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Elias Brountzos - One of the best experts on this subject based on the ideXlab platform.

Erik Schadde - One of the best experts on this subject based on the ideXlab platform.

  • Simultaneous hepatic and portal vein ligation induces rapid Liver Hypertrophy: A study in pigs
    Surgery, 2019
    Co-Authors: Erik Schadde, Boris Guiu, Rebecca A. Deal, Jennifer A. Kalil, Bulent Arslan, J. Tasse, Pim B. Olthof, Jan Heil, Andreas A. Schnitzbauer, Shriram Jakate
    Abstract:

    Abstract Background Liver Hypertrophy induced by partial portal vein occlusion (PVL) is accelerated by adding simultaneous parenchymal transection (“ALPPS procedure”). This preclinical experimental study in pigs tests the hypothesis that simultaneous ligation of portal and hepatic veins of the Liver also accelerates regeneration by abrogation of porto-portal collaterals without need for operative transection. Methods A pig model of portal vein occlusion was compared with the novel model of simultaneous portal and hepatic vein occlusion, where major hepatic veins draining the portal vein–deprived lobe were identified with intraoperative ultrasonography and ligated using pledgeted transparenchymal sutures. Kinetic growth was compared, and the portal vein system was then studied after 7 days using epoxy casts of the portal circulation. Portal vein flow and portal pressure were measured, and Ki-67 staining was used to evaluate the proliferative response. Results Pigs were randomly assigned to portal vein occlusion (n = 8) or simultaneous portal and hepatic vein occlusion (n = 6). Simultaneous portal and hepatic vein occlusion was well tolerated and led to mild cytolysis, with no necrosis in the outflow vein–deprived Liver sectors. The portal vein–supplied sector increased by 90 ± 22% (mean ± standard deviation) after simultaneous portal and hepatic vein occlusion compared with 29 ± 18% after PVL (P Conclusion This study in pigs found that simultaneous portal and hepatic vein occlusion led to rapid Hypertrophy without necrosis of the deportalized Liver. The findings suggest that the use of simultaneous portal and hepatic vein occlusion accelerates Liver Hypertrophy for extended Liver resections and should be evaluated further.

  • rapid Liver Hypertrophy after portal vein occlusion correlates with the degree of collateralization between lobes a study in pigs
    Journal of Gastrointestinal Surgery, 2018
    Co-Authors: Rebecca A. Deal, Pim B. Olthof, Charles Frederiks, Lauren Williams, Konstantin Dirscherl, Xavier M Keutgen, Edie Y Chan, Daniel J Deziel, Martin Hertl, Erik Schadde
    Abstract:

    Associating Liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces more rapid Liver growth than portal vein ligation (PVL). Transection of parenchyma in ALPPS may prevent the formation of collaterals between lobes. The aim of this study was to determine if abrogating the formation of collaterals through parenchymal transection impacted growth rate. Twelve Yorkshire Landrace pigs were randomized to undergo ALPPS, PVL, or “partial ALPPS” by varying degrees of parenchymal transection. Hepatic volume was measured after 7 days. Portal blood flow and pressure were measured. Portal vein collaterals were examined from epoxy casts. PVL, ALPPS, and partial ALPPS led to volume increases of the RLL by 15.5% (range 3–22), 64% (range 45–76), and 32% (range 18–77), respectively, with significant differences between PVL and ALPPS/partial ALPPS (p < 0.05). In PVL and partial ALPPS, substantial new portal vein collaterals were found. The number of collaterals correlated inversely with the growth rate (p = 0.039). Portal vein pressure was elevated in all models after ligation suggesting hyperflow to the portal vein-supplied lobe (p < 0.05). These data suggest that Liver Hypertrophy following PVL is inversely proportional to the development of collaterals. Hypertrophy after ALPPS is likely more rapid due to reduction of collaterals through transection.

  • rapid Liver Hypertrophy after portal vein occlusion correlates with the degree of collateralization between lobes a study in pigs
    Journal of Gastrointestinal Surgery, 2018
    Co-Authors: Rebecca A. Deal, Pim B. Olthof, Charles Frederiks, Lauren Williams, Konstantin Dirscherl, Xavier M Keutgen, Edie Y Chan, Daniel J Deziel, Martin Hertl, Erik Schadde
    Abstract:

    Background Associating Liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces more rapid Liver growth than portal vein ligation (PVL). Transection of parenchyma in ALPPS may prevent the formation of collaterals between lobes. The aim of this study was to determine if abrogating the formation of collaterals through parenchymal transection impacted growth rate.

  • hepatic parenchymal transection increases Liver volume but not function after portal vein embolization in rabbits
    Surgery, 2017
    Co-Authors: Pim B. Olthof, Erik Schadde, Krijn P. Van Lienden, Michal Heger, Kora De Bruin, Joanne Verheij, Roelof J Bennink, Thomas M Van Gulik
    Abstract:

    Background Associating Liver partition with portal vein ligation for staged hepatectomy induces more extensive Liver Hypertrophy than ligation alone; however, the mechanisms underlying the accelerated Liver regrowth and the functional quality of the hypertrophic Liver are presently elusive. This study, therefore, investigated the effect of parenchymal transection on Liver volume and function after portal vein embolization in a standardized rabbit model. Methods Twelve rabbits were subjected to portal vein embolization of the cranial Liver lobes and randomized between parenchymal transection of the left lateral Liver lobe versus no transection (portal vein embolization only). Liver volume of the nonembolized Liver lobe was assessed using computed tomography–volumetry, and Liver uptake function was determined by 99m Tc-mebrofenin hepatobiliary scintigraphy before and 3 and 7 days after portal vein embolization. Results The increase in nonembolized Liver volume 3 days after portal vein embolization was 2.7-fold greater in the transected group compared with the portal vein embolization only group (56 ± 16% vs 21 ± 12%, respectively, P P Conclusion Parenchymal transection after portal vein embolization increases Liver growth in terms of volume but not function. These results indicate that the rapid volume increase observed after associating Liver partition with portal vein ligation for staged hepatectomy does not coincide with the clinically more relevant functional increase. Quantitative Liver function tests might be essential in associating Liver partition with portal vein ligation for staged hepatectomy to better assess the Hypertrophy response and improve clinical decision-making.

  • salvage parenchymal Liver transection for patients with insufficient volume increase after portal vein occlusion an extension of the alpps approach
    Ejso, 2013
    Co-Authors: C Tschuor, Erik Schadde, Kristopher P Croome, Gregory Sergeant, V Cano, Victoria Ardiles, Ksenija Slankamenac, Rodrigo Sanchez Claria, E De Santibaňes, Roberto Hernandezalejandro
    Abstract:

    Abstract Background Portal vein ligation (PVL) or embolization (PVE) are standard approaches to induce Liver Hypertrophy of the future Liver remnant (FLR) prior to hepatectomy in primarily non-resectable Liver tumors. However, this approach fails in about one third of patients. Recently, the new “ALPPS” approach has been described that combines PVL with parenchymal transection to induce rapid Liver Hypertrophy. This series explores whether isolated parenchymal transection boosts Liver Hypertrophy in scenarios of failed PVL/PVE. Methods A multicenter database with 170 patients undergoing portal vein manipulation to increase the size of the FLR was screened for patients undergoing isolated parenchymal transection as a salvage procedure. Three patients who underwent PVL/PVE with subsequent insufficient volume gain and subsequently underwent parenchymal Liver transection as a salvage procedure were identified. Patient characteristics, volume increase, postoperative complications and outcomes were analyzed. Results The first patient underwent Liver transection 16 weeks after failed PVL with a standardized FLR (sFLR) of 30%, which increased to 47% in 7 days. The second patient showed a sFLR of 25% 28 weeks after PVL and subsequent PVE of segment IV, which increased to 41% in 7 days after transection. The third patient underwent Liver partition 8 weeks after PVE with a sFLR of 19%, which increased to 37% in six days. All patients underwent a R0 resection. Conclusion Failed PVE or PVL appears to represent a good indication for the isolated parenchymal Liver transection according to the newly developed ALPPS approach.

Jacques Belghiti - One of the best experts on this subject based on the ideXlab platform.

Georgia Tsoumakidou - One of the best experts on this subject based on the ideXlab platform.

Clifford R Elcombe - One of the best experts on this subject based on the ideXlab platform.

  • mode of action and human relevance analysis for nuclear receptor mediated Liver toxicity a case study with phenobarbital as a model constitutive androstane receptor car activator
    Critical Reviews in Toxicology, 2014
    Co-Authors: Clifford R Elcombe, Richard C Peffer, Douglas C Wolf, Jason P Bailey, Remi Bars, David R Bell, Russell C Cattley, Stephen S Ferguson, David R Geter, Amber K Goetz
    Abstract:

    AbstractThe constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce Liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent Liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced Liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of Liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, Liver Hypertrophy and decreased apoptosis; with in...

  • mode of action and human relevance analysis for nuclear receptor mediated Liver toxicity a case study with phenobarbital as a model constitutive androstane receptor car activator
    Critical Reviews in Toxicology, 2014
    Co-Authors: Clifford R Elcombe, Richard C Peffer, Douglas C Wolf, Jason P Bailey, Remi Bars, David R Bell, Russell C Cattley, Stephen S Ferguson, David R Geter, Amber K Goetz
    Abstract:

    The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce Liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent Liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced Liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of Liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, Liver Hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces Liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent Liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased Liver tumor risk.

  • human constitutive androstane receptor car and pregnane x receptor pxr support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo
    Toxicological Sciences, 2010
    Co-Authors: Jillian Ross, Roland C Wolf, Simon Plummer, Anja Rode, Nico Scheer, Conrad C Bower, Ortwin Vogel, Colin J Henderson, Clifford R Elcombe
    Abstract:

    Mouse nongenotoxic hepatocarcinogens phenobarbital (PB) and chlordane induce hepatomegaly characterized by Hypertrophy and hyperplasia. Increased cell proliferation is implicated in the mechanism of tumor induction. The relevance of these tumors to human health is unclear. The xenoreceptors, constitutive androstane receptors (CARs), and pregnane X receptor (PXR) play key roles in these processes. Novel "humanized" and knockout models for both receptors were developed to investigate potential species differences in hepatomegaly. The effects of PB (80 mg/kg/4 days) and chlordane (10 mg/kg/4 days) were investigated in double humanized PXR and CAR (huPXR/huCAR), double knockout PXR and CAR (PXRKO/CARKO), and wild-type (WT) C57BL/ 6J mice. In WT mice, both compounds caused increased Liver weight, hepatocellular Hypertrophy, and cell proliferation. Both compounds caused alterations to a number of cell cycle genes consistent with induction of cell proliferation in WT mice. However, these gene expression changes did not occur in PXRKO/CARKO or huPXR/huCAR mice. Liver Hypertrophy without hyperplasia was demonstrated in the huPXR/huCAR animals in response to both compounds. Induction of the CAR and PXR target genes, Cyp2b10 and Cyp3a11, was observed in both WT and huPXR/huCAR mouse lines following treatment with PB or chlordane. In the PXRKO/CARKO mice, neither Liver growth nor induction of Cyp2b10 and Cyp3a11 was seen following PB or chlordane treatment, indicating that these effects are CAR/ PXR dependent. These data suggest that the human receptors are able to support the chemically induced hypertrophic responses but not the hyperplastic (cell proliferation) responses. At this time, we cannot be certain that hCAR and hPXR when expressed in the mouse can function exactly as the genes do when they are expressed in human cells. However, all parameters investigated to date suggest that much of their functionality is maintained.