京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18878号 / 医博第3989号 / 新制||医||1008(附属図書館) / 31829 / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂井 義治, 教授 坂田 隆造, 教授 平岡 眞寛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction: The reason for the inability of performing the liver resection for colorectal carcinoma metastasis is usually insufficient remnant liver parenchyma after liver resection (future liver remnant volume - FLRV). The current standard method of increasing FLRV is the embolization of the branch of portal vein (portal vein embolization - PVE) on the side of the tumor, and then suspended after hypertrophy of the non-embolised lobe liver resection. Unfortunately, there are some patients who do not increase liver volume despite perfectly executed PVE. Besides that, FLRV occurs during the time necessary for hypertrophy progression of metastatic disease. Therefore, we are trying to find the appropriate way to encourage the growth of remaining liver parenchyma and accelerate hypertrophy of the contralateral liver lobe. From our previous experience (IGA MZ NS 10240), it is possible to be optimistic that there hope is the way of hematopoietic progenitor cells (HPC - adult stem cells) after previous PVE to non-embolised branches of the portal vein. These cells do not only accelerate liver regeneration, but are also able to improve its function (function of the liver) which is especially important for patients after neoadjuvant chemotherapy (steatohepatitis or steatofibrosis), and for patients with...

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13540号 / 論医博第2280号 / 新制||医||1066(附属図書館) / (主査)教授 小濱 和貴, 教授 近藤 尚己, 教授 妹尾 浩 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Complicações vasculares do transplante hepático podem causar alterações de perfusão e drenagem do enxerto com prejuízo à sua função, comprometendo a qualidade de vida e a sobrevida do receptor. A angioplastia transluminal percutânea é uma opção de tratamento para estas complicações. No entanto, pela falta de trabalhos dedicados para população pediátrica, não há consenso sobre sua segurança em longo prazo e qual técnica seria a mais adequada. Este estudo teve como objetivo avaliar a resposta terapêutica do tratamento endovascular percutâneo da estenose de veia porta em crianças submetidas ao transplante de fígado. Entre agosto de 2000 e agosto de 2009, foram realizados 254 transplantes hepáticos no Instituto da Criança Professor Pedro de Alcântara do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Quinze delas (5,9%; 15/254) desenvolveram estenose de veia porta com indicação de tratamento. O diagnóstico da lesão foi confirmado pela ultrassonografia em todos os casos. O tratamento da estenose consistiu inicialmente na angioplastia com balão por acesso transparietohepático ao sistema porta, sendo o implante de stent indicado nos casos de estenose residual maior que 30%, ou na recidiva da estenose. A idade média do grupo tratado foi de 4,5 anos ± 2,9 anos (mediana de 3,6 anos) e o peso médio, de 15,3 kg ± 5,7 kg (mediana de 14,6 kg). Dez pacientes (66,7%; 10/15) foram tratados com sucesso por uma única sessão de angioplastia com balão. Outra criança (1/15; 6,7%) foi tratada com sucesso por implante de stent indicado pela estenose residual > 30% após a tentativa de tratamento com balão numa mesma sessão. Outras quatro, inicialmente tratadas por angioplastia com balão (26,7%; 4/15), evoluíram com recidiva da estenose após 19 dias, 2 meses, 8 meses e 2 anos do tratamento e foram submetidas a nova angioplastia, desta vez com implante de stent. O tempo médio de seguimento foi de 7,4 anos ± 2,6 anos (mediana de 7,9 anos) com taxa de perviedade primária foi de 73,3% (11/15) e taxa de perviedade primária assistida, obtida pela reintervenção precoce da re-estenose da veia porta antes de sua obstrução, de 100%. A angioplastia com balão da estenose de veia porta após transplante hepático em crianças demonstrou ser um método seguro e efetivo neste grupo de pacientes no seguimento avaliado. Os casos tratados com stent apresentaram índices semelhantes de segurança e sucesso terapêutico / Vascular complications of liver transplantation can compromise grafts perfusion and drainage affecting its function and recipients quality of life. Percutaneous transluminal angioplasty is an option for these complications. However, especially in children, there is no consensus about its long-term safety and which technique would be most appropriate. This study has the objective to evaluate the therapeutic response of percutaneous endovascular treatment of portal vein stenosis in children submitted to liver transplantation. Between August 2000 and August 2009, 254 liver transplants were performed at the Instituto da Criança - Professor Pedro de Alcântara do Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo. Fifteen of them (5.9%, 15/254) developed portal vein stenosis confirmed by ultrasound in all cases. The treatment of the portal vein stenosis consisted initially in balloon angioplasty. The stent was indicated in residual (greater than 30%) or recurrent stenosis. The mean age of the treated group was 4.5 years ± 2.9 years (median 3.6 years) and the mean weight was 15.3 kg ± 5.7 kg (median 14.6 kg). Ten patients (66.7%, 10/15) were successfully treated by a single session of balloon angioplasty. Another child (1/15, 6.7%) was successfully treated by stent due to residual stenosis after balloon angioplasty. Four other children (26.7%, 4/15) developed recurrent stenosis after 19 days, 2 months, 8 months and 2 years of initial treatment with balloon and underwent to a new angioplasty this time, with stent. The primary patency rate was 73.3% (11/15) and the assisted primary patency rate, determined by early intervention before portal vein occlusion, was 100%. Follow-up time was 7.4 years ± 2.6 years (median 7.9 years). Balloon angioplasty of portal vein stenosis after liver transplantation in children demonstrated to be a safe and effective method in this group of patients during the follow-up period of this research. Cases treated with stent had similar rates of safety and therapeutic successes

Complicações vasculares do transplante hepático podem causar alterações de perfusão e drenagem do enxerto com prejuízo à sua função, comprometendo a qualidade de vida e a sobrevida do receptor. A angioplastia transluminal percutânea é uma opção de tratamento para estas complicações. No entanto, pela falta de trabalhos dedicados para população pediátrica, não há consenso sobre sua segurança em longo prazo e qual técnica seria a mais adequada. Este estudo teve como objetivo avaliar a resposta terapêutica do tratamento endovascular percutâneo da estenose de veia porta em crianças submetidas ao transplante de fígado. Entre agosto de 2000 e agosto de 2009, foram realizados 254 transplantes hepáticos no Instituto da Criança Professor Pedro de Alcântara do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Quinze delas (5,9%; 15/254) desenvolveram estenose de veia porta com indicação de tratamento. O diagnóstico da lesão foi confirmado pela ultrassonografia em todos os casos. O tratamento da estenose consistiu inicialmente na angioplastia com balão por acesso transparietohepático ao sistema porta, sendo o implante de stent indicado nos casos de estenose residual maior que 30%, ou na recidiva da estenose. A idade média do grupo tratado foi de 4,5 anos ± 2,9 anos (mediana de 3,6 anos) e o peso médio, de 15,3 kg ± 5,7 kg (mediana de 14,6 kg). Dez pacientes (66,7%; 10/15) foram tratados com sucesso por uma única sessão de angioplastia com balão. Outra criança (1/15; 6,7%) foi tratada com sucesso por implante de stent indicado pela estenose residual > 30% após a tentativa de tratamento com balão numa mesma sessão. Outras quatro, inicialmente tratadas por angioplastia com balão (26,7%; 4/15), evoluíram com recidiva da estenose após 19 dias, 2 meses, 8 meses e 2 anos do tratamento e foram submetidas a nova angioplastia, desta vez com implante de stent. O tempo médio de seguimento foi de 7,4 anos ± 2,6 anos (mediana de 7,9 anos) com taxa de perviedade primária foi de 73,3% (11/15) e taxa de perviedade primária assistida, obtida pela reintervenção precoce da re-estenose da veia porta antes de sua obstrução, de 100%. A angioplastia com balão da estenose de veia porta após transplante hepático em crianças demonstrou ser um método seguro e efetivo neste grupo de pacientes no seguimento avaliado. Os casos tratados com stent apresentaram índices semelhantes de segurança e sucesso terapêutico / Vascular complications of liver transplantation can compromise grafts perfusion and drainage affecting its function and recipients quality of life. Percutaneous transluminal angioplasty is an option for these complications. However, especially in children, there is no consensus about its long-term safety and which technique would be most appropriate. This study has the objective to evaluate the therapeutic response of percutaneous endovascular treatment of portal vein stenosis in children submitted to liver transplantation. Between August 2000 and August 2009, 254 liver transplants were performed at the Instituto da Criança - Professor Pedro de Alcântara do Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo. Fifteen of them (5.9%, 15/254) developed portal vein stenosis confirmed by ultrasound in all cases. The treatment of the portal vein stenosis consisted initially in balloon angioplasty. The stent was indicated in residual (greater than 30%) or recurrent stenosis. The mean age of the treated group was 4.5 years ± 2.9 years (median 3.6 years) and the mean weight was 15.3 kg ± 5.7 kg (median 14.6 kg). Ten patients (66.7%, 10/15) were successfully treated by a single session of balloon angioplasty. Another child (1/15, 6.7%) was successfully treated by stent due to residual stenosis after balloon angioplasty. Four other children (26.7%, 4/15) developed recurrent stenosis after 19 days, 2 months, 8 months and 2 years of initial treatment with balloon and underwent to a new angioplasty this time, with stent. The primary patency rate was 73.3% (11/15) and the assisted primary patency rate, determined by early intervention before portal vein occlusion, was 100%. Follow-up time was 7.4 years ± 2.6 years (median 7.9 years). Balloon angioplasty of portal vein stenosis after liver transplantation in children demonstrated to be a safe and effective method in this group of patients during the follow-up period of this research. Cases treated with stent had similar rates of safety and therapeutic successes

The site of confluence of the artery and the portal vein in the liver still appears to be controversial. Anatomical studies suggested a presinusoidal or an intrasinusoidal confluence in the first, second or even final third of the sinusoids. The objective of this investigation was to study the problem with functional biochemical techniques. Rat livers were perfused through the hepatic artery and simultaneously either in the orthograde direction from the portal vein to the hepatic vein or in the retrograde direction from the hepatic vein to the portal vein. Arterial how was linearly dependent on arterial pressure between 70 cm H2O and 120 cm H2O at a constant portal or hepatovenous pressure of 18 cm H2O. An arterial pressure of 100 cm H2O was required for the maintenance of a homogeneous orthograde perfusion of the whole parenchyma and of a physiologic ratio of arterial to portal how of about 1:3. Glucagon was infused either through the artery or the portal vein and hepatic vein, respectively, to a submaximally effective ''calculated'' sinusoidal concentration after mixing of 0.1 nmol/L. During orthograde perfusions, arterial and portal glucagon caused the same increases in glucose output. Yet during retrograde perfusions, hepatovenous glucagon elicited metabolic alterations equal to those in orthograde perfusions, whereas arterial glucagon effected changes strongly reduced to between 10% and 50%. Arterially infused trypan blue was distributed homogeneously in the parenchyma during orthograde perfusions, whereas it reached clearly smaller areas of parenchyma during retrograde perfusions. Finally, arterially applied acridine orange was taken up by all periportal hepatocytes in the proximal half of the acinus during orthograde perfusions but only by a much smaller portion of periportal cells in the proximal third of the acinus during retrograde perfusions. These findings suggest that in rat liver, the hepatic artery and the portal vein mix before and within the first third of the sinusoids, rather than in the middle or even last third.

Cirrhosis is a leading cause of death in the United States and has severe and costly complications. Because of the clinical significance of cirrhosis, it is important that noninvasive methods be developed to detect cirrhosis early and to monitor its progression with advancing liver disease. Previous studies on portal venous hemodynamics have been performed mainly with ultrasound with mixed results. Magnetic Resonance Imaging offers several advantages over ultrasound including acquisition of both high quality anatomical and hemodynamic information. Phase-Contrast MR was used to gather velocity data for the portal venous system. Methods were developed to perform registration, segmentation and isolation of the portal vein geometries and velocity data. Computational Fluid Dynamics was also employed to further investigate the flow within the portal vein. Velocity data for the portal vein, superior mesenteric vein, splenic vein and the right or left portal vein was acquired in varying numbers for both data sets. Even with the limited number of subjects a few parameters were significant. Patients with cirrhosis had a significantly increased portal vein area and a significantly decreased average velocity per liver volume and velocity variance. Patients with cirrhosis had a significantly increased splenic vein area and average flow rate per liver volume. While these results are preliminary due to small sample size, they are promising and require further investigation and more subjects including varying stages of disease.

Fundação de Amparo a Pesquisa no Estado do Rio Grande do Sul / The aim of the study is measure the impact of the mesenteric infusion of different N compounds: alanine, arginine and ammonium bicarbonate on oxygen uptake by splanchnic tissues relative the ureagenesis and gluconeogenesis. In an attempt to quantify the digestibility diet initially and after visceral metabolism, a trial with four multicatheterized wethers (45±2 kg body weight) was conducted as a 4 × 4 Latin Square feeding Tifton hay (2,5 %) and protein concentrate (0,7%) with 210 minutes daily periods during 4 days. The data obtained in the digestibility trial were complementary to those obtained in metabolism trial. The blood flow through portal- drained viscera (PDV) and total splanchnic tissues (ST) were determined by downstream dilution of 15 g/L p-aminohippurate (PAH) infused continuously (1.5mL/min) into the mesenteric vein. In parallel, wethers were continually infused into the mesenteric vein with aphysiological saline (0.15 MNaCl) solution during 90 minutes followed by the infusion, during more 120 minutes, of either solution: physiological saline (control), 0.25 MNH4HCO3, 0.25 M L-alanine or 0.125 M L-arginine, all of them infused at a rate of 1.5 mL/min to provide 375 μmol N/min. The infusion of nitrogenous compounds and their greater hepatic uptake increased hepatic O2 spent as a result of an increase in ureagenesis, which was not observed for gluconeogenesis. The higher ammonia portal circulation increases urea synthesis and thus the energy cost. O2 expense associated with the urea synthesis is higher than O2 expense related to gluconeogenesis. Increased alanine or arginine uptake by liver did not change the cost of O2. Moreover, it was not possible to compare the amino acids in study, since the infusion of arginine did not change any of the variables examined. / O objetivo do estudo foi avaliar o impacto da ureagênese e da neoglicogênese sobre o gasto visceral de oxigênio e se a infusão mesentérica de arginina, alanina e bicarbonato de amônio aumentam o consumo de energia pelo sistema visceral. Também foi avaliado se há diferença no gasto de energia pelos tecidos viscerais em função do tipo de composto nitrogenado infundido. Foram conduzidos dois ensaios com ovinos, sendo um para avaliar a digestibilidade da dieta e outro para avaliar parâmetros relacionados ao metabolismo visceral. Foram utilizados quatro ovinos machos (45±2 kg de peso corporal) com catéteres permanentes implantados cirurgicamente, em um delineamento experimental Quadrado Latino 4x4 alimentados com feno de tifton + concentrado em quantidades restritas a 2,5% PV para a oferta de volumoso e 0,7% PV para a oferta de concentrado. Os dados obtidos no ensaio de digestibilidade foram complementares aos obtidos no ensaio de metabolismo. Os animais passaram por quatro períodos com duração de um dia, onde em cada período foi infundido um dos tratamentos, sendo eles: solução fisiológica (controle), alanina, arginina e bicarbonato de amônio, totalizando quatro dias consecutivos de avaliação por animal. As infusões foram efetuadas na veia mesentérica com o auxílio de uma bomba de infusão contínua com capacidade de infundir concomitantemente o tratamento e o marcador de fluxo sanguíneo (PAH). Foram obtidas amostras de sangue em três diferentes pontos, sendo eles: artéria carótida, veia hepática e veia porta, em diferentes horários. Foram realizadas análises de gasometria, hematócrito e concentração sanguínea dos nutrientes: glicose, ureia, amônia, hemoglobina e de ácido paramino-hipúrico. A infusão de compostos nitrogenados e maior captação hepática dos mesmos, aumentou o gasto hepático de O2 como consequência de um aumento na ureagênese, o que não foi observado para a neoglicogênese. O incremento da circulação portal de amônia aumenta a síntese de ureia e consequentemente o custo energético. O gasto de O2 associado à síntese de ureia é maior do que o gasto de O2 relacionado à neoglicogênese. O aumento da carga hepática de alanina ou de arginina não alterou o gasto de O2 por este órgão. Ainda, não foi possível comparar os aminoácidos em estudo, visto que a infusão de arginina não alterou nenhuma das variáveis observadas.

Hintergrund: Ziel der Studie war der Vergleich von Patienten mit duktalem Pankreaskarzinom (PDAC) im progressionsfreien und Gesamtüberleben sowie im Rezidivmuster in Abhängigkeit einer Resektion der Vena portae oder der Vena mesenterica superior (PV/SMV). Methoden: Es wurde eine retrospektive Analyse durchgeführt. Hierbei wurden Patienten betrachtet, die zwischen 2005 und 2015 eine pyloruserhaltende partielle Pankreatoduodenektomie (PPPD), eine klassische Pankreatoduodenektomie (kPD) oder eine totale Pankreatektomie (TP) erhielten. Diese wurden in drei Gruppen eingeteilt. Die P+I+- Gruppe bestand aus Patienten mit Venenresektion (P+), bei denen eine pathohistologische Infiltration der PV oder SMV vorlag (I+). Fand sich bei durchgeführter Venenresektion keine portalvenöse Infiltration (I-), wurden die Patienten der P+I--Gruppe zugeordnet. Als Kontrollgruppe galten Patienten ohne Venenresektion (P-I-), welche zu denen der P+I+- Gruppe gematcht wurden. Die statistischen Analysen wurden mit dem R Softwarepaket durchgeführt. Das Signifikanzlevel wurde für alle Berechnungen auf α = 0,05 festgelegt. Ergebnisse: Insgesamt wurden 179 Patienten eingeschlossen. 113 erhielten eine portalvenöse Resektion. Davon hatten 36 (31,9%) eine pathohistologische Lumeninfiltration (P+I+), bei 77 (68,1%) lag dagegen keine Infiltration vor (P+I-). 66 Patienten ohne Venenresektion wurden zu den Patienten der P+I+-Gruppe gematcht (P-I-). Zwischen den drei Gruppen waren die meisten pathohistologischen Parameter vergleichbar. 17 Patienten (9,5%) wurden neoadjuvant therapiert, davon erhielten 16 eine Venenresektion (P+). Für das Gesamtüberleben konnten signifikante Unterschiede nachgewiesen werden (11,9 Monate [P+I+] vs. 16,1 Monate [P+I-] vs. 20,1 Monate [P-I-]; p=0,01). In der univariaten Überlebensanalyse konnte für den erhöhten präoperativen CA19-9 Wert, den Resektionsstatus (R), den Lymphknotenstatus (N), das Lymphknotenverhältnis (LNR), die mikroskopische Veneninvasion (V) sowie die pathohistologisch gesicherte Infiltration der PV/SMV ein negativer Einfluss nachgewiesen werden. In der multivariaten Analyse blieb die wahre Infiltration der PV/SMV als einziger signifikanter negativer Einflussfaktor auf das Gesamtüberleben erhalten (p=0,014). Die Inzidenz an Fernmetastasen war in der P+I+- Gruppe signifikant erhöht (75% [P+I+] vs. 45,8% [P+I-] vs. 54,7% [P-I-], p=0,01). Für ein Lokalrezidiv fanden sich dagegen keine Häufigkeitsunterschiede zwischen den Gruppen (p=0,96). Das mediane progressionsfreie Überleben war für Patienten der P+I+-Gruppe signifikant verkürzt (7,4 Monate [P+I+] vs. 10,9 Monate [P+I-] vs. 11,6 Monate [P-I-]; p=0,02). Die Lumeninfiltration der PV/SMV, die mikroskopische Veneninvasion (V), der präoperative CA19-9 Wert sowie der Differenzierungsgrad (G) waren negative Einflussfaktoren auf das progressionsfreie Überleben. In der multivariaten Analyse blieben die pathohistologisch gesicherte Infiltration sowie das Grading als negative unabhängige Einflussfaktoren nachweisbar. In 25% der Fälle manifestierte sich das Rezidiv initial in der Leber. Schlussfolgerung: Die pathohistologisch gesicherte Infiltration der PV/SMV ist ein unabhängiger Risikofaktor für das progressionsfreie und das Gesamtüberleben. Die Inzidenz an Fernmetastasen ist für die Patienten der P+I+-Gruppe erhöht. Eine potentiell kurative venöse Resektion kann den Einfluss der aggressiven Tumorbiologie und des fortgeschrittenen Krankheitsbildes nicht vollständig kompensieren. / Background. The present study aims to evaluate the longterm outcome and metastatatic pattern of patients who underwent an operation for pancreatic ductal adenocarcinoma (PDAC) with portal or superior mesenteric vein (PV/SMV) resection. Methods. Patients who underwent a pylorus preserving pancreaticoduodenectomy (PPPD), Whipple procedure (kPD) or total pancreatoduodenectomy (TP) between 2005 and 2015 were retrospectively analyzed. The patients were categorized in three subgroups. Those whom received a vein resection with pathohistological tumor invasion of the PV/SMV (P+I+) those at whom underwent vein resection but without pathohistological tumor invasion (P+I-) and lastly a third group (P-I-) matched to the P+I+ included patients without vein resection. Statistical analysis was performed using the R software package. The significance level for all calculations was set at α = 0.05. Results. The study cohort included 179 patients, 113 of whom underwent simultaneous PV/SMV resection. 36 patients (31,9%) had pathohistological tumor infiltration (P+I+), 77 (68,1%) did not (P+I-). 66 patients without vein resection (P-I-) were balanced by the P+I+ group. Most of pathohistological tumor characteristics were comparable between groups. 17 patients (9.5%) received neoadjuvant therapy, 16 of them were in vein resection group (P+). The study revealed differences in overall median survival (11.9 months [P+I+] vs. 16.1 months [P+I-] vs. 20.1 months [P-I-]; p=0.01). Univariate survival analysis shown negative consequences for CA19-9, resection margin (R), status of nodal metastasis (N), lymph node ratio (LNR), microvascular vein invasion (V) and true invasion of the PV/SMV. Multivariate survival analysis identified true invasion of the PV/SMV as the only significant, negative prognostic factor (p= 0.01). Whereas the incidence of local tumor recurrence was comparable (p=0.96), the proportion of patients with distant metastasis showed significant differences (75% [P+I+] vs. 45.8% [P+I-] vs 54.7% [P-I-]; p=0.01). The median time to progression were significantly shorter if the PV/SMV was infiltrated (7,4 months [P+I+] vs. 10,9 months [P+I-] vs. 11,6 months [P-I-]; p=0.02). Univariate progression analysis revealed significances for true invasion of the PV/SMV, microvascular vein invasion (V), CA19-9 and histologic classification (G). Multivariate progression analysis detected pathohistological invasion of the PV/SMV and histologic classification (G) as independent factors. Initial liver metastasis occurred in 25% of the patients. Conclusions. Pathohistological invasion of the PV/SMV is an independent risk factor for overall and progression free survival. Patients of P+I+-group had a higher incidence of distant metastasis, local progression is comparable. Even radical and complete resection cannot completely compensate for aggressive tumor biology and advanced disease. Modifiziert nach Mierke et al., 2016

Le foie possède une capacité de régénération importante qui lui permet de reconstituer son volume suite à une agression. L’induction d’une régénération hépatique est réalisée en pratique courante en chirurgie hépatique afin de préparer le foie à une hépatectomie majeure. Elle est également utilisée dans de nombreux modèles animaux afin de favoriser la prise de greffe hépatocytaire au cours de la transplantation d’hépatocytes pour le traitement de maladies métaboliques héréditaires hépatiques. Les principaux objectifs de ce travail ont été d’étudier une méthode peu invasive pour induire une importante régénération hépatique : d’une part pour élargir les possibilités de prise en charge des patients nécessitant une hépatectomie, et d’autre part pour favoriser la prise de greffe des hépatocytes transplantés pour le traitement des maladies métaboliques héréditaires hépatiques.Dans un premier temps, nous avons mis au point chez le rat une technique d’embolisation portale partielle résorbable répétée (EPPRR) visant à entrainer un stimulus additionnel de régénération hépatique. Ces travaux ont validé le concept de la méthode d’EPPRR en montrant une augmentation de la prolifération hépatocytaire et une hypertrophie dans la partie du foie non embolisée.Ce protocole d’EPPRR a ensuite été appliqué dans un modèle préclinique de gros animal. Nous avons étudié chez le porc les conséquences de l’EPPRR et montré que cette technique était reproductible, bien tolérée, et qu’elle permettait une hypertrophie de la partie du foie non embolisée.Parallèlement, nous avons appliqué l’EPPRR avant transplantation d’hépatocytes chez le rat. A partir du foie de rats transgéniques exprimant la GFP (green fluorescent protein), nous avons pu isoler des hépatocytes GFP+. Ces cellules ont été transplantées dans le foie de rats receveurs GFP- en association avec une EPPRR. Nous avons montré que le stimulus de régénération répété provoqué par l’EPPRR permettait une augmentation de la prise de greffe.En conclusion, l’EPPRR est une technique peu invasive capable d’induire une régénérative hépatique efficace. Cette approche pourrait jouer un rôle dans la prise en charge des tumeurs hépatique et l’optimisation de la transplantation d’hépatocytes pour le traitement des maladies métaboliques héréditaires hépatiques. / The liver has an important regenerative capacity allowing reconstitution of the hepatic volume after an aggression. The induction of liver regeneration is used in routine clinical practice before liver surgery in order to prepare the liver for major hepatectomy. It is also used in numerous animal models in order to increase hepatocyte engraftment during hepatocyte transplantation for the treatment of inherited metabolic liver diseases. The main objective of this work was to evaluate a minimally invasive approach to induce substantial liver regeneration: firstly, to expand the therapeutic options for patients requiring an hepatectomy, and secondly to increase the engraftment of transplanted hepatocytes for the treatment of inherited metabolic liver diseases.In a first study, we developed in the rat model a technique of repeated reversible portal vein embolization (RRPVE) to induce an additional stimulus of liver regeneration. This study established the proof of concept of the RRPVE method, showing an increase in hepatocyte proliferation and hypertrophy in the non-embolized liver.This RRPVE protocol was then used in a preclinical model of large animal. We studied in swine the consequences of the RRPVE and showed that the procedure was reproducible, well tolerated, and allowed hypertrophy of the non-embolized liver.In parallel, we applied RRPVE before hepatocyte transplantation in the rat model. From the liver of transgenic rats expressing GFP (green fluorescent protein), we were able to isolate GFP+ hepatocytes. These cells were transplanted in the liver of recipient GFP- rats in association with RRPVE. We demonstrated that the repetition of the regeneration stimulus induced by RRPVE allowed increased hepatocyte engraftment.In conclusion, RRPVE is a minimally invasive technique able to induce efficient liver regeneration. This approach could play a part in the management of hepatic malignancies and the optimization of hepatocyte transplantation in the treatment of inherited metabolic liver diseases.