republic,Department of Surgery, Charles University, Faculty of Medicine in Pilsen, Teaching Hospital Pilsen, Pilsen, Czech Republic,Address for correspondence: Vaclav Liska, Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Alej Svobody 1655/76 323 00, Pilsen, Czech Republic.
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Preoperative Chemotherapy on Functional Liver Regeneration for Colorectal Liver Metastases Assessed With 99mTc-GSA SPECT/CT Imaging. Int Surg 2018. [DOI: 10.9738/intsurg-d-16-00209.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective:
To investigate the functional liver regeneration after chemotherapy and liver resection for colorectal liver metastases (CRLM).
Background/Purpose:
Preoperative chemotherapy followed by liver resection for CRLM has been increasing; however, its negative impact on liver regeneration remains unknown.
Methods:
From January 2009 to December 2013, we enrolled 40 selected patients who underwent major hepatectomy without viral hepatitis and severe liver fibrosis. CRLM patients with preoperative chemotherapy (CT-CRLM group, n = 12) and patients without preoperative chemotherapy (control group, n = 28) were evaluated. Liver volume (LV) and functional liver volume (FLV) was assessed using Tc-99m–labeled galactosyl human serum albumin (99mTc-GSA) scintigraphy, single-photon emission computed tomography (SPECT), CT-fused images. Preoperative, future remnant liver, and post 1-month values were compared.
Results:
Median course of preoperative chemotherapy was 8 (range: 6–16). Preoperative background factors were almost identical including resection rate and functional resection rate. In the CT-CRLM group and in the control group, the percentage increases in LV were 39.3% ± 29.0% and 23.2% ± 23.5% (P = 0.037), and FLV were 79.4% ± 43.1% and 57.0% ± 33.4% (P = 0.417), respectively; absolute differences in LV were 216.2 ± 155.7 cm3 and 148.7 ± 134.7 cm3 (P = 0.086) and FLV were 19.4% ± 8.5%/m2 and 17.4% ± 7.9%/m2 (P = 0.235), respectively. We found no obvious tendency for negative influence on liver functional regeneration by the preoperative regimens for CRLM.
Conclusions:
Several courses of preoperative chemotherapy may not affect functional liver regeneration for CRLM patients after major hepatectomy.
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10
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Bouhlel A, Bejaoui M, Ben Mosbah I, Hadj Abdallah N, Ribault C, Viel R, Hentati H, Corlu A, Ben Abdennebi H. Thymoquinone protects rat liver after partial hepatectomy under ischaemia/reperfusion through oxidative stress and endoplasmic reticulum stress prevention. Clin Exp Pharmacol Physiol 2018; 45:943-951. [PMID: 29733120 DOI: 10.1111/1440-1681.12961] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 03/29/2018] [Accepted: 04/26/2018] [Indexed: 12/31/2022]
Abstract
Ischaemia reperfusion (I/R) is associated with liver injury and impaired regeneration during partial hepatectomy (PH). The aim of this study was to investigate the effect of thymoquinone (TQ), the active compound of essential oil obtained from Nigella sativa seeds, on rat liver after PH. Male Wistar rats were divided equally into four groups (n = 6) receiving an oral administration of either vehicle solution (sham and PH groups) or TQ at 30 mg/kg (TQ and TQ + PH groups) for 10 consecutive days. Then, rats underwent PH (70%) with 60 minutes of ischaemia followed by 24 hours of reperfusion (PH and TQ + PH groups). Alanine aminotransferase (ALT) activity and histopathological damage were determined. Also, antioxidant parameters, liver regeneration index, hepatic adenosine triphosphate (ATP) content, endoplasmic reticulum (ER) stress and apoptosis were assessed. In response to PH under I/R, liver damage was significantly alleviated by TQ treatment as evidenced by the decrease in ALT activity (P < .01) and histological findings (P < .001). In parallel, TQ preconditioning increased hepatic antioxidant capacities. Moreover, TQ improved mitochondrial function (ATP, P < .05), attenuated ER stress parameters and repressed the expression of apoptotic effectors. Taken together, our results suggest that TQ preconditioning could be an effective strategy to reduce liver injury after PH under I/R. The protective effects were mediated by the increase of antioxidant capacities and the decrease of ER stress and apoptosis.
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Affiliation(s)
- Ahlem Bouhlel
- Faculté de Pharmacie, Unité de Biologie et Anthropologie Moléculaire Appliquées au Développement et à la Santé (UR12ES11), Université de Monastir, Monastir, Tunisia
| | - Mohamed Bejaoui
- Faculté de Pharmacie, Unité de Biologie et Anthropologie Moléculaire Appliquées au Développement et à la Santé (UR12ES11), Université de Monastir, Monastir, Tunisia
| | - Ismail Ben Mosbah
- Institut Mondor Recherche Biomédicale (IMRB), Université Paris-Est, Créteil, France
- Biopredic International, Rennes, France
| | - Najet Hadj Abdallah
- Faculté de Pharmacie, Unité de Biologie et Anthropologie Moléculaire Appliquées au Développement et à la Santé (UR12ES11), Université de Monastir, Monastir, Tunisia
| | - Catherine Ribault
- INSERM, INRA, Université Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), UMR_S1241, UMR_A 1341, Rennes, France
| | - Roselyne Viel
- Université de Rennes 1, US18, UMS 3480 Biosit, Biogenouest, Plateforme H2P2, Rennes, France
| | - Hassen Hentati
- Institut Mondor Recherche Biomédicale (IMRB), Université Paris-Est, Créteil, France
| | - Anne Corlu
- INSERM, INRA, Université Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), UMR_S1241, UMR_A 1341, Rennes, France
| | - Hassen Ben Abdennebi
- Faculté de Pharmacie, Unité de Biologie et Anthropologie Moléculaire Appliquées au Développement et à la Santé (UR12ES11), Université de Monastir, Monastir, Tunisia
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11
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Overman MJ, Ferrarotto R, Raghav K, George B, Qiao W, Machado KK, Saltz LB, Mazard T, Vauthey JN, Hoff PM, Hobbs B, Loyer EM, Kopetz S. The Addition of Bevacizumab to Oxaliplatin-Based Chemotherapy: Impact Upon Hepatic Sinusoidal Injury and Thrombocytopenia. J Natl Cancer Inst 2018; 110:888-894. [DOI: 10.1093/jnci/djx288] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 12/13/2017] [Indexed: 01/06/2023] Open
Affiliation(s)
- Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Renata Ferrarotto
- Department of Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Binsah George
- Division of Internal Medicine, The University of Texas Medical School, Houston, TX
| | - Wei Qiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Karime K Machado
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | | | - J N Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Paulo M Hoff
- Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Brian Hobbs
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Evelyn M Loyer
- Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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12
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Zhao J, van Mierlo KMC, Gómez-Ramírez J, Kim H, Pilgrim CHC, Pessaux P, Rensen SS, van der Stok EP, Schaap FG, Soubrane O, Takamoto T, Viganò L, Winkens B, Dejong CHC, Olde Damink SWM, Martín Pérez E, Cho JY, Choi YR, Phillips W, Michael M, Panaro F, Chenard MP, Verhoef C, Grünhagen DJ, Vara J, Scatton O, Hashimoto T, Makuuchi M, De Rosa G, Ravarino N. Systematic review of the influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases. Br J Surg 2017; 104:990-1002. [PMID: 28542731 DOI: 10.1002/bjs.10572] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 02/07/2017] [Accepted: 03/29/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND The impact of chemotherapy-associated liver injury (CALI) on postoperative outcome in patients undergoing partial hepatectomy for colorectal liver metastases (CRLM) remains controversial. The objective of this study was to clarify the effect of CALI (sinusoidal dilatation (SD), steatosis and steatohepatitis) on postoperative morbidity and mortality by investigating a large data set from multiple international centres. METHODS PubMed and Embase were searched for studies published between 1 January 2004 and 31 December 2013 with keywords 'chemotherapy', 'liver resection', 'outcome' and 'colorectal metastases' to identify potential collaborating centres. Univariable and multivariable analyses were performed using binary logistic regression models, with results presented as odds ratios (ORs) with 95 per cent confidence intervals. RESULTS A consolidated database comprising 788 patients who underwent hepatectomy for CRLM in eight centres was obtained. In multivariable analyses, severe SD was associated with increased major morbidity (Dindo-Clavien grade III-V; OR 1·73, 95 per cent c.i. 1·02 to 2·95; P = 0·043). Severe steatosis was associated with decreased liver surgery-specific complications (OR 0·52, 95 per cent c.i. 0·27 to 1·00; P = 0·049), whereas steatohepatitis was linked to an increase in these complications (OR 2·08, 1·18 to 3·66; P = 0·012). Subgroup analysis showed that lobular inflammation was the sole component associated with increased overall morbidity (OR 2·22, 1·48 to 3·34; P = 0·001) and liver surgery-specific complications (OR 3·35, 2·11 to 5·32; P < 0·001). Finally, oxaliplatin treatment was linked to severe SD (OR 2·74, 1·67 to 4·49; P < 0·001). CONCLUSION An increase in postoperative major morbidity and liver surgery-specific complications was observed after partial hepatectomy in patients with severe SD and steatohepatitis. Postoperative liver failure occurred more often in patients with severe SD.
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Affiliation(s)
- J Zhao
- Department of Surgery, Maastricht University Medical Centre and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - K M C van Mierlo
- Department of Surgery, Maastricht University Medical Centre and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - J Gómez-Ramírez
- Hepatopancreaticobiliary Surgery Unit, Department of Surgery, Hospital Universitario de la Princesa, Madrid, Spain
| | - H Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National College of Medicine, Seongnam, Korea
| | - C H C Pilgrim
- Hepatopancreaticobiliary Service, Upper Gastrointestinal Surgery, The Alfred Hospital, and Division of Cancer Surgery, Peter MacCallum Cancer Centre, Department of Surgery, University of Melbourne, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - P Pessaux
- Digestive Surgery and Transplantation, Hôpital de Hautepierre, University Hospital of Strasbourg, Strasbourg, France
| | - S S Rensen
- Department of Surgery, Maastricht University Medical Centre and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - E P van der Stok
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - F G Schaap
- Department of Surgery, Maastricht University Medical Centre and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - O Soubrane
- Department of Hepatobiliary Surgery and Liver Transplant, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Université Denis Diderot, Paris, France
| | - T Takamoto
- Department of Hepatopancreaticobiliary Surgery, Japanese Red Cross Medical Centre, Tokyo, Japan
| | - L Viganò
- Division of Hepatobiliary and General Surgery, Humanitas Clinical and Research Centre, Humanitas University, Rozzano, Italy
| | - B Winkens
- Department of Methodology and Statistics, Maastricht University Medical Centre, and CAPHRI School for Public Health and Primary Care, Maastricht, The Netherlands
| | - C H C Dejong
- Department of Surgery, Maastricht University Medical Centre and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands.,GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - S W M Olde Damink
- Department of Surgery, Maastricht University Medical Centre and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands.,Department of Hepatopancreaticobiliary Surgery and Liver Transplantation, Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, UK
| | | | - E Martín Pérez
- Hepatopancreaticobiliary Surgery Unit, Department of Surgery, Hospital Universitario de la Princesa, Madrid, Spain
| | - J Y Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National College of Medicine, Seongnam, Korea
| | - Y R Choi
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National College of Medicine, Seongnam, Korea
| | - W Phillips
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Department of Surgery, University of Melbourne, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - M Michael
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Department of Surgery, University of Melbourne, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - F Panaro
- Digestive Surgery and Transplantation, Hôpital de Hautepierre, University Hospital of Strasbourg, University of Strasbourg, Strasbourg, France
| | - M-P Chenard
- Department of Pathology, Hôpital de Hautepierre, University hospital of Strasbourg, University of Strasbourg, Strasbourg, France
| | - C Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - D J Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - J Vara
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France
| | - O Scatton
- Department of Digestive and Hepatobiliary Surgery, La Pitié Hospital, Université Pierre et Maris Curie, Paris, France
| | - T Hashimoto
- Department of Hepatopancreaticobiliary Surgery, Japanese Red Cross Medical Centre, Tokyo, Japan
| | - M Makuuchi
- Department of Hepatopancreaticobiliary Surgery, Japanese Red Cross Medical Centre, Tokyo, Japan
| | - G De Rosa
- Department of Pathology, Mauriziano Umberto I Hospital, Turin, Italy
| | - N Ravarino
- Department of Pathology, Mauriziano Umberto I Hospital, Turin, Italy
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van Mierlo KMC, Schaap FG, Dejong CHC, Olde Damink SWM. Liver resection for cancer: New developments in prediction, prevention and management of postresectional liver failure. J Hepatol 2016; 65:1217-1231. [PMID: 27312944 DOI: 10.1016/j.jhep.2016.06.006] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 06/03/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatic failure is a feared complication that accounts for up to 75% of mortality after extensive liver resection. Despite improved perioperative care, the increasing complexity and extensiveness of surgical interventions, in combination with an expanding number of resections in patients with compromised liver function, still results in an incidence of postresectional liver failure (PLF) of 1-9%. Preventive measures aim to enhance future remnant liver size and function. Numerous non-invasive techniques to assess liver function and predict remnant liver volume are being developed, along with introduction of novel surgical strategies that augment growth of the future remnant liver. Detection of PLF is often too late and treatment is primarily symptomatic. Current therapeutic research focuses on ([bio]artificial) liver function support and regenerative medicine. In this review we discuss the current state and new developments in prediction, prevention and management of PLF, in light of novel insights into the aetiology of this complex syndrome. LAY SUMMARY Liver failure is the main cause of death after partial liver resection for cancer, and is presumably caused by an insufficient quantity and function of the liver remnant. Detection of liver failure is often too late, and current treatment focuses on relieve of symptoms. New research initiatives explore artificial support of liver function and stimulation of regrowth of the remnant liver.
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Affiliation(s)
- Kim M C van Mierlo
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Frank G Schaap
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Cornelis H C Dejong
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Steven W M Olde Damink
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Institute of Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
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Park S, Kim HY, Kim H, Park JH, Kim JH, Kim KH, Kim W, Choi IS, Jung YJ, Kim JS. Changes in Noninvasive Liver Fibrosis Indices and Spleen Size During Chemotherapy: Potential Markers for Oxaliplatin-Induced Sinusoidal Obstruction Syndrome. Medicine (Baltimore) 2016; 95:e2454. [PMID: 26765438 PMCID: PMC4718264 DOI: 10.1097/md.0000000000002454] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Oxaliplatin-based regimens are standard treatments for the patients with colorectal cancer (CRC) and advanced gastric cancer (AGC). However, owing to hepatic sinusoidal obstruction syndrome (SOS), the use of oxaliplatin sometimes results in splenomegaly. The aim of the present study was to evaluate the correlation between chemotherapy-associated changes of noninvasive liver fibrosis indices and volumetric changes of the spleen.From February 2004 to April 2014, patients with CRC or AGC receiving oxaliplatin-based chemotherapy were studied. The possibility of SOS development was evaluated before and after the oxaliplatin exposure with splenic volume index (SVI). Four different noninvasive liver fibrosis indices were used for risk analysis, namely age-platelet index (API), AST-to-platelet ratio index (APRI), platelet-to-spleen ratio (PSR), and fibrosis-4 score (FIB-4).A total of 275 patients were eligible for evaluation: 200 patients had CRC and 75 patients had AGC. Using the cutoff of SVI increase ≥ 0.3, 113 patients (41.1%) were positive for splenomegaly. The changes of indices significantly correlated with SVI increase. Adjusted odds ratios for those indices were as follows: API = 1.16 (95% confidential interval [CI], 1.01-1.32; P = .03); APRI = 2.45 (95% CI, 1.30-4.63; P = .01); PSR = 0.69 (95% CI, 0.59-0.80; P < .01); and FIB-4 = 1.37 (95% CI, 1.16-1.63; P < .01). Optimal cutoff values with statistical significance were calculated and suggested.The changes of noninvasive liver fibrosis indices showed a good correlation with the increase in the spleen volume during oxaliplatin-based chemotherapy. Validation of these indices for monitoring of oxaliplatin-induced hepatic SOS is warranted.
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Affiliation(s)
- Sehhoon Park
- From the Department of Internal Medicine (SP), Seoul National University Hospital, Seoul; Department of Internal Medicine (HYK, JHP, KHK, WK, ISC, YJJ, J-SK), Seoul National University Boramae Medical Center, Seoul; Department of Pathology (HK), Seoul National University Bundang Hospital, Bundang-gu, Seongnam; and Department of Pathology (JHK), Seoul National University Boramae Medical Center, Seoul, Korea
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Bednarsch J, Jara M, Lock JF, Malinowski M, Pratschke J, Stockmann M. Noninvasive diagnosis of chemotherapy induced liver injury by LiMAx test--two case reports and a review of the literature. BMC Res Notes 2015; 8:99. [PMID: 25889706 PMCID: PMC4403679 DOI: 10.1186/s13104-015-1055-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Accepted: 03/12/2015] [Indexed: 02/06/2023] Open
Abstract
Background Chemotherapy-induced liver injury is a well-known phenomenon after neoadjuvant therapy of liver metastasis and contributes to postoperative morbidity and mortality. Still there is no suitable test available to reliably determine functional impairment and hepatic regeneration after chemotherapy. Case presentation We report two cases of caucasian patients who underwent repeated liver function assessments using LiMAx (maximum liver function capacity), Indocyanine plasma disappearance rate and biochemical liver function parameters in the course of adjuvant oxaliplatin-based chemotherapy. Both patients yielded a decrease from their initial liver function determined by LiMAx. Liver regeneration assessed functional recovery within 4 weeks in case of mild functional impairment after cessation of chemotherapy or within 8 weeks in case of major functional deterioration. Indocyanine plasma disappearance rate and biochemical parameters remained stable or without a clear trend in case of minor functional impairment. This is the first report using a dynamic liver function test to evaluate the impact and recovery from chemotherapy associated liver injury. Conclusions The LiMAx test might be a sensitive tool to diagnose mild functional impairment after chemotherapy when standard liver function tests have remained within normal ranges and might be capable to assess the course of regeneration after chemotherapy. This could be useful to optimize individual chemotherapy-free interval before liver surgery can be carried out safely.
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Affiliation(s)
- Jan Bednarsch
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Maximilian Jara
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Johan Friso Lock
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Maciej Malinowski
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Johann Pratschke
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Martin Stockmann
- Department of General, Visceral and Transplantation Surgery, Charité University Hospital, Augustenburger Platz 1, 13353, Berlin, Germany.
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Conotte R, Colet JM. A metabonomic evaluation of the monocrotaline-induced sinusoidal obstruction syndrome (SOS) in rats. Toxicol Appl Pharmacol 2014; 276:147-56. [DOI: 10.1016/j.taap.2014.02.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 01/31/2014] [Accepted: 02/12/2014] [Indexed: 12/20/2022]
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Morine Y, Shimada M, Utsunomiya T. Evaluation and management of hepatic injury induced by oxaliplatin-based chemotherapy in patients with hepatic resection for colorectal liver metastasis. Hepatol Res 2014; 44:59-69. [PMID: 23551330 DOI: 10.1111/hepr.12107] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 02/19/2013] [Accepted: 02/24/2013] [Indexed: 12/23/2022]
Abstract
Patients with colorectal liver metastasis (CRLM) can be cured with surgical resection. Recent advances in systemic chemotherapy, including molecular target agents, can be used to introduce "conversion surgery" and achieve R0 resection even in patients with initially unresectable CRLM. Furthermore, neoadjuvant chemotherapy also tries to be applied in patients with resectable CRLM to maximize the remnant liver and reduce the residual micrometastasis before surgery. The development of chemotherapy-induced hepatic injuries is increasingly being recognized, including sinusoidal obstructive syndrome (SOS), steatosis, steatohepatitis and biliary sclerosis. Especially, oxaliplatin (L-OHP)-based chemotherapy in clinical settings appears to be primarily associated with SOS. Various reports have tried to demonstrate the rationale of the correlation between L-OHP-based chemotherapy and SOS for the following hepatic surgery. While we can recognize that this pathophysiological disadvantage leads to hepatic dysfunction and the increasing postoperative morbidity, the essential part of this problem including clinical disadvantage, onset mechanism, evaluation systems, and targeted agents for prevention and treatment of SOS continue to be unclear. In this review, we summarize the current experience with hepatic injury induced by L-OHP-based chemotherapy, focusing on SOS-based on clinical and experimental data, in order to assist in the resolution of these identified factors. Finally, the need for reliable methods to identify the risk of SOS, to evaluate SOS status and to predict the safety of surgical treatment in patients with chemotherapy prior to surgery will be emphasized.
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Affiliation(s)
- Yuji Morine
- Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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18
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Schmidt S, Denys A, Pastor CM. Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green. J Hepatol 2013; 59:631-2. [PMID: 23665042 DOI: 10.1016/j.jhep.2013.04.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 04/08/2013] [Accepted: 04/09/2013] [Indexed: 12/14/2022]
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Cardinale V, De Filippis G, Corsi A, La Penna A, Rossi M, Catalano C, Bianco P, De Santis A, Alvaro D. An isolate alpha-fetoprotein producing gastric cancer liver metastasis emerged in a patient previously affected by radiation induced liver disease. World J Hepatol 2013; 5:398-403. [PMID: 23898374 PMCID: PMC3724969 DOI: 10.4254/wjh.v5.i7.398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Revised: 11/05/2011] [Accepted: 11/14/2012] [Indexed: 02/06/2023] Open
Abstract
We report a case of an isolated hepatic neoplasia which originated in a site of the liver previously affected by radiation induced liver disease (RILD) in a patient resected for gastric cancer and referred to us for high serum alpha-fetoprotein (AFP) levels. This case challenged us in distiguishing, even histologically, between primary liver cancer and AFP producing gastric cancer metastasis. Only a panel of immunohistochemical markers allowed the definitive diagnosis of liver metastasis of endodermal stem cell-derived and AFP producing gastric cancer. We discuss the criteria for a differential diagnosis, as well as the possible link between RILD and emergence of liver neoplasia.
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Affiliation(s)
- Vincenzo Cardinale
- Vincenzo Cardinale, Domenico Alvaro, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00185 Rome, Italy
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Golse N, Bucur PO, Adam R, Castaing D, Sa Cunha A, Vibert E. New paradigms in post-hepatectomy liver failure. J Gastrointest Surg 2013; 17:593-605. [PMID: 23161285 DOI: 10.1007/s11605-012-2048-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 10/04/2012] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Liver failure after hepatectomy remains the most feared postoperative complication. Many risk factors are already known, related to patient's comorbidities, underlying liver disease, received treatments and type of resection. Preoperative assessment of functional liver reserve must be a priority for the surgeon. METHODS Physiopathology of post-hepatectomy liver failure is not comparable to fulminant liver failure. Liver regeneration is an early phenomenon whose cellular mechanisms are beginning to be elucidated and allowing most of the time to quickly recover a functional organ. In some cases, microscopic and macroscopic disorganization appears. The hepatocyte hyperproliferation and the asynchronism between hepatocytes and non-hepatocyte cells mitosis probably play a major role in this pathogenesis. RESULTS Many peri- or intra-operative techniques try to prevent the occurrence of this potentially lethal complication, but a better understanding of involved mechanisms might help to completely avoid it, or even to extend the possibilities of resection. CONCLUSION Future prevention and management may include pharmacological slowing of proliferation, drug or physical modulation of portal flow to reduce shear-stress, stem cells or immortalized hepatocytes injection, and liver bioreactors. Everything must be done to avoid the need for transplantation, which remains today the most efficient treatment of liver failure.
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Affiliation(s)
- Nicolas Golse
- Centre Hépatobiliaire, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris XI, Paris, France.
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Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg 2012; 256:e7-8; author reply e16-7. [PMID: 22868374 DOI: 10.1097/sla.0b013e318265fd51] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Elias-Miró M, Massip-Salcedo M, Raila J, Schweigert F, Mendes-Braz M, Ramalho F, Jiménez-Castro MB, Casillas-Ramírez A, Bermudo R, Rimola A, Rodes J, Peralta C. Retinol binding protein 4 and retinol in steatotic and nonsteatotic rat livers in the setting of partial hepatectomy under ischemia/reperfusion. Liver Transpl 2012; 18:1198-1208. [PMID: 22685091 DOI: 10.1002/lt.23489] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Steatotic livers show increased hepatic damage and impaired regeneration after partial hepatectomy (PH) under ischemia/reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. The known function of retinol-binding protein 4 (RBP4) is to transport retinol in the circulation. We examined whether modulating RBP4 and/or retinol could protect steatotic and nonsteatotic livers in the setting of PH under I/R. Steatotic and nonsteatotic livers from Zucker rats were subjected to PH (70%) with 60 minutes of ischemia. RBP4 and retinol levels were measured and altered pharmacologically, and their effects on hepatic damage and regeneration were studied after reperfusion. Decreased RBP4 levels were observed in both liver types, whereas retinol levels were reduced only in steatotic livers. RBP4 administration exacerbated the negative consequences of liver surgery with respect to damage and liver regeneration in both liver types. RBP4 affected the mobilization of retinol from steatotic livers, and this revealed actions of RBP4 independent of simple retinol transport. The injurious effects of RBP4 were not due to changes in retinol levels. Treatment with retinol was effective only for steatotic livers. Indeed, retinol increased hepatic injury and impaired liver regeneration in nonsteatotic livers. In steatotic livers, retinol reduced damage and improved regeneration after surgery. These benefits of retinol were associated with a reduced accumulation of hepatocellular fat. Thus, strategies based on modulating RBP4 could be ineffective and possibly even harmful in both liver types in the setting of PH under I/R. In terms of clinical applications, a retinol pretreatment might open new avenues for liver surgery that specifically benefit the steatotic liver.
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Affiliation(s)
- Maria Elias-Miró
- August Pi i Sunyer Institute for Biomedical Research, Barcelona, Spain
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Ezzat T, Dhar DK, Olde Damink SWM. Sinusoidal obstruction syndrome: correct dosing of monocrotaline and the validity of the rat model. J Surg Oncol 2012; 107:448-9. [PMID: 22991282 DOI: 10.1002/jso.23265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 08/24/2012] [Indexed: 11/07/2022]
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Periasamy S, Yang SS, Chen SY, Chang CC, Liu MY. Prophylactic Sesame Oil Attenuates Sinusoidal Obstruction Syndrome by Inhibiting Matrix Metalloproteinase–9 and Oxidative Stress. JPEN J Parenter Enteral Nutr 2012; 37:529-37. [DOI: 10.1177/0148607112454299] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Narita M, Oussoultzoglou E, Fuchshuber P, Chenard MP, Rosso E, Yamamoto K, Jaeck D, Bachellier P. Prolonged Portal Triad Clamping Increases Postoperative Sepsis after Major Hepatectomy in Patients with Sinusoidal Obstruction Syndrome and/or Steatohepatitis. World J Surg 2012; 36:1848-57. [DOI: 10.1007/s00268-012-1565-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Narita M, Oussoultzoglou E, Chenard MP, Fuchshuber P, Rather M, Rosso E, Addeo P, Jaeck D, Bachellier P. Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization. Ann Surg Oncol 2012; 19:2230-7. [PMID: 22402811 DOI: 10.1245/s10434-011-2112-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Indexed: 01/28/2023]
Abstract
BACKGROUND Indocyanine green (ICG) retention is a validated test of hepatic function in patients with chronic liver disease. The underlying mechanism for the impairment of ICG retention in patients undergoing chemotherapy for colorectal liver metastases (CLM) remains unclear. We sought to elucidate the mechanism for impairment of ICG retention in patients with CLM. METHODS Clinicopathologic data of 98 patients with CLM undergoing hepatectomy were analyzed. The archived nontumoral liver parenchyma bearing no CLM were immunostained with CD34 antibody to determine the sinusoidal capillarization. RESULTS Of 98 patients, 80 received preoperative chemotherapy. Sinusoidal obstruction syndrome (SOS) occurred in 39 patients (39.8%). The development of SOS in patients receiving oxaliplatin-based chemotherapy was significantly higher compared to those receiving non-oxaliplatin-based chemotherapy (P=0.003). SOS was independently associated with abnormal ICG retention rate at 15 minutes (ICG-R15) (odds ratio 3.45, 95% confidence interval 1.31-9.04, P=0.012) and CD 34 overexpression (odds ratio 18.76, 95% confidence interval 4.58-76.81, P<0.001). ICG-R15 correlated with CD34 expression within the nontumoral liver parenchyma (r=0.707, P<0.001) and severity of SOS (r=0.423, P<0.001). CD34 positive areas were likely situated at the peripheral area of SOS, and both SOS score and number of cycles of oxaliplatin-based chemotherapy significantly correlated with CD34 expression (r=0.629, P<0.001 and r=0.522, P<0.001, respectively). CONCLUSIONS These results suggest that the deterioration of hepatic functional reserve due to SOS is associated with sinusoidal capillarization, indicated by CD34 overexpression within nontumoral liver parenchyma adjacent to SOS.
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Affiliation(s)
- Masato Narita
- Centre de Chirurgie Viscérale et de Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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Peng J, Wei YS, Peng HP. Colorectal chemotherapy-associated liver injury. Shijie Huaren Xiaohua Zazhi 2011; 19:3359-3364. [DOI: 10.11569/wcjd.v19.i32.3359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The increasing use of more effective chemotherapy in patients with colorectal cancer has raised awareness of the potential liver injuries induced by systemic drugs, such as fluorouracil, oxaliplatin and irinotecan. Chemotherapy-associated liver injuries can be revealed by histopathologic examination of nontumoral liver tissue. There are two broad categories of chemotherapy-induced liver injury: non-alcoholic fatty liver disease and sinusoidal injury. Many reports suggest that liver injuries may increase morbidity and mortality in patients who undergo hepatic resection for colorectal liver metastases, while some researchers have opposing views. This review describes the main types of chemotherapy-related liver injury and current controversy over this topic.
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Ezzat TM, Dhar DK, Newsome PN, Malagó M, Olde Damink SWM. Use of hepatocyte and stem cells for treatment of post-resectional liver failure: are we there yet? Liver Int 2011; 31:773-84. [PMID: 21645208 DOI: 10.1111/j.1478-3231.2011.02530.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Post-operative liver failure following extensive resections for liver tumours is a rare but significant complication. The only effective treatment is liver transplantation (LT); however, there is a debate about its use given the high mortality compared with the outcomes of LT for chronic liver diseases. Cell therapy has emerged as a possible alternative to LT especially as endogenous hepatocyte proliferation is likely inhibited in the setting of prior chemo/radiotherapy. Both hepatocyte and stem cell transplantations have shown promising results in the experimental setting; however, there are few reports on their clinical application. This review identifies the potential stem cell sources in the body, and highlights the triggering factors that lead to their mobilization and integration in liver regeneration following major liver resections.
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Affiliation(s)
- Tarek M Ezzat
- HPB and Liver Transplantation Surgery, Royal Free Hospital, University College London, Pond Street, London, UK
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Rubbia-Brandt L, Tauzin S, Brezault C, Delucinge-Vivier C, Descombes P, Dousset B, Majno PE, Mentha G, Terris B. Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans. Mol Cancer Ther 2011; 10:687-96. [PMID: 21330458 DOI: 10.1158/1535-7163.mct-10-1072] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.
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Affiliation(s)
- Laura Rubbia-Brandt
- Service de Pathologie Clinique, Hôpitaux Universitaires de Genève, 1211 Geneva, Switzerland.
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Narita M, Oussoultzoglou E, Chenard MP, Rosso E, Casnedi S, Pessaux P, Bachellier P, Jaeck D. Sinusoidal obstruction syndrome compromises liver regeneration in patients undergoing two-stage hepatectomy with portal vein embolization. Surg Today 2010; 41:7-17. [PMID: 21191686 DOI: 10.1007/s00595-010-4414-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2010] [Accepted: 06/16/2010] [Indexed: 02/07/2023]
Abstract
PURPOSE Several factors have been reported to affect liver regeneration after portal vein embolization (PVE); however, the effect of sinusoidal obstruction syndrome (SOS) has not been evaluated. Therefore, we assessed the effect of SOS on liver regeneration after PVE in patients with multiple bilobar colorectal liver metastases scheduled to undergo two-stage hepatectomy (TSH) combined with PVE. METHODS The subjects of this study were 78 patients prospectively scheduled to undergo TSH between December 1996 and August 2009. Archived formalin-fixed, paraffin-embedded nontumoral tissue samples were collected from the 1st- and 2nd-stage hepatectomies in 42 and 45 patients, respectively, and SOS and steatohepatitis were diagnosed pathologically. We analyzed the clinicopathological variables affecting liver regeneration after PVE. RESULTS Sinusoidal obstruction syndrome was diagnosed in 11 (26.2%) and 20 patients (44.4%) at the time of the 1st- and 2nd-stage hepatectomy, respectively. Patients with SOS at the 1st-stage hepatectomy had a significantly lower hypertrophy ratio of the future remnant liver (FRL) after PVE than patients without SOS (16.8 ± 24.0 vs 55.6 ± 32.5; P < 0.001). Multivariate logistic regression analysis revealed that SOS was an independent factor predicting lower FRL hypertrophy after PVE (Δ% FRL <20: hazard ratio 31.7, 95% confidence interval 2.84-355.12; P = 0.005). The incidence of postoperative transient liver failure after the 2nd-stage hepatectomy in patients presenting with SOS was higher than that in those without SOS, but the difference did not reach significance (25.0% vs 4.0%; P = 0.052). Steatohepatitis was confirmed at the 1st- and 2nd-stage hepatectomy in 6 (14.3%) and 3 (6.7%) patients, respectively. CONCLUSION Sinusoidal obstruction syndrome inhibits FRL hypertrophy after PVE and induces postoperative liver failure. Therefore, an alternative strategy is needed to perform TSH safely in the presence of SOS.
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Affiliation(s)
- Masato Narita
- Centre de Chirurgie Viscérale et de Transplantation, Hôpitaux Universitaires de Strasbourg, Avenue Molière, 67098 Strasbourg Cedex, France
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Abstract
Sinusoidal obstruction syndrome (SOS), formerly named venoocclusive disease, is a well-known complication of hematopoietic stem cell transplantation and ingestion of food or drinks contaminated by pyrrolizidine alkaloids. Many other drugs and toxins have been associated with SOS, including several chemotherapeutic agents and immunosuppressors. SOS contributes to significant morbidity and mortality in all these settings. This review describes the histologic lesions of SOS, details its pathogenesis as it is understood today, specifies the recent data on its causes and how it may influence clinical management of colorectal liver metastases, and discusses the current knowledge on diagnosis and preventive options.
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Rubbia-Brandt L, Lauwers GY, Wang H, Majno PE, Tanabe K, Zhu AX, Brezault C, Soubrane O, Abdalla EK, Vauthey JN, Mentha G, Terris B. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology 2010; 56:430-9. [PMID: 20459550 DOI: 10.1111/j.1365-2559.2010.03511.x] [Citation(s) in RCA: 223] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
AIMS Because of its efficacy, oxaliplatin (OX) is increasingly used as a chemotherapeutic agent in the treatment of colorectal liver metastases (CRLM). Oxaliplatin-associated liver toxicity has been reported and can affect clinical practice, but studies on its prevalence and a full pathological description are lacking. The aims of this study were to fill this gap by providing, from a pathologist's perspective, a detailed assessment of the spectrum of hepatic lesions associated with OX, to suggest a scoring system to quantify them, and to investigate the protective effect of bevacizumab against OX-associated damage. METHODS AND RESULTS The spectrum of oxaliplatin-associated liver lesions was investigated in a multi-institutional series of surgically resected CRLM (n = 385). Among 274 patients treated by OX, 54% had moderate/severe sinusoidal obstruction syndrome (SOS). Peliosis, centrilobular perisinusoidal/venular fibrosis and nodular regenerative hyperplasia (NRH) developed in 10.6%, 47% and 24.5%, respectively. The 111 patients treated by surgery alone had no lesions. Hepatic lesions were less severe in patients treated with OX/bevacizumab (n = 70) compared with the group treated by OX alone (n = 204), with an incidence of moderate/severe SOS (31.4% versus 62.2%), peliosis (4.3% versus 14.6%), NRH (11.4% versus 28.9%, respectively) and centrilobular/venular fibrosis (31.4% versus 52%, respectively) (P < 0.001). CONCLUSIONS Pathologists should be aware of the distinctive lesions associated with OX and of their high prevalence. OX-related lesions are less frequent in patients treated with bevacizumab, suggesting that this drug has a preventive effect. Uniform criteria for diagnosis and grading of OX-associated lesions should help to include histological data in the optimal multidisciplinary management of CRLM.
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Nodular regenerative hyperplasia secondary to neoadjuvant chemotherapy for colorectal liver metastases. Case Rep Med 2009; 2009:457975. [PMID: 19997518 PMCID: PMC2787019 DOI: 10.1155/2009/457975] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Accepted: 10/06/2009] [Indexed: 12/17/2022] Open
Abstract
Liver resection is the only curative treatment for patients with colorectal liver metastases (CLMs). Neoadjuvant chemotherapy can improve resectability but has a potential harmful effect on the nontumorous liver. Patients with chemotherapy-induced hepatic injury undergoing liver surgery have higher risks of post-resectional morbidity. We present two cases of patients without pre-existent liver disease treated with oxaliplatin-based chemotherapy followed by surgical resection of their CLMs. Their intra-operative liver specimen showed morphologic abnormalities characteristic of nodular regenerative hyperplasia (NRH). NRH led to portal hypertension in both patients that resulted in deleterious post-resectional complications and death of one patient. Interestingly, the other patient underwent two repeat nonanatomic liver resections because of recurrent CLMs. The intra-operative liver specimen still showed signs of NRH and sinusoidal congestion, but the post-resectional courses were uneventful. Nevertheless, caution is recommended in patients with suspected NRH. Careful volumetric analysis should guide the operative strategy. When future remnant liver volume is regarded insufficient, portal vein embolization or restrictive surgery should be considered.
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