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Background & Aims: Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms. Methods: Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model. Results: Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% vs. 3.09%, p = 0.0023) and fibrosis (3.75% vs. 2.70%, p = 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 vs. 1.0, p = 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% vs. 37.5%, p = 0.0084) with a higher mean tumor volume (234 vs. 3 µm3, p = 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 vs. 2.92, p = 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load. Conclusions: Maternal obesity increases female offspring's susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition. Impact and implications: The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.
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BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is one of the leading cause of hepatocellular carcinoma (HCC). This association is supported by the translocation of bacteria products into the portal system, which acts on the liver through the gut-liver axis. We hypothesize that portosystemic shunting can disrupt this relationship, and prevent NAFLD-associated HCC. METHODS: HCC carcinogenesis was tested in C57BL/6 mice fed a high-fat high-sucrose diet (HFD) and injected with diethylnitrosamine (DEN) at two weeks of age, and in double transgenic LAP-tTA and TRE-MYC (LAP-Myc) mice fed a methionine-choline-deficient diet. Portosystemic shunts were established by transposing the spleen to the sub-cutaneous tissue at eight weeks of age. RESULTS: Spleen transposition led to a consistent deviation of part of the portal flow and a significant decrease in portal pressure. It was associated with a decrease in the number of HCC in both models. This effect was supported by the presence of less severe liver steatosis after 40 weeks, and lower expression levels of liver fatty acid synthase. Also, shunted mice exhibited lower liver oxygen levels, a key factor in preventing HCC as confirmed by the development of less HCCs in mice with hepatic artery ligation. CONCLUSIONS: The present data show that portosystemic shunting prevents NAFLD-associated HCC, utilizing two independent mouse models. This effect is supported by the development of less steatosis, and a restored liver oxygen level. Portal pressure modulation and shunting deserve further exploration as potential prevention/treatment options for NAFLD and HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Oxigênio/metabolismo , Modelos Animais de DoençasRESUMO
Artificial intelligence (AI) refers to computer algorithms used to complete tasks that usually require human intelligence. Typical examples include complex decision-making and- image or speech analysis. AI application in healthcare is rapidly evolving and it undoubtedly holds an enormous potential for the field of solid organ transplantation. In this review, we provide an overview of AI-based approaches in solid organ transplantation. Particularly, we identified four key areas of transplantation which could be facilitated by AI: organ allocation and donor-recipient pairing, transplant oncology, real-time immunosuppression regimes, and precision transplant pathology. The potential implementations are vast-from improved allocation algorithms, smart donor-recipient matching and dynamic adaptation of immunosuppression to automated analysis of transplant pathology. We are convinced that we are at the beginning of a new digital era in transplantation, and that AI has the potential to improve graft and patient survival. This manuscript provides a glimpse into how AI innovations could shape an exciting future for the transplantation community.
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Inteligência Artificial , Transplante de Órgãos , Algoritmos , Previsões , Humanos , OncologiaRESUMO
Evidence suggests that liver graft quality impacts on posttransplant recurrence of hepatocellular carcinoma (HCC). As of today, selection criteria only use variables related to tumor characteristics. Within the Scientific Registry of Transplant Recipients, we identified patients with HCC who underwent liver transplantation between 2004 and 2016 (development cohort, n = 10 887). Based on tumor recurrence rates, we fitted a competing-risk regression incorporating tumor- and donor-related factors, and we developed a prognostic score. Results were validated both internally and externally in the Australia and New Zealand Liver Transplant Registry. Total tumor diameter (subhazard ratio [sub-HR] 1.52 [1.28-1.81]), alpha-feto protein (sub-HR 1.27 [1.23-1.32], recipient male gender (sub-HR 1.43 [1.18-1.74]), elevated donor body mass index (sub-HR 1.26 [1.01-1.58]), and shared graft allocation policy (sub-HR 1.20 [1.01-1.43]) were independently associated with tumor recurrence. We next developed the Darlica score (sub-HR 2.72 [2.41-3.08] P < 0.001) that allows identifying risky combinations between a given donor and a given recipient. Results were validated internally (n = 3 629) and externally in the Australia and New Zealand Liver Transplant Registry (n = 370). The current score is based on variables that are readily available at the time of graft offer. It allows identifying hazardous donor-recipient combinations in terms of risk of tumor recurrence and overall survival.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Carcinoma Hepatocelular/cirurgia , Humanos , Neoplasias Hepáticas/cirurgia , Doadores Vivos , Masculino , Recidiva Local de Neoplasia , Estudos Retrospectivos , Fatores de RiscoAssuntos
Infecções por Coronavirus/prevenção & controle , Coronavirus , Salas Cirúrgicas , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Guias de Prática Clínica como Assunto , Centro Cirúrgico Hospitalar/organização & administração , Betacoronavirus , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Atenção à Saúde , Surtos de Doenças , Europa (Continente) , Humanos , Medicina Perioperatória , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , SARS-CoV-2 , Sociedades MédicasRESUMO
Hypothermic and normothermic ex vivo liver perfusions promote organ recovery after donation after circulatory death (DCD). We tested whether these perfusions can reduce the risk of hepatocellular carcinoma (HCC) recurrence in a 1h-DCD syngeneic transplantation model, using Fischer F344 rats. DCD grafts were machine perfused for 2h with hypothermic perfusion (HOPE) or normothermic perfusion (NORMO), and transplanted. After reperfusion, we injected HCC cells into the vena porta. On day 28 after transplantation, we assessed tumour volumes by MRI. Control rats included transplantations with Fresh and non-perfused DCD livers. We observed apoptotic-necrotic hepatocyte foci in all DCD grafts, which were more visible than in the Fresh liver grafts. Normothermic perfusion allowed a faster post-transplant recovery, with lower day 1 levels of transaminases compared with the other DCD. Overall, survival was similar in all four groups and all animals developed HCCs. Total tumor volume was lower in the Fresh liver recipients compared to the DCD and DCD+HOPE recipients. Volumes in DCD+NORMO recipients were not significantly different from those in the Fresh group. This experiment confirms that ischemia/reperfusion injury promotes HCC cell engraftment/growth after DCD liver transplantation. Using the present extreme 1h ischemia model, both hypothermic and normothermic perfusions were not effective in reducing this risk.
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Circulação Sanguínea , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Transplante de Fígado , Recidiva Local de Neoplasia/terapia , Animais , Bile/metabolismo , Linhagem Celular Tumoral , Feminino , Sobrevivência de Enxerto , Recidiva Local de Neoplasia/patologia , Oxigênio/metabolismo , Perfusão , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/patologiaRESUMO
PURPOSE OF REVIEW: Organ transplantation is an effective treatment for selected patients with end-stage organ disease or specific cancer types. Its main limitations are the chronic lack of grafts and the lifetime need for immunosuppression. The advent of autologous organs generated into xenogeneic species has the potential to solve these issues. RECENT FINDINGS: The current review discusses about the recent discoveries in the filed of organ generation by interspecific pre and postimplantation embryo complementation. Moreover, it describes the recent progress in postnatal xenogeneic liver repopulation and the transplantation of chimeric tissues and organs. SUMMARY: Thanks to the groundbreaking discoveries of the last few years, these strategies are becoming more and more real, yet with still a number of key steps to overcome.
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Transplante de Órgãos/métodos , Quimeras de Transplante/imunologia , Transplante Heterólogo/métodos , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Humanos , Tolerância Imunológica/imunologia , Terapia de Imunossupressão , Tolerância ao Transplante/imunologiaRESUMO
Liver transplantation is widely indicated as a curative treatment for selected patients with hepatocellular carcinoma. However, with recent therapeutic advances, as well as efforts to increase the donor pool, liver transplantation has been carefully expanded to patients with other primary or secondary malignancies in the liver. Cholangiocarcinoma, colorectal and neuroendocrine liver metastases, and hepatic epithelioid haemangioendothelioma are amongst the most relevant new indications. In this review we discuss the fundamental concepts of this ambitious undertaking, as well as the newest indications for liver transplantation, with a special focus on future perspectives within the recently established concept of transplant oncology.
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Liver transplantation (LT) has become the standard of care for selected primary and secondary malignancies. Considered a contra-indication to transplantation until recently, unresectable colorectal liver metastases (CRLM) have gained interest since the publication of the SECA trial by the University of Oslo. It showed a 5-year overall survival of 60%, comparable to the one of standard transplant indication. This report generated multiple questions about the place of LT for CRLM and gave raise to several trials aiming at answering them. The present review is exploring this topic, defining the current state of the field, and extrapolating the future milestones.
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According to the Juvenile Diabetes Research Foundation (JDRF), almost 1. 25 million people in the United States (US) have type 1 diabetes, which makes them dependent on insulin injections. Nationwide, type 2 diabetes rates have nearly doubled in the past 20 years resulting in more than 29 million American adults with diabetes and another 86 million in a pre-diabetic state. The International Diabetes Ferderation (IDF) has estimated that there will be almost 650 million adult diabetic patients worldwide at the end of the next 20 years (excluding patients over the age of 80). At this time, pancreas transplantation is the only available cure for selected patients, but it is offered only to a small percentage of them due to organ shortage and the risks linked to immunosuppressive regimes. Currently, exogenous insulin therapy is still considered to be the gold standard when managing diabetes, though stem cell biology is recognized as one of the most promising strategies for restoring endocrine pancreatic function. However, many issues remain to be solved, and there are currently no recognized treatments for diabetes based on stem cells. In addition to stem cell resesarch, several ß-cell substitutive therapies have been explored in the recent era, including the use of acellular extracellular matrix scaffolding as a template for cellular seeding, thus providing an empty template to be repopulated with ß-cells. Although this bioengineering approach still has to overcome important hurdles in regards to clinical application (including the origin of insulin producing cells as well as immune-related limitations), it could theoretically provide an inexhaustible source of bio-engineered pancreases.
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BACKGROUND & AIMS: There is growing evidence that liver graft ischemia-reperfusion (I/R) is a risk factor for hepatocellular carcinoma (HCC) recurrence, but the mechanisms involved are unclear. Herein, we tested the hypothesis that mesenteric congestion resulting from portal blood flow interruption induces endotoxin-mediated Toll-like receptor 4 (Tlr4) engagement, resulting in elevated liver cancer burden. We also assessed the role of remote ischemic preconditioning (RIPC) in this context. METHODS: C57Bl/6j mice were exposed to standardized models of liver I/R injury and RIPC, induced by occluding the hepatic and femoral blood vessels. HCC was induced by injecting RIL-175 cells into the portal vein. We further evaluated the impact of the gut-liver axis (lipopolysaccharide (LPS)-Tlr4 pathway) in this context by studying mice with enhanced (lipopolysaccharide infusion) or defective (Tlr4-/- mice, gut sterilization, and Tlr4 antagonist) Tlr4 responses. RESULTS: Portal triad clamping provoked upstream mesenteric venous engorgement and increased bacterial translocation, resulting in aggravated tumor burden. RIPC prevented this mechanism by preserving intestinal integrity and reducing bacterial translocation, thereby mitigating HCC recurrence. These observations were linked to the LPS-Tlr4 pathway, as supported by the high and low tumor burden displayed by mice with enhanced or defective Tlr4 responses, respectively. CONCLUSIONS: Modulation of the gut-liver axis and the LPS-Tlr4 response by RIPC, gut sterilization, and Tlr4 antagonism represents a potential therapeutic target to prevent I/R lesions, and to alleviate HCC recurrence after liver transplantation and resection. LAY SUMMARY: Cancer recurrence can occur after liver resection or liver transplantation for hepatocellular carcinoma (HCC). This study suggests that intestinal venous congestion, which often occurs during liver surgery, favors the translocation of gut-derived bacterial products in the portal vein, thereby facilitating cancer recurrence by enhancing the signaling of Toll-like receptor 4 in the liver. Using a mouse model of HCC recurrence, we show that strategies that (i) reduce bacterial translocation (by gut decontamination, or by protecting the intestine from venous ischemia damage) or (ii) inhibit Tlr4 signaling in the liver, could reduce cancer recurrence.
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Neoplasias Hepáticas Experimentais/etiologia , Transplante de Fígado/efeitos adversos , Fígado/lesões , Traumatismo por Reperfusão/complicações , Animais , Intestinos/irrigação sanguínea , Intestinos/microbiologia , Precondicionamento Isquêmico , Fígado/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/prevenção & controle , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/fisiologiaRESUMO
PURPOSE: In vivo liver cancer research commonly uses rodent models. One of the limitations of such models is the lack of accurate and reproducible endpoints for a dynamic assessment of growing tumor nodules. The aim of this study was to validate a noninvasive, true volume segmentation method using two rat hepatocellular carcinoma (HCC) models, correlating magnetic resonance imaging (MRI) with histological volume measurement, and with blood levels of α-fetoprotein. MATERIALS AND METHODS: We used 3T clinical MRI to quantify tumor volume with follow-up over time. Using two distinct rat HCC models, calculated MRI tumor volumes were correlated with volumes from histological sections, or with blood levels of α-fetoprotein. Eleven rats, comprising six Buffalo rats (n = 9 scans) and five Fischer rats (n = 14 tumors), were injected in the portal vein with 2.5 × 105 and 2.0 × 106 syngeneic HCC cells, respectively. Longitudinal (T1) relaxation time- and transverse (T2) relaxation time-weighted MR images were acquired. RESULTS: The three-dimensional (3D) T1-weighted gradient echo had 0.35-mm isotropic resolution allowing accurate semi-automatic volume segmentation. 2D T2-weighted imaging provided high tumor contrast. Segmentation of combined 3D gradient echo T1-weighted images and 2D turbo spin echo T2-weighted images provided excellent correlation with histology (y = 0.866x + 0.034, R² = 0.997 p < .0001) and with α-fetoprotein (y = 0.736x + 1.077, R² = 0.976, p < .0001). There was robust inter- and intra-observer reproducibility (intra-class correlation coefficient > 0.998, p < .0001). CONCLUSIONS: We have developed a novel, noninvasive contrast imaging protocol which enables semi-automatic 3D volume quantification to analyze nonspherical tumor nodules and to follow up the growth of tumor nodules over time.
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Carcinoma Hepatocelular/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Carga Tumoral , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Imageamento Tridimensional/métodos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Ratos , Ratos Endogâmicos BUF , Ratos Endogâmicos F344 , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Software , Fatores de Tempo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Liver transplantation (LT) for hepatocellular carcinoma (HCC) is strategically challenging because the very good mid-term outcomes of this treatment jar with the risk of cancer recurrence. Although Milan criteria (MC) tap the balance on the safe side, they tend to be considered too restrictive and new, enlarged criteria have been conceived in order to enlarge the pool of potential recipients. Some extended criteria are more audacious then others, but they seem to be well tailored on the local reality they are applied to. Being HCC epidemiology and organs availability very variable between regions, a universally valid 'upper limit' is yet to be determinable.
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Blastocyst complementation refers to the injection of cells into a blastocyst. The technology allows for the creation of chimeric animals, which have the potential to be used as an unlimited source of organ donors. Pluripotent stem cells could be generated from a patient in need of a transplantation and injected into a large animal blastocyst (potentially of a pig), leading to the creation of organ(s) allowing immunosuppression-free transplantation. Various chimera combinations have already been generated, but one of the most recent steps leads to the creation of human-pig chimeras, which could be studied at an embryo stage. Although still far from clinical reality, the potential application is almost unlimited. The present review illustrates the historical steps of intra- and interspecific blastocyst complementation in rodents and large animals, specifically looking at its potential for generation of organ grafts. We also speculate on how it could change transplant indications, on its economic impact, and on the linked ethical concerns.
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Blastocisto/metabolismo , Quimera/metabolismo , Células-Tronco Pluripotentes/citologia , Transplante Heterólogo , Animais , Diferenciação Celular/fisiologia , Proteínas do Sistema Complemento/metabolismo , Humanos , SuínosRESUMO
Kupffer cells represent the first line of defense against tumor cells in the liver. Myeloid-derived suppressor cells (MDSC) have recently been observed in the liver parenchyma of tumor-bearing animals. The present study investigates the function of the MDSC subsets, and their impact on Kupffer cell phenotype and function. RIL-175 mouse hepatocellular carcinoma (HCC) cells were injected into the median liver lobe of C57BL/6 mice. Three weeks later, the median lobe hosting the tumor nodule was removed, and Kupffer cells and MDSCs were sorted from the remaining liver. Mouse livers devoid of HCC served as control. Kupffer cells expressed less co-stimulatory CD86 and MHCII and more co-inhibitory CD274 molecules in HCC-bearing livers than in control livers. Corresponding to this phenotype, Kupffer cells from HCC-bearing mice were less efficient in their function as antigen-presenting cells. Three CD11b+ cell populations were identified and sorted from HCC-bearing mice. These cells had various phenotypes with different levels of MDSC-specific surface markers (Ly6Ghigh cells, Gr1high cells, and Ly6Clow cells), and may be considered as bonafide MDSCs given their suppression of antigen-specific T cell proliferation. Primary isolated Kupffer cells in co-culture with the three MDSC subsets showed a decrease in CCL2 and IL-18 secretion, and an increase in IL-10 and IL-1ß secretion, and an increased expression of CD86, CD274, and MHCII. In conclusion, these data demonstrated the existence of three MDSC subsets in HCC-bearing animals. These cells altered Kupffer cell function and may decrease the migration and activation of anticancer effector cells in the liver.
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Because of the wide availability of genetically modified animals, mouse orthotopic liver transplantation is often preferred over rat liver transplantation. We present a simplified mouse liver transplantation technique and compare transplantation outcomes with versus without hepatic artery anastomosis. Instruments for liver implantation were designed and printed with a 3-dimensional (3D) printer. The suprahepatic vena cava anastomosis was performed with a 10-0 running suture. The vena porta and infrahepatic vena cava were joined on extraluminal cuffs, using the 3D-printed device for spatial alignment and stabilization. The hepatic artery was reconstructed in half of the recipients using intraluminal stents. Liver function tests (3, 7, and 28 days) and histology (7 and 28 days) were assessed after transplantation. We performed 22 consecutive syngeneic C57BL/6 mouse orthotopic liver transplantations. The median portal clamping time was 12.5 ± 1.5 minutes. The survival rate at 4 weeks was 100% for both arterialized and nonarterialized recipients (n = 7, 4 recipients of each group being killed for early histology at day 7). Liver function tests at 3, 7, and 28 days were similar between arterialized versus nonarterialized groups. Liver parenchyma demonstrated only irrelevant abnormalities in both groups. The proposed device allows for a shorter clamping time compared with the published literature. Using this technique, the artery does not need to be anastomosed, with no impact on graft and recipient outcomes. The device is available for 3D printing. Liver Transplantation 22 1688-1696 2016 AASLD.
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Aloenxertos/irrigação sanguínea , Artéria Hepática/cirurgia , Transplante de Fígado/instrumentação , Transplante de Fígado/métodos , Fígado/irrigação sanguínea , Anastomose Cirúrgica , Animais , Sobrevivência de Enxerto , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Duração da Cirurgia , Veia Porta/cirurgia , Impressão Tridimensional , Taxa de Sobrevida , Veia Cava Inferior/cirurgiaRESUMO
Liposuction is a well-established procedure that is generally safe. However, rare complications can occur. The authors report on a 38-year-old woman who underwent combined abdominoplasty and liposuction at a private clinic. Four hours after the procedure, severe hypovolemic shock developed and required emergency transfer to a tertiary-care center. After primary fluid resuscitation, abdominal ultrasonography and computerized tomography revealed severe right-sided liver trauma, with active bleeding and free intra-abdominal fluid. Two attempts at right hepatic artery embolization failed to fully control the bleeding, and surgical hemostasis was required. After a 2-week hospitalization, the patient was discharged, and she returned to work 3 months later. Although it appears that this is the first reported case of liver trauma during liposuction, this potential complication should be kept in mind and identified early to permit efficient and effective management.
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Abdominoplastia/efeitos adversos , Lipectomia/efeitos adversos , Fígado/lesões , Adulto , Eletrocoagulação , Feminino , Hemorragia/etiologia , Hemorragia/cirurgia , Humanos , Choque/etiologiaRESUMO
Hepatic ischemia/reperfusion (I/R) injury is a common clinical challenge. Despite accumulating evidence regarding its mechanisms and potential therapeutic approaches, hepatic I/R is still a leading cause of organ dysfunction, morbidity, and resource utilization, especially in those patients with underlying parenchymal abnormalities. In the oncological setting, there are growing concerns regarding the deleterious impact of I/R injury on the risk of post-surgical tumor recurrence. This review aims at giving the last updates regarding the role of hepatic I/R and liver parenchymal quality injury in the setting of oncological liver surgery, using a "bench-to-bedside" approach. Relevant medical literature was identified by searching PubMed and hand scanning of the reference lists of articles considered for inclusion. Numerous preclinical models have depicted the impact of I/R injury and hepatic parenchymal quality (steatosis, age) on increased cancer growth in the injured liver. Putative pathophysiological mechanisms linking I/R injury and liver cancer recurrence include an increased implantation of circulating cancer cells in the ischemic liver and the upregulation of proliferation and angiogenic factors following the ischemic insult. Although limited, there is growing clinical evidence that I/R injury and liver quality are associated with the risk of post-surgical cancer recurrence. In conclusion, on top of its harmful early impact on organ function, I/R injury is linked to increased tumor growth. Therapeutic strategies tackling I/R injury could not only improve post-surgical organ function, but also allow a reduction in the risk of cancer recurrence.
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Neoplasias Hepáticas/cirurgia , Fígado/lesões , Fígado/patologia , Recidiva Local de Neoplasia/etiologia , Inoculação de Neoplasia , Traumatismo por Reperfusão/complicações , Animais , Adesão Celular , Movimento Celular , Proliferação de Células , Humanos , Hipóxia/complicações , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/secundário , Recidiva Local de Neoplasia/fisiopatologia , Recidiva Local de Neoplasia/secundário , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica , Traumatismo por Reperfusão/fisiopatologia , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND & AIMS: Liver transplantation from marginal donors is associated with ischemia/reperfusion (I/R) lesions, which may increase the risk of post-transplant hepatocellular carcinoma (HCC) recurrence. Graft reperfusion prior to retrieval (as for extracorporeal membrane oxygenation--ECMO) can prevent I/R lesions. The impact of I/R on the risk of cancer recurrence was assessed on a syngeneic Fischer-rat liver transplantation model. METHODS: HCC cells were injected into the vena porta of all recipients at the end of an orthotopic liver transplantation (OLT). Control donors were standard heart-beating, ischemic ones (ISC), underwent 10 min or 30 min inflow liver clamping prior to retrieval, and ischemic/reperfused (ISC/R) donors underwent 2h liver reperfusion after the clamping. RESULTS: I/R lesions were confirmed in the ISC group, with the presence of endothelial and hepatocyte injury, and increased liver function tests. These lesions were in part reversed by the 2h reperfusion in the ISC/R group. HCC growth was higher in the 10 min and 30 min ISC recipients (p = 0.018 and 0.004 vs. control, as assessed by MRI difference between weeks one and two), and was prevented in the ISC/Rs (p = 0.04 and 0.01 vs. ISC). These observations were associated with a stronger pro-inflammatory cytokine profile in the ISC recipients only, and the expression of hypoxia and HCC growth-enhancer genes, including Hmox1, Hif1a and Serpine1. CONCLUSIONS: This experiment suggests that ischemia/reperfusion lesions lead to an increased risk of post-transplant HCC recurrence and growth. This observation can be reversed by graft reperfusion prior to retrieval.
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Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Fígado/irrigação sanguínea , Recidiva Local de Neoplasia/prevenção & controle , Traumatismo por Reperfusão/complicações , Animais , Carcinoma Hepatocelular/patologia , Heme Oxigenase (Desciclizante)/genética , Interleucina-6/sangue , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Endogâmicos F344 , Reperfusão , Serotonina/sangueRESUMO
Liver transplantation for hepatocellular carcinoma (HCC) results in a specific condition where the immune response is potentially directed against both allogeneic and cancer antigens. We have investigated the level of anti-cancer immunity during allogeneic immune response. Dark Agouti-to-Lewis and Lewis-to-Lewis rat liver transplantations were performed and the recipients anti-cancer immunity was analysed at the time of alloimmune activation. The occurrence of rejection in the allogeneic recipients was confirmed by a shorter survival (p<0.01), increased liver function tests (p<0.01), the presence of signs of rejection on histology, and a donor-specific ex vivo mixed lymphocyte reaction. At the time of alloimmune activation, blood mononuclear cells of the allogeneic group demonstrated increased anti-cancer cytotoxicity (p<0.005), which was related to an increased natural killer (NK) cell frequency (p<0.05) and a higher monocyte/macrophage activation level (p<0.01). Similarly, liver NK cell anti-cancer cytotoxicity (p<0.005), and liver monocyte/macrophage activation levels (p<0.01) were also increased. The alloimmune-associated cytotoxicity was mediated through the NKG2D receptor, whose expression was increased in the rejected graft (p<0.05) and on NK cells and monocyte/macrophages. NKG2D ligands were expressed on rat HCC cells, and its inhibition prevented the alloimmune-associated cytotoxicity. Although waiting for in vivo validation, alloimmune-associated cytotoxicity after rat liver transplantation appears to be linked to increased frequencies and levels of activation of NK cells and monocyte/macrophages, and is at least in part mediated through the NKG2D receptor.