RESUMEN
OBJECTIVE: To compare the perioperative outcomes of robotic liver surgery (RLS) and laparoscopic liver surgery (LLS) in various settings. BACKGROUND: Clear advantages of RLS over LLS have rarely been demonstrated, and the associated costs of robotic surgery are generally higher than those of laparoscopic surgery. Therefore, the exact role of the robotic approach in minimally invasive liver surgery remains to be defined. METHODS: In this international retrospective cohort study, the outcomes of patients who underwent RLS and LLS for all indications between 2009 and 2021 in 34 hepatobiliary referral centers were compared. Subgroup analyses were performed to compare both approaches across several types of procedures: (1) minor resections in the anterolateral (2, 3, 4b, 5, and 6) or (2) posterosuperior segments (1, 4a, 7, 8), and (3) major resections (≥3 contiguous segments). Propensity score matching was used to mitigate the influence of selection bias. The primary outcome was textbook outcome in liver surgery (TOLS), previously defined as the absence of intraoperative incidents ≥grade 2, postoperative bile leak ≥grade B, severe morbidity, readmission, and 90-day or in-hospital mortality with the presence of an R0 resection margin in case of malignancy. The absence of a prolonged length of stay was added to define TOLS+. RESULTS: Among the 10.075 included patients, 1.507 underwent RLS and 8.568 LLS. After propensity score matching, both groups constituted 1.505 patients. RLS was associated with higher rates of TOLS (78.3% vs 71.8%, P < 0.001) and TOLS+ (55% vs 50.4%, P = 0.026), less Pringle usage (39.1% vs 47.1%, P < 0.001), blood loss (100 vs 200 milliliters, P < 0.001), transfusions (4.9% vs 7.9%, P = 0.003), conversions (2.7% vs 8.8%, P < 0.001), overall morbidity (19.3% vs 25.7%, P < 0.001), and microscopically irradical resection margins (10.1% vs. 13.8%, P = 0.015), and shorter operative times (190 vs 210 minutes, P = 0.015). In the subgroups, RLS tended to have higher TOLS rates, compared with LLS, for minor resections in the posterosuperior segments (n = 431 per group, 75.9% vs 71.2%, P = 0.184) and major resections (n = 321 per group, 72.9% vs 67.5%, P = 0.086), although these differences did not reach statistical significance. CONCLUSIONS: While both produce excellent outcomes, RLS might facilitate slightly higher TOLS rates than LLS.
Asunto(s)
Hepatectomía , Laparoscopía , Puntaje de Propensión , Procedimientos Quirúrgicos Robotizados , Humanos , Hepatectomía/métodos , Femenino , Masculino , Laparoscopía/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Complicaciones Posoperatorias/epidemiología , Resultado del Tratamiento , Hepatopatías/cirugíaRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is known to have a heterogeneous desmoplastic tumour microenvironment (TME) with a large number of immunosuppressive cells. Recently, high B-cell infiltration in PDAC has received growing interest as a potential therapeutic target. METHODS: Our literature review summarises the characteristics of tumour-associated tertiary lymphoid structures (TLSs) and highlight the key studies exploring the clinical outcomes of TLSs in PDAC patients and the direct effect on the TME. RESULTS: The location, density and maturity stages of TLSs within tumours play a key role in determining the prognosis and is a new emerging target in cancer immunotherapy. DISCUSSION: TLS development is imperative to improve the prognosis of PDAC patients. In the future, studying the genetics and immune characteristics of tumour infiltrating B cells and TLSs may lead towards enhancing adaptive immunity in PDAC and designing personalised therapies.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Estructuras Linfoides Terciarias , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patología , Estructuras Linfoides Terciarias/inmunología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Pronóstico , Linfocitos Infiltrantes de Tumor/inmunología , Resultado del Tratamiento , Inmunoterapia/métodosRESUMEN
BACKGROUND: Solid benign liver lesions (BLL) are increasingly discovered, but clear indications for surgical treatment are often lacking. Concomitantly, laparoscopic liver surgery is increasingly performed. The aim of this study was to assess if the availability of laparoscopic surgery has had an impact on the characteristics and perioperative outcomes of patients with BLL. METHODS: This is a retrospective international multicenter cohort study, including patients undergoing a laparoscopic or open liver resection for BLL from 19 centers in eight countries. Patients were divided according to the time period in which they underwent surgery (2008-2013, 2014-2016, and 2017-2019). Unadjusted and risk-adjusted (using logistic regression) time-trend analyses were performed. The primary outcome was textbook outcome (TOLS), defined as the absence of intraoperative incidents ≥ grade 2, bile leak ≥ grade B, severe complications, readmission and 90-day or in-hospital mortality, with the absence of a prolonged length of stay added to define TOLS+. RESULTS: In the complete dataset comprised of patients that underwent liver surgery for all indications, the proportion of patients undergoing liver surgery for benign disease remained stable (12.6% in the first time period, 11.9% in the second time period and 12.1% in the last time period, p = 0.454). Overall, 845 patients undergoing a liver resection for BLL in the first (n = 374), second (n = 258) or third time period (n = 213) were included. The rates of ASA-scores≥3 (9.9%-16%,p < 0.001), laparoscopic surgery (57.8%-77%,p < 0.001), and Pringle maneuver use (33.2%-47.2%,p = 0.001) increased, whereas the length of stay decreased (5 to 4 days,p < 0.001). There were no significant changes in the TOLS rate (86.6%-81.3%,p = 0.151), while the TOLS + rate increased from 41.7% to 58.7% (p < 0.001). The latter result was confirmed in the risk-adjusted analyses (aOR 1.849,p = 0.004). CONCLUSION: The surgical treatment of BLL has evolved with an increased implementation of the laparoscopic approach and a decreased length of stay. This evolution was paralleled by stable TOLS rates above 80% and an increase in the TOLS + rate.
Asunto(s)
Enfermedades del Sistema Digestivo , Laparoscopía , Neoplasias Hepáticas , Humanos , Estudios Retrospectivos , Estudios de Cohortes , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Tiempo de Internación , Laparoscopía/efectos adversos , Hepatectomía/efectos adversos , Enfermedades del Sistema Digestivo/cirugía , Neoplasias Hepáticas/cirugía , Resultado del TratamientoRESUMEN
INTRODUCTION: CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic ('COVID' cohort, 16/03/2020-10/05/2020), with 12-month follow-up. RESULTS: Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, p = 0.004) or received palliative anti-cancer therapy (20.5% vs. 26.5%, p = 0.045). Ultimately, fewer patients in the COVID cohort underwent surgical resection (6.4% vs. 9.3%, p = 0.036), whilst more patients received no anti-cancer treatment (69.3% vs. 59.2% p = 0.009). Despite these differences, there was no difference in median overall survival between the COVID and pre-COVID cohorts, (3.5 (IQR 2.8-4.1) vs. 4.4 (IQR 3.6-5.2) months, p = 0.093). CONCLUSION: Pathways for patients with PDAC were significantly disrupted during the first wave of the COVID-19 pandemic, with fewer patients receiving standard treatments. However, no significant impact on survival was discerned.
Asunto(s)
COVID-19 , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Pandemias , COVID-19/epidemiología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/tratamiento farmacológico , Estudios de Cohortes , Reino Unido/epidemiología , Estudios RetrospectivosRESUMEN
The human liver is regarded as a lymphoid organ that contributes to both local and systemic immune response. Intrahepatic immune cells including regulatory T cells (Tregs) reside in the hepatic microenvironment which is enriched with proinflammatory cytokines, chemokines and metabolites. In addition, the hepatic microenvironment has the unique ability to establish and maintain immune tolerance despite the continuous influx of the gut derived microbial products via the portal vein. Regulatory T cells play a crucial role in maintaining the hepatic tolerogenic state; however, the phenotypic stability, function and survival of Tregs in the inflamed liver microenvironment is still poorly understood. Despite this, Tregs immunotherapy remains as an appealing therapeutic option in autoimmune and immune mediated liver diseases. In order to advance cell therapy, it is important for us to further our understanding of the hepatic microenvironment, with the aim of developing ways to modify the hostile, inflamed environment to one which is more favourable. By doing so, T cell stability and function would be enhanced, resulting in improved clinical outcomes.
Asunto(s)
Hígado/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/fisiología , Humanos , Tolerancia Inmunológica/inmunología , Inmunoterapia/métodos , Hígado/patología , Hígado/fisiología , Hepatopatías/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Blood group O or B recipients wait longer for a kidney transplant. We studied the distribution of anti-ABO blood group antibody titres in patients awaiting a kidney transplant, and modelled the effect of altering the UK National Kidney Allocation Scheme to allow for patients with 'LOW' titres (≤1:8, ≤3 dilutions) to receive a deceased donor ABOi (ddABOi) transplant. In a prospective study of 239 adult patients on the waiting list for a transplant in 2 UK centres, ABO-antibody titres (anti-A and anti-B) were measured. Based on the proportions of 'LOW' anti-A or anti-B antibodies, four simulations were performed to model the current allocation rules compared with variations allowing ddABOi allocation under various conditions of blood group, HLA matching, and waiting time. The simulations permitting ddABOi resulted in more blood group B recipients being transplanted, with median waiting time reduced for this group of recipients, and more equitable waiting times across blood groups. Additionally, permitting ddABOi resulted in greater numbers of 000MM allocations overall in compatible transplants under modelled conditions. Changing allocation in the UK to permit ddABOi in patients with 'LOW' titres would not change the total number of transplants, but redistributes allocation more equitably amongst blood groups, altering waiting times accordingly.
Asunto(s)
Sistema del Grupo Sanguíneo ABO , Trasplante de Riñón , Donantes de Tejidos , Listas de Espera , Sistema del Grupo Sanguíneo ABO/inmunología , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Obtención de Tejidos y ÓrganosAsunto(s)
Carcinoma Hepatocelular , Laparoscopía , Neoplasias Hepáticas , Humanos , Anciano , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Puntaje de Propensión , Hepatectomía , Estudios Retrospectivos , Complicaciones Posoperatorias/cirugía , Tiempo de InternaciónRESUMEN
PURPOSE: To determine the heritability of spine curve using plain radiographs and to identify risk factors for spine curvature including age, body mass index, smoking, bone mineral density (BMD), and lumbar disc degeneration (LDD). METHODS: A classical twin study of 110 MZ and 136 DZ adult female twins. Demographic and clinical information obtained from long spine radiographs, lumbar spine degeneration on spine MR scan, and BMD assessed by DEXA at hip and lumbar spine were included in multiple logistic regression models to determine risk factors for spine curvature. RESULTS: Heritability estimates ranged between 41 (19-59) % for pelvic incidence to 61 (46-72) % for thoracic kyphosis; with lumbar lordosis and cervical lordosis having 59 (42-71) % and 43 (23-59) % heritability, respectively. For each spine curve, the model showing the best fit contained additive genetic and shared environmental components with no contribution from the unique environment. Significant risk factors for increased thoracic kyphosis were lumbar spine BMD, age, and cervical lordosis; for pelvic incidence were lumbar spine BMD and lumbar lordosis; for lumbar lordosis were cervical lordosis, pelvic incidence and LDD; and age alone predicted cervical lordosis (p = 0.001). CONCLUSION: In this sample of middle-aged and elderly women, there were significant genetic influences on all spine curves but particularly thoracic kyphosis and lumbar lordosis. The strongest predictor for lumbar lordosis was LDD (p < 0.0001) which is itself genetically determined in part. For thoracic kyphosis, BMD was strongly associated and remained so (for lumbar BMD) with the inclusion of age, showing BMD to be an independent risk factor. This work highlights the genetic factors influencing normal spine curvature in women.
Asunto(s)
Densidad Ósea/genética , Enfermedades en Gemelos , Degeneración del Disco Intervertebral , Curvaturas de la Columna Vertebral , Adulto , Enfermedades en Gemelos/epidemiología , Enfermedades en Gemelos/genética , Femenino , Humanos , Degeneración del Disco Intervertebral/epidemiología , Degeneración del Disco Intervertebral/genética , Factores de Riesgo , Curvaturas de la Columna Vertebral/epidemiología , Curvaturas de la Columna Vertebral/genéticaRESUMEN
BACKGROUND: Mortality after severe complications after hepatectomy (failure to rescue) is strongly linked to center volume. The aim of this study was to evaluate the risk factors for failure to rescue after hepatectomy in a high-volume center. METHODS: Retrospective study of 1,826 consecutive patients who underwent hepatectomy from 2011 to 2018. The primary outcome was a 90-day failure to rescue, defined as death within 90 days posthepatectomy after a severe (Clavien-Dindo grade 3+) complication. Risk factors for 90-day failure to rescue were evaluated using a multivariable binary logistic regression model. RESULTS: The cohort had a median age of 65.3 years, and 56.6% of patients were male. The commonest indication for hepatectomy was colorectal metastasis (58.9%), and 46.9% of patients underwent major or extra-major hepatectomy. Severe complications developed in 209 patients (11.4%), for whom the 30- and 90-day failure to rescue rates were 17.0% and 35.4%, respectively. On multivariable analysis, increasing age (P = .006) and modified Frailty Index (P = .044), complication type (medical or combined medical/surgical versus surgical; P < .001), and body mass index (P = .018) were found to be significant independent predictors of 90-day failure to rescue. CONCLUSION: Older and frail patients who experience medical complications are particularly at risk of failure to rescue after hepatectomy. These results may inform preoperative counseling and may help to identify candidates for prehabilitation. Further study is needed to assess whether failure to rescue rates could be reduced by perioperative interventions.
Asunto(s)
Hepatectomía , Complicaciones Posoperatorias , Humanos , Masculino , Anciano , Femenino , Hepatectomía/efectos adversos , Estudios Retrospectivos , Centros de Atención Terciaria , Factores de Riesgo , Reino Unido/epidemiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
The presence of CD8+ T cells in the cytoplasm of biliary epithelial cells (BEC) has been correlated with biliary damage associated with primary biliary cholangitis (PBC). Here, we characterise the mechanism of CD8+ T cell invasion into BEC. CD8+ T cells observed within BEC were large, eccentric, and expressed E-cadherin, CD103 and CD69. They were also not contained within secondary vesicles. Internalisation required cytoskeletal rearrangements which facilitated contact with BEC. Internalised CD8+ T cells were observed in both non-cirrhotic and cirrhotic diseased liver tissues but enriched in PBC patients, both during active disease and at the time of transplantation. E-cadherin expression by CD8+ T cells correlated with frequency of internalisation of these cells into BEC. E-cadherin+ CD8+ T cells formed ß-catenin-associated interactions with BEC, were larger than E-cadherin- CD8+ T cells and invaded into BEC more frequently. Overall, we unveil a distinct cell-in-cell structure process in the liver detailing the invasion of E-cadherin+ CD103+ CD69+ CD8+ T cells into BEC.
Asunto(s)
Conductos Biliares , Cirrosis Hepática Biliar , Humanos , Conductos Biliares/metabolismo , Cirrosis Hepática Biliar/patología , Linfocitos T CD8-positivos/metabolismo , Células Epiteliales/metabolismo , Cadherinas/metabolismoRESUMEN
INTRODUCTION: Patients with liver disease and portal hypertension frequently require surgery carrying high morbidity and mortality. Accurately estimating surgical risk remains challenging despite improved medical and surgical management. AREAS COVERED: This review aims to outline a comprehensive approach to preoperative assessment, appraise methods used to predict surgical risk, and provide an up-to-date overview of outcomes for patients with cirrhosis undergoing non-hepatic surgery. EXPERT OPINION: Robust preoperative, individually tailored, and precise risk assessment can reduce peri- and postoperative complications in patients with cirrhosis. Established prognostic scores aid stratification, providing an estimation of postoperative mortality, albeit with limitations. VOCAL-Penn Risk Score may provide greater precision than established liver severity scores. Amelioration of portal hypertension in advance of surgery may be considered, with prospective data demonstrating hepatic venous pressure gradient as a promising surrogate marker of postoperative outcomes. Morbidity and mortality vary between types of surgery with further studies required in patients with more advanced liver disease. Patient-specific considerations and practicing precision medicine may allow for improved postoperative outcomes.
Asunto(s)
Hipertensión Portal , Medicina de Precisión , Humanos , Estudios Prospectivos , Cirrosis Hepática/cirugía , Fibrosis , Hipertensión Portal/etiología , Hipertensión Portal/cirugíaRESUMEN
The seventh leading cause of cancer-related death globally, pancreatic ductal adenocarcinoma (PDAC) involves the exocrine pancreas and constitutes greater than 90% of all pancreatic cancers. Surgical resection in combination with systemic chemotherapy with or without radiation remains the mainstay of treatment and the only potentially curative treatment option. While there has been improvement in systemic chemotherapy, long-term survival among patients with PDAC remains poor. Improvement in the understanding of tumorigenesis, genetic mutations, the tumor microenvironment (TME), immunotherapies, as well as targeted therapies continued to drive advances in PDAC treatment. We herein review the TME, genetic landscape, as well as various metabolic pathways associated with PDAC tumorigenesis relative to emerging therapies.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinogénesis , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/terapia , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
BACKGROUND: Despite the worldwide increase of both obesity and the use of minimally invasive liver surgery (MILS), evidence regarding the safety and eventual benefits of MILS in obese patients is scarce. The aim of this study was therefore to compare the outcomes of non-obese and obese patients (BMI 18.5-29.9 and BMI≥30, respectively) undergoing MILS and OLS, and to assess trends in MILS use among obese patients. METHODS: In this retrospective cohort study, patients operated at 20 hospitals in eight countries (2009-2019) were included and the characteristics and outcomes of non-obese and obese patients were compared. Thereafter, the outcomes of MILS and OLS were compared in both groups after propensity-score matching (PSM). Changes in the adoption of MILS during the study period were investigated. RESULTS: Overall, 9963 patients were included (MILS: n = 4687; OLS: n = 5276). Compared to non-obese patients (n = 7986), obese patients(n = 1977) were more often comorbid, less often received preoperative chemotherapy or had a history of previous hepatectomy, had longer operation durations and more intraoperative blood loss (IOBL), paralleling significantly higher rates of wound- and respiratory-related complications. After PSM, MILS, compared to OLS, was associated, among both non-obese and obese patients, with less IOBL (200 ml vs 320 ml, 200 ml vs 400 ml, respectively), lower rates of transfusions (6.6% vs 12.8%, 4.7% vs 14.7%), complications (26.1% vs 35%, 24.9% vs 34%), bile leaks(4% vs 7%, 1.8% vs 4.9%), liver failure (0.7% vs 2.3%, 0.2% vs 2.1%), and a shorter length of stay(5 vs 7 and 4 vs 7 days). A cautious implementation of MILS over time in obese patients (42.1%-53%, p < .001) was paralleled by stable severe morbidity (p = .433) and mortality (p = .423) rates, despite an accompanying gradual increase in surgical complexity. CONCLUSIONS: MILS is increasingly adopted and associated with perioperative benefits in both non-obese and obese patients.
Asunto(s)
Laparoscopía , Neoplasias Hepáticas , Humanos , Puntaje de Propensión , Estudios Retrospectivos , Laparoscopía/efectos adversos , Neoplasias Hepáticas/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Hepatectomía/efectos adversos , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Estudios de Cohortes , Pérdida de Sangre Quirúrgica , Obesidad/complicaciones , Obesidad/cirugía , Tiempo de InternaciónRESUMEN
(1) Background: colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Its first main metastatic diffusion spreads to the liver. Different mechanisms such as the epithelial-mesenchymal transition and angiogenesis are the characteristics of this invasion. At this stage, different options are possible and still in debate, especially regarding the use of targeted therapeutics and biotherapies. (2) Methods: A review of the literature has been done focusing on the clinical management of liver metastasis of colorectal cancer and the contribution of biotherapies in this field. (3) Results: In a clinical setting, surgeons and oncologists consider liver metastasis in CRC into two groups to launch adapted therapeutics: resectable and non-resectable. Around these two entities, the combination of targeted therapies and biotherapies are of high interest and are currently tested to know in which molecular and clinical conditions they have to be applied to impact positively both on survival and quality of life of patients.
RESUMEN
Pancreatic ductal adenocarcinomas (PDAC) represent one of the deadliest cancers worldwide. Survival is still low due to diagnosis at an advanced stage and resistance to treatment. Herein, we review the main types of liquid biopsy able to help in both prognosis and adaptation of treatments.
RESUMEN
The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies.
Asunto(s)
Colangitis Esclerosante/etiología , Mucosa Intestinal/inmunología , Hígado/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ácidos y Sales Biliares/fisiología , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/inmunología , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/fisiología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Enfermedades Inflamatorias del Intestino/etiología , Cirrosis Hepática Biliar/etiología , Receptores Citoplasmáticos y Nucleares/fisiología , Linfocitos T Reguladores/inmunología , Vancomicina/farmacologíaRESUMEN
Background: Ex situ donor liver machine perfusion is a promising tool to assess organ viability prior to transplantation and platform to investigate novel therapeutic interventions. However, the wide variability in donor and graft characteristics between individual donor livers limits the comparability of results. We investigated the hypothesis that the development of a split liver ex situ machine perfusion protocol provides the ideal comparative controls in the investigation of machine perfusion techniques and therapeutic interventions, thus leading to more comparable results. Methods: Four discarded human donor livers were surgically split following identification and separation of right and left inflow and outflow vessels. Each lobe, on separate perfusion machines, was subjected to normothermic perfusion using an artificial hemoglobin-based oxygen carrier solution for 6 h. Metabolic parameters as well as hepatic artery and portal vein perfusion parameters monitored. Results: Trends in hepatic artery and portal vein flows showed a general increase in both lobes throughout each perfusion experiment, even when normalized for tissue weight. Progressive decreases in perfusate lactate and glucose levels exhibited comparable trends in between lobes. Conclusion: Our results demonstrate comparability between right and left lobes when simultaneously subjected to normothermic machine perfusion. In the pre-clinical setting, this model provides the ideal comparative controls in the investigation of therapeutic interventions.
RESUMEN
Liver transplantation is the only recognized effective treatment for end-stage liver disease. However, organ shortages have become the main challenge for patients and physicians within the transplant community. Waiting list mortality remains an issue with around 10% of patients dying whilst waiting for an available organ. The post-transplantation period is also associated with an adverse complication rate for these specific cohorts of high-risk patients, particularly regarding patient and graft survival. Ischaemia reperfusion injury (IRI) has been highlighted as the mechanism of injury that increases parenchymal damage, which eventually lead to significant graft dysfunction and other poor outcome indicators. The consequences of IRI in clinical practice such as reperfusion syndrome, primary non-function of graft, allograft dysfunction, ischaemic biliary damage and early biliary complications can be life-threatening. IRI dictates the development of a significant inflammatory response that drives the pathway to eventual cell death. The main mechanisms of IRI are mitochondrial damage due to low oxygen tension within the hepatic micro-environment and severe adenosine triphosphate (ATP) depletion during the ischaemic period. After the restoration of normal blood flow, this damage is further enhanced by reoxygenation as the mitochondria respond to reperfusion by releasing reactive oxygen species (ROS), which in turn activate Kupffer cells within the hepatic micro-environment, leading to a pro-inflammatory response and eventual parenchymal cell apoptosis and associated tissue degradation. Machine perfusion (MP) is one emergent strategy considered to be one of the most important advances in organ preservation, restoration and transplantation. Indeed, MP has the potential to rescue frequently discarded organs and has been shown to limit the extent of IRI, leading to suppression of the deleterious pro-inflammatory response. This immunomodulation reduces the prevalence of allograft rejection, the use of immunosuppression therapy and minimizes post-transplant complications. This review aims to update the current knowledge of MP with a focus on normothermic machine liver perfusion (NMLP) and its potential role in immune response pathways.
Asunto(s)
Preservación de Órganos , Animales , Humanos , Sistema Inmunológico , PerfusiónRESUMEN
The liver is an important contributor to the human immune system and it plays a pivotal role in the creation of both immunoreactive and tolerogenic conditions. Liver transplantation provides the best chance of survival for both children and adults with liver failure or cancer. With current demand exceeding the number of transplantable livers from donors following brain death, improved knowledge, technical advances and the desire to prevent avoidable deaths has led to the transplantation of organs from living, ABO incompatible (ABOi), cardiac death donors and machine based organ preservation with acceptable results. The liver graft is the most well-tolerated, from an immunological perspective, of all solid organ transplants. Evidence suggests successful cessation of immunosuppression is possible in ~20-40% of liver transplant recipients without immune mediated graft injury, a state known as "operational tolerance." An immunosuppression free future following liver transplantation is an ambitious but perhaps not unachievable goal. The initial immune response following transplantation is a sterile inflammatory process mediated by the innate system and the mechanisms relate to the preservation-reperfusion process. The severity of this injury is influenced by graft factors and can have significant consequences. There are minimal experimental studies that delineate the differences in the adaptive immune response to the various forms of liver allograft. Apart from ABOi transplants, antibody mediated hyperacute rejection is rare following liver transplant. T-cell mediated rejection is common following liver transplantation and its incidence does not differ between living or deceased donor grafts. Transplantation in the first year of life results in a higher rate of operational tolerance, possibly due to a bias toward Th2 cytokines (IL4, IL10) during this period. This review further describes the current understanding of the immunological response toward liver allografts and highlight the areas of this topic yet to be fully understood.