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BACKGROUND: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) is a novel two-stage strategy to induce rapid hypertrophy of the future liver remnant (FLR) when patients are in danger of postoperative liver failure due to insufficient FLR. However, the effects of ALPPS on colorectal liver metastases (CRLM) are not clear so far. The aim of our study was to determine whether ALPPS induces proliferation, apoptosis, or vascularization compared to standard (one-stage) liver resection. METHODS: Six patients who underwent ALPPS were matched with 12 patients undergoing standard liver resection regarding characteristics of the metastases (size, number), time of appearance (syn-/metachronous), preoperative chemotherapy, primary tumor (localization, TNM stage, grading), and patient variables (gender, age). The largest resected metastasis was used for the analyses. Tissue was stained for tumor cell proliferation (Ki67), apoptosis (TUNEL, caspase-3), vascularization (CD31), and pericytes (αSMA). RESULTS: Vascularization (CD31; p = 0.149), proliferation (Mib-1; p = 0.244), and αSMA expression (p = 0.205) did not significantly differ between the two groups, although a trend towards less proliferation and αSMA expression was observed in patients undergoing ALPPS. Concerning apoptosis, caspase-3 staining showed significantly fewer apoptotic cells upon ALPPS (p < 0.0001), but this was not confirmed by TUNEL staining (p = 0.7344). CONCLUSIONS: ALPPS does not induce proliferation, apoptosis, or vascularization of CRLM when compared to standard liver resection.
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Apoptosis , Proliferación Celular , Neoplasias Colorrectales/cirugía , Hepatectomía , Neoplasias Hepáticas/cirugía , Neovascularización Patológica , Vena Porta/cirugía , Anciano , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Hipertrofia , Ligadura , Fallo Hepático/prevención & control , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Vena Porta/patología , PronósticoRESUMEN
Ultra high frequency (UHF) ultrasound enables the visualization of very small structures that cannot be detected by conventional ultrasound. The utilization of UHF imaging as a new imaging technique for the 3D-in-vivo chorioallantoic membrane (CAM) model can facilitate new insights into tissue perfusion and survival. Therefore, human renal cystic tissue was grafted onto the CAM and examined using UHF ultrasound imaging. Due to the unprecedented resolution of UHF ultrasound, it was possible to visualize microvessels, their development, and the formation of anastomoses. This enabled the observation of anastomoses between human and chicken vessels only 12 h after transplantation. These observations were validated by 3D reconstructions from a light sheet microscopy image stack, indocyanine green angiography, and histological analysis. Contrary to the assumption that the nutrient supply of the human cystic tissue and the gas exchange happens through diffusion from CAM vessels, this study shows that the vasculature of the human cystic tissue is directly connected to the blood vessels of the CAM and perfusion is established within a short period. Therefore, this in-vivo model combined with UHF imaging appears to be the ideal platform for studying the effects of intravenously applied therapeutics to inhibit renal cyst growth.
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Membrana Corioalantoides , Riñón Poliquístico Autosómico Dominante , Ultrasonografía , Animales , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/diagnóstico por imagen , Humanos , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Ultrasonografía/métodos , Pollos , Riñón/diagnóstico por imagen , Riñón/irrigación sanguínea , Imagenología Tridimensional/métodosRESUMEN
BACKGROUND: Pneumonia in liver transplant recipients is one of the most common infections in the early phase after transplantation. The diagnosis is based on clinical signs combined with positive microbiological samples taken from the lower respiratory tract. However, the role of bacterial colonization is not clear, nor is its association with pneumonia or its long-term consequences. The aim of this study was to investigate the association between positive microbiological findings and clinically relevant pneumonia and analyze different clinical and laboratory parameters for their association with pneumonia in liver transplant recipients. METHODS: This was a retrospective analysis of 266 adult orthotopic liver transplantations between January 2008 and December 2013. A multidisciplinary in-house specialist panel established and confirmed the diagnosis of clinically relevant pneumonia in microbiologically positive patients. RESULTS: Of the 266 transplantations analyzed, 54 patients (20%) showed microbiologically positive trachea-bronchial cultures during the first 21 days after liver transplantation. Of those 54 patients, 24 (44.4%) had pneumonia as rated by the multidisciplinary specialist panel. Presence of gram-negative Enterobacteriaceae (P = .013) and positive chest radiologic findings (P = .035) were associated with pneumonia in microbiological-positive patients. Although patients with pneumonia had the lowest long-term survival, those without pneumonia but with positive microbiological cultures had still worse survival compared with the Model for End-Stage Liver Disease-matched control group without positive cultures (P = .012). CONCLUSIONS: Gram-negative Enterobacteriaceae and positive radiologic findings were associated with pneumonia in liver transplant recipients with positive microbiological trachea-bronchial cultures. Recipients with bacterial colonization without pneumonia also showed decreased long-term survival.
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Enfermedad Hepática en Estado Terminal , Trasplante de Hígado , Neumonía , Adulto , Enfermedad Hepática en Estado Terminal/complicaciones , Enfermedad Hepática en Estado Terminal/cirugía , Humanos , Trasplante de Hígado/efectos adversos , Neumonía/diagnóstico , Neumonía/etiología , Sistema Respiratorio , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Receptores de TrasplantesRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with adverse outcomes that have barely improved over the last decade. About half of all patients present with metastasis at the time of diagnosis, and the 5-year overall survival rate across all stages is only 6%. Innovative in vivo research models are necessary to combat this cancer and to discover novel treatment strategies. The chorioallantoic membrane (CAM) model represents one 3D in vivo methodology that has been used in a large number of studies on different cancer types for over a century. This model is based on a membrane formed within fertilized chicken eggs that contain a dense network of blood vessels. Because of its high cost-efficiency, simplicity, and versatility, the CAM model appears to be a highly valuable research tool in the pursuit of gaining more in-depth insights into PDAC. A summary of the current literature on the usage of the CAM model for the investigation of PDAC was conducted and subdivided into angiogenesis, drug testing, modifications, personalized medicine, and further developments. On this comprehensive basis, further research should be conducted on PDAC in order to improve the abysmal prognosis of this malignant disease.
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Citrate is important for lipid synthesis and epigenetic regulation in addition to ATP production. We have previously reported that cancer cells import extracellular citrate via the pmCiC transporter to support their metabolism. Here, we show for the first time that citrate is supplied to cancer by cancer-associated stroma (CAS) and also that citrate synthesis and release is one of the latter's major metabolic tasks. Citrate release from CAS is controlled by cancer cells through cross-cellular communication. The availability of citrate from CAS regulated the cytokine profile, metabolism and features of cellular invasion. Moreover, citrate released by CAS is involved in inducing cancer progression especially enhancing invasiveness and organ colonisation. In line with the in vitro observations, we show that depriving cancer cells of citrate using gluconate, a specific inhibitor of pmCiC, significantly reduced the growth and metastatic spread of human pancreatic cancer cells in vivo and muted stromal activation and angiogenesis. We conclude that citrate is supplied to tumour cells by CAS and citrate uptake plays a significant role in cancer metastatic progression.
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Fibroblastos Asociados al Cáncer/metabolismo , Ácido Cítrico/metabolismo , Neoplasias Pancreáticas/metabolismo , Fibroblastos Asociados al Cáncer/fisiología , Línea Celular Tumoral , Epigénesis Genética , Humanos , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Neoplasias Pancreáticas/patología , Células del Estroma/metabolismo , Microambiente Tumoral/fisiología , Neoplasias PancreáticasRESUMEN
BACKGROUND: Incisional surgical site infections (iSSI) in hepatopancreatobiliary (HPB) surgery usually lead to prolonged hospital stays, consume valuable resources, and impact on patients' outcome. Prophylactic closed incision negative pressure wound therapy (ciNPWT) to decrease wound complications has become available. Owing to an increasing number of studies, evidence for superiority in many indication areas has accumulated; however, in general surgery, there are a few data and those have shown contradictory results. METHODS: In this monocentric, prospective, randomized, controlled, two-armed study, the influence of ciNPWT on incisional surgical site infection rates after HPB operations will be investigated. A total of 222 patients will be randomized 1:1 to an interventional group (7-day treatment with ciNPWT) or a control group (treated with gauze dressing). The primary parameter to evaluate efficacy is the rate of incisional SSIs within 30 days after surgery. Additionally, several clinically relevant secondary outcomes will be assessed. DISCUSSION: A reduction in the rate of incisional SSIs would not only lead to a significant cost reduction and shorter postoperative length of stay, but may also improve postoperative quality of life for patients. While earlier publications have shown advantages for ciNPWT, recent studies did not confirm a positive effect regarding iSSI rate. Even if iSSI rate is not reduced, findings obtained from the secondary endpoints may be of clinical relevance, such as reduction of wound complication rates. TRIAL REGISTRATION: This trial has been registered in the German Clinical Trials Register, DRKS 00015136 . Registered on 19 February 2019 and has been approved by the local ethics committee of the University of Regensburg: 18-1225-101.
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Terapia de Presión Negativa para Heridas , Infección de la Herida Quirúrgica , Humanos , Terapia de Presión Negativa para Heridas/efectos adversos , Estudios Prospectivos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Infección de la Herida Quirúrgica/diagnóstico , Infección de la Herida Quirúrgica/prevención & control , Cicatrización de HeridasRESUMEN
In 1988, Rudolf Pichlmayr pioneered split liver transplantation (SLT), enabling the transplantation of one donor liver into two recipients - one pediatric and one adult patient. In the same year, Henri Bismuth and colleagues performed the first full right/full left split procedure with two adult recipients. Both splitting techniques were rapidly adopted within the transplant community. However, a SLT is technically demanding, may cause increased perioperative complications, and may potentially transform an excellent deceased donor organ into two marginal quality grafts. Thus, crucial evaluation of donor organs suitable for splitting and careful screening of potential SLT recipients is warranted. Furthermore, the logistic background of the splitting procedure as well as the organ allocation policy must be adapted to further increase the number and the safety of SLT. Under defined circumstances, in selected patients and at experienced transplant centers, SLT outcomes can be similar to those obtained in full organ LT. Thus, SLT is an important tool to reduce the donor organ shortage and waitlist mortality, especially for pediatric patients and small adults. The present review gives an overview of technical aspects, current developments, and clinical outcomes of SLT.
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Enfermedad Hepática en Estado Terminal/cirugía , Hepatectomía/métodos , Trasplante de Hígado/métodos , Selección de Paciente , Adulto , Aloinjertos/anatomía & histología , Aloinjertos/normas , Aloinjertos/cirugía , Niño , Selección de Donante/métodos , Selección de Donante/normas , Selección de Donante/tendencias , Enfermedad Hepática en Estado Terminal/mortalidad , Supervivencia de Injerto , Hepatectomía/tendencias , Humanos , Hígado/anatomía & histología , Hígado/cirugía , Trasplante de Hígado/normas , Trasplante de Hígado/tendencias , Tamaño de los Órganos , Asignación de Recursos/normas , Donantes de Tejidos , Resultado del Tratamiento , Listas de Espera/mortalidadRESUMEN
Mammalian target of rapamycin complex 2 (mTORC2) with its pivotal component rapamycin-insensitive companion of mTOR (RICTOR) is the major regulator of AKT phosphorylation and is increasingly implicated in tumor growth and progression. In cutaneous melanoma, an extremely aggressive and highly metastatic disease, RICTOR overexpression is involved in tumor development and invasiveness. Therefore, we investigated the impact of RICTOR inhibition in melanoma cells in vitro and in vivo with special emphasis on hepatic metastasis. Moreover, our study focused on the interaction of tumor cells and hepatic stellate cells (HSC) which play a crucial role in the hepatic microenvironment. In silico analysis revealed increased RICTOR expression in melanoma cells and tissues and indicated higher expression in advanced melanoma stages and metastases. In vitro, transient RICTOR knock-down via siRNA caused a significant reduction of tumor cell motility. Using a syngeneic murine splenic injection model, a significant decrease in liver metastasis burden was detected in vivo. Moreover, stimulation of melanoma cells with conditioned medium (CM) from activated HSC or hepatocyte growth factor (HGF) led to a significant induction of AKT phosphorylation and tumor cell motility. Blocking of RICTOR expression in cancer cells diminished constitutive and HGF-induced AKT phosphorylation as well as cell motility. Interestingly, RICTOR blockade also led to an abrogation of CM-induced effects on AKT phosphorylation and motility in melanoma cells. In conclusion, these results provide first evidence for a critical role of mTORC2/RICTOR in melanoma liver metastasis via cancer cell/HSC interactions.
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Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Melanoma/genética , Melanoma/patología , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Animales , Línea Celular Tumoral , Movimiento Celular , Modelos Animales de Enfermedad , Expresión Génica , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma Experimental , Ratones , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteína Asociada al mTOR Insensible a la Rapamicina/metabolismo , Transducción de Señal , Carga TumoralRESUMEN
Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo. Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro. Moreover, RICTOR inhibition led to impaired phosphorylation/activity of AGC kinases (AKT, SGK1). Interestingly, hypoxia-induced expression of hypoxia-induced factor-1α (HIF-1α) was diminished and secretion of vascular-endothelial growth factor-A (VEGF-A) was impaired upon targeting RICTOR. Stable RICTOR knock-down led to significant inhibition of tumor growth in subcutaneous and orthotopic tumor models which was accompanied by significant reduction of tumor cell proliferation. Finally, immunohistochemical analyses of 85 human PDAC samples revealed significantly poorer survival in patients with higher RICTOR expression. In conclusion, these findings provide first evidence for mTORC2/RICTOR as an attractive novel target for treatment of human PDAC.
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Neoplasias Pancreáticas/genética , Proteína Asociada al mTOR Insensible a la Rapamicina/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Transducción de Señal , TransfecciónRESUMEN
Subcutaneous tumor models are widely used in angiogenesis research. Due to the relative simplicity, these mouse models are ideal for the evaluation of molecular hypotheses. In addition, these models are frequently used to assess anti-angiogenic efficacy during drug development. Finally, subcutaneous models can be performed with either xenogeneic or syngeneic tumors, both harboring advantages and drawbacks. Herein, we describe the use of subcutaneous xenograft models in anticancer research.