As dissecções da artéria vertebral causam acidentes vasculares cerebrais isquêmicos e hemorrágicos. A dissecção arterial é a ruptura da sua parede com formação de hematoma intramural. Podem ser espontâneas, acometendo a artéria vertebral extra ou intracraniana. O tratamento em geral é clínico, porém em alguns casos está indicada intervenção. A via endovascular é uma importante alternativa, permitindo o tratamento específico da lesão em alguns casos, mas na maioria sacrificando a artéria vertebral, após teste de tolerância à oclusão. Com o objetivo de analisar os aspectos clínicos e técnicos do tratamento endovascular, estudamos de forma prospectiva 15 pacientes. Três apresentavam dissecções traumáticas (todas extracranianas) e 12 espontâneas, dos quais dois tiveram traumatismos menores como desencadeantes. Cinco pacientes apresentaram dissecções extracranianas, oito, intracranianas e dois, combinadas. No grupo das extracranianas, a principal indicação de tratamento foi a presença de fístula arteriovenosa, em três dos cinco pacientes. No grupo da intracranianas, foi a presença de hemorragia meníngea. Nos quatro pacientes com acidente vascular isquêmico, a indicação de tratamento deveu-se à presença de pseudoaneurismas que não involuíram com tratamento clínico. Nesse grupo, dois pacientes tinham dissecção extracraniana, um, intra e um, combinada. Um paciente apresentou intolerância à oclusão e foi encaminhado para tratamento conservador. Dos 14 pacientes tratados, um teve como estratégia a oclusão seletiva da lesão, 11 a oclusão da artéria vertebral proximal à lesão e dois oclusão acima e abaixo da lesão. Os materiais utilizados foram balões destacáveis em sete pacientes, molas de destaque livre em 6 e molas eletricamente destacáveis associadas a molas de destaque livre em 1 paciente. Dois pacientes apresentaram complicações do tratamento, e um paciente, recidiva de fístula arteriovenosa, todos resolvidos sem seqüelas. A angiografia controle revelou oclusão total do segmento dissecado ou do pseudoaneurisma em 9 pacientes, reversão do fluxo em quatro e preservação da artéria vertebral com oclusão da lesão em um. Num período de seguimento de 8,6 meses não se registraram recorrências. O tratamento foi eficiente na prevenção de ressangramentos e na trombose dos pseudoaneurismas e apresenta segurança em relação a complicações. / Vertebral artery dissections can cause brain ischemia and hemorrhage. Arterial dissection consist of mural tears with subsequent intramural hematoma formation. They may occur either spontaneously or as a consequence of traumatism, in the extracranial or intracranial vertebral artery. The treatment is usually clinical, but in some instances intervention is indicated. The endovascular approach is an important tool, allowing specific treatment of the lesion in some cases, but sacrificing the vertebral artery in most cases. With the aim of analyze the clinical and technical aspects of the endovascular treatment, we studied prospectively 15 patients treated by endovascular approach. Three presented traumatic dissections (all extracranial) and 12 spontaneous dissections, two of which after minor traumatic events. Five patients had extracranial dissections, eight, intracranial and two, combined. In the extracranial dissection group, the main indication for treatment was the presence of an arteriovenous fistula (three of five patients). In the intracranial group, it was subarachnoid hemorrhage. Four patients presenting with brain isquemia were treated because of pseudoaneurysms that did not resolve in clinical treatment. In this group 2 patients had extracranial dissections, one had intracranial and one had both. One patient did not tolerate occlusion and was treated clinically. Fourteen patients were treated by endovascular means, one with selective lesion occlusion, 12 with proximal vertebral artery occlusion and two with proximal and distal vertebral artery occlusion. The embolic material were detachable balloons in 7 patients, platinum microcoils in 6 patients and electrically detachable platinum microcoils and platinum microcoils in one patient. Two patients presented complications, and one presented recurrence of an arteriovenous fistula, all resolved without sequelae. Angiographic controls disclosed total occlusion of the segment with dissection or of the pseudoaneurysm in 9 patients, retrograde flow in 4 and vertebral artery preservation with selective lesion occlusion in 1. During a mean follow-up period of 8,6 months no recurrence was observed. The treatment was efficient in preventing recurrent hemorrhage and promoting pseudoaneurysms thrombosis, besides it was a safe treatment option.

Introdução: O desenvolvimento de novos procedimentos cirúrgicos minimamente invasivos para o tratamento dos sintomas do trato urinário inferior (LUTS), relacionados à hiperplasia prostática benigna (HPB), está se tornando importante campo de pesquisa, na medida em que tenta minimizar os efeitos adversos e complicações decorrentes dos tratamentos convencionais. A embolização das artérias prostáticas (EAP) vem sendo utilizada como alternativa para o tratamento de pacientes com HPB. O objetivo deste trabalho é avaliar e comparar a segurança e eficácia da EAP para o tratamento dos LUTS em pacientes com HPB, utilizando microesferas (Embospheres®) de 100-300 um e 300-500 um. Métodos: Realizou-se estudo de ensaio clínico fase II, prospectivo, no período entre agosto de 2011 e junho de 2013, pela Disciplina de Urologia e Departamento de Radiologia do HCFMUSP. O protocolo de pesquisa foi aprovado pela Comissão de Ética para Análise de Projetos de Pesquisa (CAPPesq) do HCFMUSP. Foram selecionados 30 pacientes com sintomas moderados ou graves (IPSS > 7), refratários ao tratamento clínico para HPB, com volume prostático entre 30g e 100g pela ressonância magnética (RM). Foram excluídos os pacientes com câncer de próstata comprovado por biópsia; prostatite ou infecção ativa do trato urinário; cirurgia ou intervenção prévia para HPB; doença com impacto sobre funcionamento da bexiga; impossibilidade para realizar RM; e distúrbio de coagulação não corrigido clinicamente. Os pacientes foram avaliados de acordo com os sintomas clínicos (IPSS e QoL), toque retal, exames laboratoriais de rotina incluindo o antígeno prostático específico (PSA), urofluxometria livre (Qmax) e RM em diferentes períodos de acompanhamento. Os procedimentos foram realizados no Serviço de Radiologia Intervencionista do HCFMUSP, por meio de punção unilateral da artéria femoral comum, sob anestesia local, usando-se microcateter, agente embolizante do tipo microesferas 100-300 ?m em 15 pacientes (Grupo A) e 300-500 ?m em 15 pacientes (Grupo B). Foi considerado sucesso técnico a identificação, cateterismo e embolização bilateral das artérias prostáticas. Definiu-se como sucesso clínico a retirada da sonda vesical nos pacientes em retenção urinária, melhora dos sintomas de acordo com o escore IPSS < 8 e índice QoL < 3. Considerou-se o valor de p < 0,05 como estatisticamente significante. Resultados: Sucesso técnico foi obtido em todos os casos. Ambos os grupos apresentaram melhoria significativa do IPSS, QoL e do Qmax, assim como redução do PSA e do volume prostático em relação aos dados demográficos (p < 0,05). Houve um aumento volumétrico prostático significativo entre 3 e 12 meses no grupo A (p < 0,05). As diferenças observadas entre os dois grupos não foram significativas, com maior ocorrência de eventos adversos (p = 0,066) e maior redução do PSA no acompanhamento de 3 meses (p = 0,056) nos pacientes tratados com microesferas de 100-300 um. Conclusão: As microesferas de 100-300 ?m e 300-500 um demonstraram serem agentes embolizantes seguros e eficazes na EAP para o tratamento dos LUTS relacionados à HPB. Embora os resultados clínicos e por imagem não tenham diferido significativamente entre os grupos de estudo, os pacientes tratados com 100-300 um apresentaram mais eventos adversos do que aqueles tratados com 300-500 um. O volume da próstata aumentou significativamente entre o terceiro e o décimo segundo mês após EAP no grupo tratado com microesferas 100-300 um, embora se mantivesse significativamente menor que antes da EAP / Introduction: The development of new minimally invasive surgical procedures for the treatment of low urinary tract symptoms (LUTS), related to benign prostatic hyperplasia (BPH), is becoming an important field of research as it attempts to minimize adverse effects and complications resulting from conventional treatments. Prostatic artery embolization (PAE) is increasingly being used as an alternative for the treatment of patients with BPH. The aim of this study was to evaluate and compare the safety and efficacy of PAE for the treatment of LUTS in patients with BPH, using microspheres (Embosphere®) of 100-300 um and 300-500 um. Methods: A prospective Phase II clinical trial was conducted between August 2011 and June 2013 by the Urology Department and the Radiology Department. The research protocol was approved by the Ethics Committee for Analysis of Research Projects (CAPPesq) of HC-FMUSP. In fact, 30 patients with moderate or severe symptoms (IPSS > 7), refractory to the clinical treatment for BPH, with a prostatic volume of 30 g and 100 g were selected by magnetic resonance imaging (MRI). Patients with the following conditions were excluded from the study: biopsy-proven prostate cancer; prostatitis or active urinary tract infection; surgery or previous intervention for BPH; diseases affecting the bladder function; impossibility to perform MRI; and clinically uncorrected coagulation disorders. Patients were evaluated according to clinical symptoms (IPSS and QoL), rectal examination, laboratory tests (PSA), uroflowmetry (Qmax) and imaging (MR) at different follow-up periods. Procedures were performed at the interventional radiology suite of the HCFMUSP, by means of unilateral puncture of the common femoral artery, under local anesthesia, using a microcatheter, microspheres type 100-300 um in 15 patients (Group A) and 300-500 um in 15 patients (Group B). Identification, catheterization and bilateral embolization of the prostatic arteries were considered technical success. Clinical success was defined as the removal of the bladder catheter and improvement of symptoms according to the IPSS score < 8 and QoL index < 3. Results: The PAE was technically successful in all cases. Both groups showed a significant improvement in IPSS, QoL and Qmax, as well as reduction of PSA and prostate volume in relation to demographic data (p < 0.05). There was a significant prostatic volumetric increase between 3 and 12 months in group A (p < 0.05). Differences observed between the two groups were not significant, with a higher number of adverse events (p = 0.066) and lower level of blood PSA at 3 months follow-up (p = 0.056) in Group A (100-300 um). Conclusion: Microspheres of 100-300 ?m and 300-500 ?m are safe and effective embolic agents in PAE for the treatment of LUTS related to BPH. Although functional results did not differ significantly between study groups, patients treated with 100-300 ?m reported more adverse events than those treated with 300-500 um. The prostate volume increased significantly between the third and the twelfth month post-PAE in the group treated with 100-300 um microspheres, although it remained significantly lower than pre-PAE

Trinta e cinco pacientes com malformações arteriovenosas raquimedulares (MAVR) foram tratados por via endovascular. Foram analisados os tipos de MAVR, bem como os aspectos clínicos e angiográficos pré e pós-tratamento endovascular. As MAVR mais freqüentes foram as fístulas arteriovenosas durais (FAD), com 17 pacientes, seguidas das malformações arteriovenosas intramedulares (MAI), fístulas arteriovenosas perimedulares (FAVP) e malformações arteriovenosas metaméricas (MAVM). A avaliação do resultado do tratamento foi dividida em sucesso técnico e clínico, sendo que o primeiro foi subdividido em sucesso técnico do procedimento e do tratamento. O sucesso técnico do procedimento foi caracterizado como oclusão total da MAVR ao final de um procedimento endovascular. O sucesso técnico do tratamento foi caracterizado pela oclusão definitiva da MAVR, independentemente do número de procedimentos. A recidiva foi definida como o reaparecimento da MAVR, identificada na angiografia durante o seguimento dos pacientes, independentemente do quadro clínico apresentado. A recidiva implicava em insucesso do procedimento, mas não necessariamente do tratamento. O sucesso clínico do tratamento foi considerado como a melhora parcial ou total dos sintomas após um período mínimo de acompanhamento de 6 meses. Nas FAD, houve predomínio do sexo masculino e da faixa etária acima dos 36 anos. O tratamento endovascular das FAD mostrou sucesso do procedimento na maioria dos casos, porém com recidiva da lesão em 56,7% dos mesmos. Quando usadas partículas, observou-se recidiva em 73,3% dos procedimentos, porém com sucesso do tratamento em 66,7 dos pacientes. Quando utilizado o adesivo tissular (\"cola\"), houve recidiva em 11,1% dos procedimentos e sucesso do tratamento em 88,9% dos pacientes. A melhora clínica foi obtida em 64,7% dos pacientes. Dos 10 pacientes tratados com MAI, a faixa etária mais freqüente foi dos 19 aos 35 anos de idade e predomínio do sexo masculino. O tratamento endovascular das MAI mostrou sucesso do procedimento em 53,3% e recidiva da lesão em 6,7% dos pacientes. O sucesso do procedimento também foi superior quando usada cola, atingindo 63,6% dos procedimentos e apenas 25,0% com partículas. O sucesso do tratamento foi de 80,0% e a melhora clínica foi observada em 40,0% dos pacientes. Somente 1 paciente com MAVM foi tratado. O tratamento objetivou a embolização parcial da lesão para alívio dos sintomas, resultado que foi obtido com sucesso. Nas FAVP houve predomínio do sexo masculino e a faixa etária mais acometida foi dos 19 aos 35 anos. O tratamento endovascular das FAVP mostrou sucesso do procedimento em 75,0% dos pacientes e ausência de recidiva. O sucesso do tratamento foi de 85,7%, com melhora clínica em todos os pacientes. O nosso estudo mostrou que as MAVR podem ser tratadas de maneira eficiente e segura através da embolização. O seguimento dos pacientes tratados com cola mostrou menor índice de recidiva do que aqueles tratados com partículas. Após a embolização, houve melhora significativa no padrão da marcha nos pacientes com FAD e MAI / Endovascular treatment was used in 35 patients with spinal cord arteriovenous malformations (SCAVM). SCAVM types, along with clinical and angiographic features of pre-op and post-op endovascular treatments were analyzed. Seventeen patients had dural arteriovenous fístulas (DAVF), being this type the most frequent SCAVM, followed by intramedullary arteriovenous malformations (IAVM), perimedullary arteriovenous fístulas (PAVF) and metameric arteriovenous malformations (MAVM). Evaluation of treatment results was divided into technical and clinical success, being the first subdivided into technical success of the procedure and treatment. The procedural\'s technical success was characterized by total SCAVM occlusion at the end of an endovascular procedure. Technical success of the treatment was characterized by definitive occlusion of the SCAVM, independent of the number of procedures. Recurrence was defined as reappearance of SCAVM, identified on angiograms during patient follow up, independent of the observed clinical situation. Recurrence implied in an unsuccessful procedure but not necessarily in treatment failure. Treatment\'s clinical success was considered partial or total symptom improvement after a minimum 6 month period follow up. Male and age over 36 years was preponderate in DAVF. Endovascular treatment in DAVF had procedural success in most cases, but with lesion recurrence in 56,7% of these patients. When particulate embolic agents were used, recurrence occurred in 73,3% of the procedures but with treatment success in 66,7% of these patients. When liquid tissue adhesive was used, there was 11,1% of recurrence and 88,9% in treatment success in these patients. Clinical improvement occurred in 64,7% of these patients. Male predominance and age between 19 to 35 years was more frequent in the 10 treated patients with IAVM. IAVM endovascular treatment was a procedural success in 53,3% and lesion recurrence in 6,7% of these patients. Procedural success was also superior when liquid tissue adhesive was used, up to 63,6% of these procedures and, only 25,0% with particulate embolic agents. Treatment success occurred in 80,0% and clinical improvement seen in 40,0% of these patients. Only 1 patient with MAVM was treated. Aim in treatment was partial lesion embolization to mitigate symptoms, which was successfully achieved. Male predominance and age between 19 to 35 years occurred in PAVF. PAVF endovascular treatment had procedural success in 75,0% and no recurrences in these patients. Treatment success occurred in 85,7% and clinical improvement in all patients. This study demonstrates that SCAVM can be treated efficiently and safely with endovascular embolization. Patient follow up revealed fewer recurrences in those treated with liquid tissue adhesive than in those with particulate embolic agents. After DAVF and IAVM embolization, patients had significant improvement in their gait

Introdução: O desenvolvimento de novos procedimentos cirúrgicos minimamente invasivos para o tratamento dos sintomas do trato urinário inferior (LUTS), relacionados à hiperplasia prostática benigna (HPB), está se tornando importante campo de pesquisa, na medida em que tenta minimizar os efeitos adversos e complicações decorrentes dos tratamentos convencionais. A embolização das artérias prostáticas (EAP) vem sendo utilizada como alternativa para o tratamento de pacientes com HPB. O objetivo deste trabalho é avaliar e comparar a segurança e eficácia da EAP para o tratamento dos LUTS em pacientes com HPB, utilizando microesferas (Embospheres®) de 100-300 um e 300-500 um. Métodos: Realizou-se estudo de ensaio clínico fase II, prospectivo, no período entre agosto de 2011 e junho de 2013, pela Disciplina de Urologia e Departamento de Radiologia do HCFMUSP. O protocolo de pesquisa foi aprovado pela Comissão de Ética para Análise de Projetos de Pesquisa (CAPPesq) do HCFMUSP. Foram selecionados 30 pacientes com sintomas moderados ou graves (IPSS > 7), refratários ao tratamento clínico para HPB, com volume prostático entre 30g e 100g pela ressonância magnética (RM). Foram excluídos os pacientes com câncer de próstata comprovado por biópsia; prostatite ou infecção ativa do trato urinário; cirurgia ou intervenção prévia para HPB; doença com impacto sobre funcionamento da bexiga; impossibilidade para realizar RM; e distúrbio de coagulação não corrigido clinicamente. Os pacientes foram avaliados de acordo com os sintomas clínicos (IPSS e QoL), toque retal, exames laboratoriais de rotina incluindo o antígeno prostático específico (PSA), urofluxometria livre (Qmax) e RM em diferentes períodos de acompanhamento. Os procedimentos foram realizados no Serviço de Radiologia Intervencionista do HCFMUSP, por meio de punção unilateral da artéria femoral comum, sob anestesia local, usando-se microcateter, agente embolizante do tipo microesferas 100-300 ?m em 15 pacientes (Grupo A) e 300-500 ?m em 15 pacientes (Grupo B). Foi considerado sucesso técnico a identificação, cateterismo e embolização bilateral das artérias prostáticas. Definiu-se como sucesso clínico a retirada da sonda vesical nos pacientes em retenção urinária, melhora dos sintomas de acordo com o escore IPSS < 8 e índice QoL < 3. Considerou-se o valor de p < 0,05 como estatisticamente significante. Resultados: Sucesso técnico foi obtido em todos os casos. Ambos os grupos apresentaram melhoria significativa do IPSS, QoL e do Qmax, assim como redução do PSA e do volume prostático em relação aos dados demográficos (p < 0,05). Houve um aumento volumétrico prostático significativo entre 3 e 12 meses no grupo A (p < 0,05). As diferenças observadas entre os dois grupos não foram significativas, com maior ocorrência de eventos adversos (p = 0,066) e maior redução do PSA no acompanhamento de 3 meses (p = 0,056) nos pacientes tratados com microesferas de 100-300 um. Conclusão: As microesferas de 100-300 ?m e 300-500 um demonstraram serem agentes embolizantes seguros e eficazes na EAP para o tratamento dos LUTS relacionados à HPB. Embora os resultados clínicos e por imagem não tenham diferido significativamente entre os grupos de estudo, os pacientes tratados com 100-300 um apresentaram mais eventos adversos do que aqueles tratados com 300-500 um. O volume da próstata aumentou significativamente entre o terceiro e o décimo segundo mês após EAP no grupo tratado com microesferas 100-300 um, embora se mantivesse significativamente menor que antes da EAP / Introduction: The development of new minimally invasive surgical procedures for the treatment of low urinary tract symptoms (LUTS), related to benign prostatic hyperplasia (BPH), is becoming an important field of research as it attempts to minimize adverse effects and complications resulting from conventional treatments. Prostatic artery embolization (PAE) is increasingly being used as an alternative for the treatment of patients with BPH. The aim of this study was to evaluate and compare the safety and efficacy of PAE for the treatment of LUTS in patients with BPH, using microspheres (Embosphere®) of 100-300 um and 300-500 um. Methods: A prospective Phase II clinical trial was conducted between August 2011 and June 2013 by the Urology Department and the Radiology Department. The research protocol was approved by the Ethics Committee for Analysis of Research Projects (CAPPesq) of HC-FMUSP. In fact, 30 patients with moderate or severe symptoms (IPSS > 7), refractory to the clinical treatment for BPH, with a prostatic volume of 30 g and 100 g were selected by magnetic resonance imaging (MRI). Patients with the following conditions were excluded from the study: biopsy-proven prostate cancer; prostatitis or active urinary tract infection; surgery or previous intervention for BPH; diseases affecting the bladder function; impossibility to perform MRI; and clinically uncorrected coagulation disorders. Patients were evaluated according to clinical symptoms (IPSS and QoL), rectal examination, laboratory tests (PSA), uroflowmetry (Qmax) and imaging (MR) at different follow-up periods. Procedures were performed at the interventional radiology suite of the HCFMUSP, by means of unilateral puncture of the common femoral artery, under local anesthesia, using a microcatheter, microspheres type 100-300 um in 15 patients (Group A) and 300-500 um in 15 patients (Group B). Identification, catheterization and bilateral embolization of the prostatic arteries were considered technical success. Clinical success was defined as the removal of the bladder catheter and improvement of symptoms according to the IPSS score < 8 and QoL index < 3. Results: The PAE was technically successful in all cases. Both groups showed a significant improvement in IPSS, QoL and Qmax, as well as reduction of PSA and prostate volume in relation to demographic data (p < 0.05). There was a significant prostatic volumetric increase between 3 and 12 months in group A (p < 0.05). Differences observed between the two groups were not significant, with a higher number of adverse events (p = 0.066) and lower level of blood PSA at 3 months follow-up (p = 0.056) in Group A (100-300 um). Conclusion: Microspheres of 100-300 ?m and 300-500 ?m are safe and effective embolic agents in PAE for the treatment of LUTS related to BPH. Although functional results did not differ significantly between study groups, patients treated with 100-300 ?m reported more adverse events than those treated with 300-500 um. The prostate volume increased significantly between the third and the twelfth month post-PAE in the group treated with 100-300 um microspheres, although it remained significantly lower than pre-PAE

La transplantation d’hépatocytes est un procédé séduisant pour remplacer les cellules déficientes dans un foie anatomiquement normal. Dans les maladies métaboliques héréditaires hépatiques (MMHH), la thérapie cellulaire présente un potentiel espoir thérapeutique. Le remplacement d'un pourcentage restreint (5-10%) d’hépatocytes déficients par des hépatocytes normaux pourrait rétablir durablement la fonction métabolique. Les résultats des essais cliniques de transplantation d'hépatocytes génétiquement modifiés ou non sont moins concluants, montrent une prise de greffe insuffisante et, dans la plupart des études, un effet thérapeutique transitoire. L’efficacité limitée de la transplantation d’hépatocytes isolés dans le traitement des MMHH semble en partie liée au faible pourcentage de la masse hépatocytaire reconstituée par les hépatocytes définitivement greffés et fonctionnels. De nombreux modèles animaux ont été développés pour étudier les facteurs pouvant augmenter le nombre et le pourcentage d’hépatocytes transplantés et greffés. Cependant, la majorité de ces modèles ne sont pas transposables en clinique car ils présentent des risques importants ou mal évalués pour les patients. Les principaux objectifs de ce travail ont été d’étudier des moyens peu invasifs pour induire une régénération hépatique et une prise de greffe hépatocytaire significatives dans le but de développer une nouvelle approche de transplantation d’hépatocytes génétiquement modifiés ex vivo pour le traitement de l’hypercholestérolémie familiale. L’effet d’une embolisation portale partielle (EPP) réversible sur la prolifération hépatocytaire et la régénération hépatique a été évalué chez le macaque. A la différence de l’EPP par un produit non résorbable, il ne s’agit pas d’une approche potentiellement délétère à long terme. Une obstruction veineuse plus complète a été provoquée en utilisant le Curaspon®, une gélatine biodégradable, en forme de poudre. Nous avons démontré pour la première fois dans la littérature l’efficacité d’une EPP réversible à induire une importante prolifération hépatocytaire et régénération hépatique. Nos données suggèrent qu’une occlusion portale initiale et temporaire est suffisante pour déclencher les mécanismes responsables d’une régénération hépatique dans le foie non-embolisé. L’utilisation du Curaspon® en poudre peut être considérée comme la forme la plus évoluée d’EPP : très distale, résorbable, qui dure suffisamment pour induire l’hypertrophie hépatique. Cette technique pourrait être indiquée dans des situations cliniques nécessitant une régénération hépatique de courte durée (ex. le traitement des cancers du foie en plusieurs étapes) ou dans des cas qui ne nécessitent pas une résection hépatique, comme la transplantation d’hépatocytes pour le traitement de MMHH. Ces résultats nous ont permis d’évaluer cette approche dans notre protocole préclinique de thérapie génique pour le traitement de l’hypercholestérolémie familiale chez le primate, par autotransplantation d’hépatocytes génétiquement modifiés ex vivo par un vecteur lentiviral. Nous avons démontré que l’EPP réversible induit une régénération hépatique du foie non-embolisé et améliore notablement les résultats de la transplantation d’hépatocytes isolés génétiquement modifiés exprimant la GFP. Seize semaines après la transplantation, les hépatocytes transduits et greffés exprimaient le transgène contrôlé par le promoteur apo-AII humain. Notre protocole a montré pour la première fois chez un gros animal que l’EPP par un produit résorbable entraine avec des conditions de sécurité optimales une repopulation hépatique importante par des hépatocytes transduits par un vecteur lentiviral, et ceci même à distance de la transplantation hépatocytaire. Les résultats encourageants de ces travaux nous ont ouvert la voie pour avancer sur notre projet préclinique et envisager la réalisation d’une étude clinique de phase I/II pour le traitement de l’hypercholestérolémie familiale. / Hepatocyte transplantation is an attractive process for replacing deficient cells in an anatomically normal liver. In metabolic liver diseases, cell therapy could be an interesting alternative to orthotopic liver transplantation. The replacement of a small percentage (5-10%) of deficient hepatocytes by normal hepatocytes could restore the metabolic defect at a long term. Data from clinical studies of hepatocyte autotransplantation or allotransplantation, genetically modified or not, provided poor results, insufficient cell engraftment in the liver parenchyma and, in the majority of cases, a transient therapeutic effect. The limited efficacy of hepatocyte transplantation in metabolic liver diseases is mainly due to the poor percentage of engrafted and finally functional hepatocytes. Numerous animal models have been developed in order to study the factors that could increase the number and the percentage of transplanted and engrafted hepatocytes. However, the majority of these models cannot be used in patients since they present important risks for them. The aim of this work was to evaluate less invasive procedures for inducing liver regeneration and significant hepatocyte engraftment in order to develop a new approach of transplantation of ex vivo genetically modified hepatocytes for the treatment of familial hypercholesterolemia. The effect of reversible portal vein embolization (PVE) on liver regeneration and hepatocyte proleferation was evaluated in monkeys. In contrast to PVE by a permanent embolizing agent, reversible PVE has not a long term deleterious effect on embolized liver. A more complete venous occlusion was obtained by using the powdered form of an absorbable gelatin sponge (Curaspon®). We showed for the first time in the literature the safe and successful use of reversible PVE for inducing significant hepatocyte proliferation and liver regeneration. Our data support that an initial occlusion of the portal branch, even if not permanent, is sufficient to start the mechanisms of liver regeneration in the contralateral lobe. Embolization with Curaspon® powder could be considered to be the ultimate form of embolization: very distal, reversible and lasting sufficiently in order to induce substantial liver hypertrophy. Our findings suggest that this method could reliably be used for clinical purposes, particularly in situations in which short-term regeneration is required (i.e. multi-step management of hepatic malignancies) or in cases where resection of the liver is not finally necessary, such as in hepatocyte transplantation for the treatment of metabolic liver diseases. These promising results on reversible PVE allowed us to evaluate this approach in our preclinical study of gene therapy for the treatment of familial hypercholesterolemia in macaques. Our protocol consisted of an autotransplantation of ex vivo genetically modified hepatocytes by a lentiviral vector. We showed that reversible PVE induces liver regeneration of the non-embolized liver segments and improves considerably hepatocyte transplantation of genetically modified cells expressing Green Fluorescent Protein (GFP). Sixteen weeks after transplantation, transduced engrafted hepatocytes expressed the transgene, which was under control of the human apo-AII promoter. Our protocol showed for the first time in a big animal that PVE by an absorbable agent leads safely to an important and long-term repopulation of the liver by lentivirally transduced hepatocytes. The extremely encouraging results of this work opened our way advancing in our preclinical study and preparing a phase I/II clinical trial for the treatment of familial hypercholesterolemia based on our protocol of autotransplantation of ex vivo genetically modified hepatocytes by a lentiviral vector.

As dissecções da artéria vertebral causam acidentes vasculares cerebrais isquêmicos e hemorrágicos. A dissecção arterial é a ruptura da sua parede com formação de hematoma intramural. Podem ser espontâneas, acometendo a artéria vertebral extra ou intracraniana. O tratamento em geral é clínico, porém em alguns casos está indicada intervenção. A via endovascular é uma importante alternativa, permitindo o tratamento específico da lesão em alguns casos, mas na maioria sacrificando a artéria vertebral, após teste de tolerância à oclusão. Com o objetivo de analisar os aspectos clínicos e técnicos do tratamento endovascular, estudamos de forma prospectiva 15 pacientes. Três apresentavam dissecções traumáticas (todas extracranianas) e 12 espontâneas, dos quais dois tiveram traumatismos menores como desencadeantes. Cinco pacientes apresentaram dissecções extracranianas, oito, intracranianas e dois, combinadas. No grupo das extracranianas, a principal indicação de tratamento foi a presença de fístula arteriovenosa, em três dos cinco pacientes. No grupo da intracranianas, foi a presença de hemorragia meníngea. Nos quatro pacientes com acidente vascular isquêmico, a indicação de tratamento deveu-se à presença de pseudoaneurismas que não involuíram com tratamento clínico. Nesse grupo, dois pacientes tinham dissecção extracraniana, um, intra e um, combinada. Um paciente apresentou intolerância à oclusão e foi encaminhado para tratamento conservador. Dos 14 pacientes tratados, um teve como estratégia a oclusão seletiva da lesão, 11 a oclusão da artéria vertebral proximal à lesão e dois oclusão acima e abaixo da lesão. Os materiais utilizados foram balões destacáveis em sete pacientes, molas de destaque livre em 6 e molas eletricamente destacáveis associadas a molas de destaque livre em 1 paciente. Dois pacientes apresentaram complicações do tratamento, e um paciente, recidiva de fístula arteriovenosa, todos resolvidos sem seqüelas. A angiografia controle revelou oclusão total do segmento dissecado ou do pseudoaneurisma em 9 pacientes, reversão do fluxo em quatro e preservação da artéria vertebral com oclusão da lesão em um. Num período de seguimento de 8,6 meses não se registraram recorrências. O tratamento foi eficiente na prevenção de ressangramentos e na trombose dos pseudoaneurismas e apresenta segurança em relação a complicações. / Vertebral artery dissections can cause brain ischemia and hemorrhage. Arterial dissection consist of mural tears with subsequent intramural hematoma formation. They may occur either spontaneously or as a consequence of traumatism, in the extracranial or intracranial vertebral artery. The treatment is usually clinical, but in some instances intervention is indicated. The endovascular approach is an important tool, allowing specific treatment of the lesion in some cases, but sacrificing the vertebral artery in most cases. With the aim of analyze the clinical and technical aspects of the endovascular treatment, we studied prospectively 15 patients treated by endovascular approach. Three presented traumatic dissections (all extracranial) and 12 spontaneous dissections, two of which after minor traumatic events. Five patients had extracranial dissections, eight, intracranial and two, combined. In the extracranial dissection group, the main indication for treatment was the presence of an arteriovenous fistula (three of five patients). In the intracranial group, it was subarachnoid hemorrhage. Four patients presenting with brain isquemia were treated because of pseudoaneurysms that did not resolve in clinical treatment. In this group 2 patients had extracranial dissections, one had intracranial and one had both. One patient did not tolerate occlusion and was treated clinically. Fourteen patients were treated by endovascular means, one with selective lesion occlusion, 12 with proximal vertebral artery occlusion and two with proximal and distal vertebral artery occlusion. The embolic material were detachable balloons in 7 patients, platinum microcoils in 6 patients and electrically detachable platinum microcoils and platinum microcoils in one patient. Two patients presented complications, and one presented recurrence of an arteriovenous fistula, all resolved without sequelae. Angiographic controls disclosed total occlusion of the segment with dissection or of the pseudoaneurysm in 9 patients, retrograde flow in 4 and vertebral artery preservation with selective lesion occlusion in 1. During a mean follow-up period of 8,6 months no recurrence was observed. The treatment was efficient in preventing recurrent hemorrhage and promoting pseudoaneurysms thrombosis, besides it was a safe treatment option.

Trinta e cinco pacientes com malformações arteriovenosas raquimedulares (MAVR) foram tratados por via endovascular. Foram analisados os tipos de MAVR, bem como os aspectos clínicos e angiográficos pré e pós-tratamento endovascular. As MAVR mais freqüentes foram as fístulas arteriovenosas durais (FAD), com 17 pacientes, seguidas das malformações arteriovenosas intramedulares (MAI), fístulas arteriovenosas perimedulares (FAVP) e malformações arteriovenosas metaméricas (MAVM). A avaliação do resultado do tratamento foi dividida em sucesso técnico e clínico, sendo que o primeiro foi subdividido em sucesso técnico do procedimento e do tratamento. O sucesso técnico do procedimento foi caracterizado como oclusão total da MAVR ao final de um procedimento endovascular. O sucesso técnico do tratamento foi caracterizado pela oclusão definitiva da MAVR, independentemente do número de procedimentos. A recidiva foi definida como o reaparecimento da MAVR, identificada na angiografia durante o seguimento dos pacientes, independentemente do quadro clínico apresentado. A recidiva implicava em insucesso do procedimento, mas não necessariamente do tratamento. O sucesso clínico do tratamento foi considerado como a melhora parcial ou total dos sintomas após um período mínimo de acompanhamento de 6 meses. Nas FAD, houve predomínio do sexo masculino e da faixa etária acima dos 36 anos. O tratamento endovascular das FAD mostrou sucesso do procedimento na maioria dos casos, porém com recidiva da lesão em 56,7% dos mesmos. Quando usadas partículas, observou-se recidiva em 73,3% dos procedimentos, porém com sucesso do tratamento em 66,7 dos pacientes. Quando utilizado o adesivo tissular (\"cola\"), houve recidiva em 11,1% dos procedimentos e sucesso do tratamento em 88,9% dos pacientes. A melhora clínica foi obtida em 64,7% dos pacientes. Dos 10 pacientes tratados com MAI, a faixa etária mais freqüente foi dos 19 aos 35 anos de idade e predomínio do sexo masculino. O tratamento endovascular das MAI mostrou sucesso do procedimento em 53,3% e recidiva da lesão em 6,7% dos pacientes. O sucesso do procedimento também foi superior quando usada cola, atingindo 63,6% dos procedimentos e apenas 25,0% com partículas. O sucesso do tratamento foi de 80,0% e a melhora clínica foi observada em 40,0% dos pacientes. Somente 1 paciente com MAVM foi tratado. O tratamento objetivou a embolização parcial da lesão para alívio dos sintomas, resultado que foi obtido com sucesso. Nas FAVP houve predomínio do sexo masculino e a faixa etária mais acometida foi dos 19 aos 35 anos. O tratamento endovascular das FAVP mostrou sucesso do procedimento em 75,0% dos pacientes e ausência de recidiva. O sucesso do tratamento foi de 85,7%, com melhora clínica em todos os pacientes. O nosso estudo mostrou que as MAVR podem ser tratadas de maneira eficiente e segura através da embolização. O seguimento dos pacientes tratados com cola mostrou menor índice de recidiva do que aqueles tratados com partículas. Após a embolização, houve melhora significativa no padrão da marcha nos pacientes com FAD e MAI / Endovascular treatment was used in 35 patients with spinal cord arteriovenous malformations (SCAVM). SCAVM types, along with clinical and angiographic features of pre-op and post-op endovascular treatments were analyzed. Seventeen patients had dural arteriovenous fístulas (DAVF), being this type the most frequent SCAVM, followed by intramedullary arteriovenous malformations (IAVM), perimedullary arteriovenous fístulas (PAVF) and metameric arteriovenous malformations (MAVM). Evaluation of treatment results was divided into technical and clinical success, being the first subdivided into technical success of the procedure and treatment. The procedural\'s technical success was characterized by total SCAVM occlusion at the end of an endovascular procedure. Technical success of the treatment was characterized by definitive occlusion of the SCAVM, independent of the number of procedures. Recurrence was defined as reappearance of SCAVM, identified on angiograms during patient follow up, independent of the observed clinical situation. Recurrence implied in an unsuccessful procedure but not necessarily in treatment failure. Treatment\'s clinical success was considered partial or total symptom improvement after a minimum 6 month period follow up. Male and age over 36 years was preponderate in DAVF. Endovascular treatment in DAVF had procedural success in most cases, but with lesion recurrence in 56,7% of these patients. When particulate embolic agents were used, recurrence occurred in 73,3% of the procedures but with treatment success in 66,7% of these patients. When liquid tissue adhesive was used, there was 11,1% of recurrence and 88,9% in treatment success in these patients. Clinical improvement occurred in 64,7% of these patients. Male predominance and age between 19 to 35 years was more frequent in the 10 treated patients with IAVM. IAVM endovascular treatment was a procedural success in 53,3% and lesion recurrence in 6,7% of these patients. Procedural success was also superior when liquid tissue adhesive was used, up to 63,6% of these procedures and, only 25,0% with particulate embolic agents. Treatment success occurred in 80,0% and clinical improvement seen in 40,0% of these patients. Only 1 patient with MAVM was treated. Aim in treatment was partial lesion embolization to mitigate symptoms, which was successfully achieved. Male predominance and age between 19 to 35 years occurred in PAVF. PAVF endovascular treatment had procedural success in 75,0% and no recurrences in these patients. Treatment success occurred in 85,7% and clinical improvement in all patients. This study demonstrates that SCAVM can be treated efficiently and safely with endovascular embolization. Patient follow up revealed fewer recurrences in those treated with liquid tissue adhesive than in those with particulate embolic agents. After DAVF and IAVM embolization, patients had significant improvement in their gait

Le devenir des branches artérielles émergentes de la proximité d’un anévrysme intracrânien et couvertes par un stent à diversion de flux lors le traitement de l’anévrysme reste controversé. Une recherche animalière de caractère translationnel a été conduite afin d’élucider le rôle du flux collatéral dans les changements hémodynamiques apportés par un stent a diversion de flux. La couverture néointimale relative aux modifications hémodynamiques aux ostia de ces artères a été également évaluée. Pour atteindre notre objectif, nous avons cherché à quantifier les changements hémodynamiques dans les artères couvertes à leurs origines et à quantifier leur surface de couverture par le tissu endothélial à 3 mois après le placement du stent à diversion de flux dans un modèle animal porcin.Méthodes Suivant une analyse de pouvoir statistique a priori, deux groupes (A, B), chacun contenant sept porcs de race large white, ont été créés, suivant un modèle de flux de circulation artérielle terminale ou anastomotique. Groupe A correspondait à une configuration artérielle de type anastomotique pour l’artère Pharyngienne ascendante droite et groupe B à une configuration terminale concernant la même branche ; cette configuration terminale a été créée par l’occlusion endovasculaire sélective des apports artériels collatéraux pour le territoire de suppléance de l’artère Pharyngienne ascendante droite. Ensuite, pour chacun des 14 animaux, un stent à diversion de flux a été placé dans la carotide interne droite couvrant ainsi l’ostium de l’artère pharyngienne ascendante homolatérale. Pour mesurer les vélocités à l’origine de cette artère, une séquence IRM de contraste de phase tridimensionnelle avec une résolution temporelle (4D) a été utilisée. Des valeurs ont été obtenues avant et après stenting. Trois mois plus tard, un travail de prélèvement anatomique suivi d’une analyse par microscopie à balayage anatomique a été a été réalisé. Une quantification surfacique a été ainsi obtenue permettant de déterminer la perméabilité des ostia des artères pharyngienne ascendante. Les données ont été ainsi analysées grâce à des tests de statistique descriptive et comparative des deux groupes prédéterminés. Des tests paramétriques et non paramétriques ont également été obtenus. Résultats La faisabilité a pu être obtenue dans tous les spécimens utilisés. Nous n’avons déploré aucune mortalité immédiate ni aucune occlusion intra-stent relatives à la procédure. Les séquences IRM de diffusion ont témoigné de l’absence d’ischémie distale à la phase aigue après la mise en place du stent, Immédiatement, en post stenting, le flux moyen dans les artères pharyngiennes ascendantes droites du groupe a été réduit d’une façon significative, quand on le compare à la valeur moyenne en pré- stenting [P = 0.0008, pouvoir statistique: 0.9548]. Au contraire, le flux moyen dans les artères pharyngiennes ascendantes droites du groupe B est resté comparable à la valeur moyenne pré- stenting. Apres trois mois de suivi, la valeur moyenne de surface perméable était significativement plus élevée dans le groupe B (527,911 ± 306,229 μm2) que dans le groupe A (89,329 ± 59,762 μm2) [P< 0.01, power: 1.00], malgré la similarité les dimensions artérielles initiales (pré-stenting) dans les deux groupes. Une corrélation positive significative a été retrouvée entre les deux groupes concernant le flux moyen post stenting et la surface moyenne de couverture aux ostia, à trois mois de suivi. / The outcome of jailing arterial branches that emerge near intracranial aneurysms during flow-diverting stent deployment remains controversial. We report an animal research study aiming to elucidate the role of collateral supply in the hemodynamic changes and neointimal modifications resulting from jailing arteries with flow-diverting stents. To serve this purpose, we sought to quantify the hemodynamic changes at the jailed arterial branches immediately after stenting, as well as quantify the ostia surface values at three months post-stenting, in the presence or absence of collateral arterial flow. Methods After a priori power analysis, two groups (A, B), each containing seven large white swine, were created according to an animal flow model for terminal and anastomotic arterial circulation. Group A corresponded to an arterial configuration with anastomotic type of arterial supply for the territory of the right Ascending Pharyngeal artery (APhA) and group B to an arterial configuration of terminal type of arterial supply for the territory of the right APhA. Subsequently, all animals were stented by flow-diverting stents, jailing the right ascending pharyngeal arteries. Mean flow rates and velocities inside the jailed branches were quantified before and after stenting by time-resolved, 3D, phase contrast MRA. After three months the jailed ostia surface values were quantified on scanning electron microscopic images. The data were analyzed using descriptive statistics and group comparisons with parametric and non-parametric tests.Results Endovascular procedures were feasible, without in situ thrombus formation or ischemic DWI findings on post-procedure MRIs. Immediately following stenting, mean flow rate values at the jailed right ascending pharyngeal arteries were reduced in group A, as compared to the pre-stenting values [P = 0.0008, power: 0.9548]. In contrast, mean flow rates for group B remained similar to the pre-stenting values. At three months post-stenting, mean ostia surface values were significantly higher for group B (527,911 ± 306,229 μm2) than for group A (89,329 ± 59,762 μm2) [P< 0.01, power: 1.00], even though the initial dimensions of the jailed ostia were similar between groups. A statistically significant correlation was found between group (A or B), mean flow rates post-stenting and ostia surface values at three months. ConclusionWhen important collateral supply was present, jailing side arteries with flow-diverters resulted in an immediate, significant reduction in flow rate inside these arteries, as compared to the pre-stenting values. In contrast, when competitive flow was absent, jailing did not result in significant flow rate reductions inside the jailed arteries. Ostium surface values at three months were significantly higher in the terminal group of jailed arteries, compared to the anastomotic group and strongly correlated with the velocity value reductions post- stenting. Key words: flow-diverting stent, collateral arteries, endothelialization, ostium, embolization, magnetic resonance angiography, magnetic resonance imaging

No description available.

Relevance of tumor infiltrating lymphocytes as a prognostic factors in patients with portal vein embolisation (PVE) and patients with PVE and administration of autologous stem cells Background: low future liver remnant volume (FLRV) is the cause of why 75% of patients with colorectal liver metastases (CLM) are primarily inoperable. Portal vein embolisation (PVE) helps to increase FLRV and so increase the operability. But PVE fails in almost 40 % of patients. Usage of stem cells (SCs) could be the way how to support the effect of PVE. Currently, there are studies of interactions of the immune system and malignancies. We do not know about papers focused on relations of the immune system and CLM in patients treated by PVE. There were not described interactions of ABC transporters and CLM at patients after PVE was performed too. Aims: the aim of this dissertation was to verify the effect of PVE and intraportal administration of SCs on the growth of FLRV and progression of the CLM. Other aims were to evaluate the tumor infiltrating lymphocytes, ABCC10 and ABCC11 transportes in patients treated by surgery for CLM after PVE and their clinical relevances. Methods: intraportal administration of SCs after PVE and their effect was explored in a group of 63 patients (43 patients with PVE alone, 20 in the group PVE with...