RESUMO
PURPOSE: To assess the safety and effectiveness of transarterial radioembolization (TARE) in the treatment of hepatic metastases from pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: A systematic search of the Embase and MEDLINE databases was conducted using keywords and Medical Subject Headings terms related to TARE and hepatic metastases from PDAC. Observational studies and clinical trials reporting overall survival (OS), hepatic progression-free survival (hPFS), or tumor response after TARE were included. RESULTS: Eight studies, comprising 145 patients with metastatic PDAC, met the inclusion criteria. No randomized controlled trials were identified, and 4 studies were prospective. Forty-four (30.3%) patients underwent previous pancreatic resection, and 66 (45.5%) had extrahepatic metastases at the time of TARE. Most studies (n = 6) used resin microspheres for TARE. The pooled disease control rate was 69.4% at a median of 3 months. The median OS from the time of TARE ranged from 3.7 to 9 months. The median hPFS ranged from 2.4 to 5.2 months. There were 31 Grade 3-4 biochemical toxicities and 4 treatment-related deaths. CONCLUSIONS: The role of TARE in patients with hepatic metastases from PDAC remains unclear owing to low patient numbers, limited prospective data, and heterogeneity in the study design. Further prospective studies are required to evaluate the role of TARE in carefully selected patients with liver-only metastatic disease.
Assuntos
Adenocarcinoma , Carcinoma Hepatocelular , Carcinoma Ductal Pancreático , Embolização Terapêutica , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Radioisótopos de Ítrio/efeitos adversos , Adenocarcinoma/terapia , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/patologia , Embolização Terapêutica/efeitos adversos , Carcinoma Hepatocelular/terapia , Estudos Retrospectivos , Neoplasias PancreáticasRESUMO
Steatotic livers are susceptible to cold ischemia, which is thought to be secondary to mitochondrial dysfunction. Ischemic preconditioning (IPC) has been reported to improve liver function in the setting of warm ischemia/reperfusion injury, but the effect of IPC on steatotic liver mitochondrial function (MF) with cold ischemia has not been previously evaluated. We aimed to evaluate MF with various severities of hepatic steatosis after various durations of cold ischemia storage with or without IPC. Male Sprague-Dawley rats were fed a normal diet or a high-fat/high-sucrose diet for 1, 2, or 4 weeks to induce mild (<30%), moderate (30%-60%), or severe (>60%) macrovesicular steatosis, respectively. Liver MF was tested with high-resolution respirometry after 1.5, 4, 8, 12, 18, and 24 hours of cold ischemia. Rats in each group (n = 10) underwent 10 minutes of IPC or no IPC before cold ischemia. The baseline (time 0) respiration was similar for lean and severely steatotic livers despite decreased mitochondrial complex I (C-I) activity in severely steatotic livers. Hepatic steatosis was associated with increased C-I-mediated leaks and decreased respiratory control ratios (RCRs) after cold ischemia. Mildly, moderately, and severely steatotic livers showed significantly lower RCRs after 8, 1.5, and 1.5 hours of cold ischemia, respectively, in comparison with lean livers. IPC restored RCRs in mildly steatotic livers to levels comparable to those in lean livers for up to 24 hours of cold ischemia via the attenuation of C-I-mediated leaks, but it had no beneficial effect on moderately and severely steatotic livers. In conclusion, steatotic livers exhibited apparent mitochondrial dysfunction through an alteration in C-I activity, and this made them more susceptible to prolonged cold ischemia. The clinically based IPC protocol used here restored MF in cases of mild hepatic steatosis by attenuating C-I-mediated leaks after prolonged cold ischemia, but it did work not in livers with moderate or severe steatosis.
Assuntos
Isquemia Fria/efeitos adversos , Complexo I de Transporte de Elétrons/metabolismo , Fígado/enzimologia , Mitocôndrias Hepáticas/enzimologia , Hepatopatia Gordurosa não Alcoólica/complicações , Traumatismo por Reperfusão/etiologia , Animais , Modelos Animais de Doenças , Precondicionamento Isquêmico/métodos , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/enzimologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/prevenção & controle , Fatores de Risco , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Steatotic livers are vulnerable to the deleterious effects of ischaemia-reperfusion injury (IRI) that occur after hepatic surgery. Ischaemic preconditioning (IPC) has been shown to abrogate the effects of IRI in patients undergoing hepatic surgery. Experimental studies have suggested that IPC may be beneficial in steatotic livers subjected to IRI. OBJECTIVE: The aim of this systematic review was to evaluate the effects of IPC on steatotic livers following hepatic IRI in experimental models. METHODS: An electronic search of the OVID Medline and EMBASE databases was performed to identify studies that reported clinically relevant outcomes in animal models of hepatic steatosis subjected to IPC and IRI. RESULTS: A total of 1093 articles were identified, of which 18 met the inclusion criteria. There was considerable heterogeneity in the type of animal model, and duration and type of IRI. Increased macrovesicular steatosis (> 30%) was associated with a poor outcome following IRI. Ischaemic preconditioning was found to be beneficial in > 30% steatotic livers and provided for decreased histological damage, improved liver function findings and increased survival. CONCLUSIONS: Experimental evidence supports the use of IPC in steatotic livers undergoing IRI. These findings may be applicable to patients undergoing liver surgery. However, clinical studies are required to validate the efficacy of IPC in this setting.
Assuntos
Isquemia Fria/efeitos adversos , Fígado Gorduroso/cirurgia , Precondicionamento Isquêmico/métodos , Fígado/irrigação sanguínea , Fígado/cirurgia , Traumatismo por Reperfusão/prevenção & controle , Isquemia Quente/efeitos adversos , Animais , Modelos Animais de Doenças , Fígado Gorduroso/complicações , Fígado Gorduroso/diagnóstico , Fígado/patologia , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/etiologia , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: There is increasing need to expand availability of donor liver grafts, including steatotic livers. Steatotic liver is associated with poor outcome post-transplantation but with conflicting results in the literature. The aim of this systematic review was to evaluate the impact of steatotic livers on liver transplantation outcomes. METHODS: An electronic search of OVID Medline and Embase databases was performed to identify clinical studies that reported outcomes of steatotic livers in liver transplantation. Data were extracted, and basic descriptive statistics were used to summarise data pooled from individual clinical studies. RESULTS: Ninety-two articles were identified, of which 34 met the inclusion criteria, and stratified analysis were performed. There was a lack of standardised definition of primary non-function or impaired primary function amongst the studies and description of type of steatosis. Severely (>60%) steatotic grafts are associated with increased risk of poor graft function, whilst moderate-severe (>30%) steatotic grafts are associated with decreased graft survival. CONCLUSIONS: Available evidence showed increased risk of poor graft outcome in moderate-severe steatotic livers. A large prospective multi-centred trial will be required to identify the true risks of steatotic livers. Consistent definition of primary non-function/impaired primary function and description of type of steatosis is also required.
Assuntos
Função Retardada do Enxerto/etiologia , Fígado Gorduroso/etiologia , Transplante de Fígado/efeitos adversos , Aloenxertos , Função Retardada do Enxerto/diagnóstico , Função Retardada do Enxerto/terapia , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/terapia , Sobrevivência de Enxerto , HumanosRESUMO
BACKGROUND: Evacuatory dysfunction after distal colorectal resection varies from incontinence to obstructed defaecation and is termed anterior resection syndrome. The aim of this study was to identify risk factors for the development of anterior resection syndrome. METHODS: All anterior resections undertaken at Auckland Hospital from 2002 to 2012 were retrospectively evaluated. An assortment of patient and peri-operative variables were recorded. Cases were stratified by the occurrence of anterior resection syndrome symptoms from 1 to 5 years post-operatively. RESULTS: A total of 277 patients were identified. Prevalence of anterior resection syndrome decreased progressively from 61 % at 1 year to 43 % at 5 years. Univariate analysis identified anastomotic height, surgeon, pT stage, procedure year and temporary diversion ileostomy as recurring significant correlates (p < 0.05). Logistic regression identified lower anastomotic height (odds ratio (OR) 2.11, 95 % confidence interval (CI) 1.05-4.27; p = 0.04) and obstructive presenting symptoms (OR 6.71, 95 % CI 1.00-44.80; p = 0.05) as independent predictors at 1 and 2 years, respectively. Post-operative chemotherapy was a predictor at 1 year (OR 1.93, 95 % CI 1.04-3.57; p = 0.03). Temporary diverting ileostomy was an independent predictor at 2 (OR 2.49, 95 % CI 1.04-5.95; p = 0.04), 3 (OR 4.17, 95 % CI 1.04-16.78; p = 0.04), 4 (OR 8.05, 95 % CI 1.21-53.6; p = 0.03), and 5 years (OR 49.60, 95 % CI 2.17-1134.71; p = 0.02) after adjusting for anastomotic height. CONCLUSIONS: Anastomotic height, post-operative chemotherapy and obstructive presenting symptoms were independent predictors at 1 and 2 years. Temporary diversion ileostomy was an independent predictor for the occurrence of anterior resection syndrome at 2, 3, 4 and 5 years even after correcting for anastomotic height. Prospective assessment is required to facilitate more accurate risk factor analysis.
Assuntos
Canal Anal/cirurgia , Colo/cirurgia , Neoplasias Colorretais/cirurgia , Constipação Intestinal/etiologia , Defecação , Incontinência Fecal/etiologia , Complicações Pós-Operatórias/etiologia , Reto/cirurgia , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Seguimentos , Humanos , Ileostomia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Síndrome , Fatores de TempoRESUMO
BACKGROUND: Ischemia-reperfusion injury is a major cause of post-liver-surgery complications. Ischemic preconditioning (IPC) has been demonstrated to protect against ischemia-reperfusion injury. Clinical studies have examined IPC in liver surgery but with conflicting results. This systematic review aimed to evaluate the effects of IPC on outcome in clinical liver surgery. METHODS: An electronic search of OVID Medline and Embase databases was performed to identify studies that reported outcomes in patients undergoing liver surgery subjected to IPC. Basic descriptive statistics were used to summarise data from individual clinical studies. RESULTS: 1093 articles were identified, of which 24 met the inclusion criteria. Seven topics were selected and analysed by subgroup. There were 10 studies in cadaveric liver transplantation, 2 in living-related liver transplantation, and 12 in liver resection. IPC decreases hepatocellular damage in liver surgery as determined by transaminases but does not translate to any significant clinical benefit in orthotopic liver transplant or liver resection. CONCLUSIONS: Available clinical evidence does not support routine use of IPC in liver surgery as it does not offer any apparent benefit in perioperative outcome. Further clinical studies will need to be carried out to determine the subset of patients that will benefit from IPC.
Assuntos
Hepatectomia/efeitos adversos , Precondicionamento Isquêmico , Transplante de Fígado/efeitos adversos , Fígado/cirurgia , Cadáver , Humanos , Fígado/fisiopatologia , Período Perioperatório , Traumatismo por Reperfusão , Resultado do TratamentoRESUMO
BACKGROUND: Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. METHODS: Livers from 10-week old leptin-deficient obese (ob/ob, nâ=â9) and lean C57 mice (nâ=â9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity. RESULTS: Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers. CONCLUSIONS: Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor livers.
Assuntos
Isquemia Fria , Fígado/metabolismo , Fígado/patologia , Fosforilação Oxidativa , Adenosina , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Alopurinol , Anaerobiose , Animais , Glicemia/metabolismo , Peso Corporal , Soluções Tampão , Respiração Celular , Transporte de Elétrons , Jejum/sangue , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Intolerância à Glucose/sangue , Intolerância à Glucose/patologia , Glutationa , Concentração de Íons de Hidrogênio , Insulina , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Mitocôndrias Hepáticas/metabolismo , Soluções para Preservação de Órgãos , Rafinose , Magreza/metabolismo , Magreza/patologiaRESUMO
BACKGROUND: The impact of hepatic steatosis on outcome following hepatic ischemia-reperfusion injury (IRI) remains controversial with conflicting clinical results. A number of experimental studies have been published examining the relationship between hepatic steatosis and IRI. This systematic review evaluates these experimental studies. METHODS: An electronic search of the Medline and Embase databases (January 1946 to June 2012) was performed to identify studies that reported relevant outcomes in animal models of hepatic steatosis subjected to IRI. RESULTS: A total of 1314 articles were identified, of which 33 met the predefined criteria and were included in the study. There was large variation in the type of animal model, duration, and type of IRI and reporting of histological findings. Increased macrovesicular steatosis (>30%) was associated with increased histological damage, liver function derangement, and reduced survival. Increased duration of warm or cold ischemia had a negative impact on all outcomes measured. Microvesicular steatosis did not influence outcome. CONCLUSIONS: Findings from this systemic review support the hypothesis that livers with >30% macrovesicular steatosis are less tolerant of IRI. Clinically, it is likely that these findings are applicable to patients undergoing hepatic resection, but further studies are required to confirm these data.
Assuntos
Fígado Gorduroso/complicações , Traumatismo por Reperfusão/complicações , Animais , Isquemia Fria , Modelos Animais de Doenças , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Testes de Função Hepática , Transplante de Fígado , Camundongos , Ratos , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Análise de Sobrevida , Isquemia QuenteRESUMO
BACKGROUNDS AND AIM: Current assessment of pre-operative liver function relies upon biochemical blood tests and histology but these only indirectly measure liver function. Mitochondrial function (MF) analysis allows direct measurement of cellular metabolic function and may provide an additional index of hepatic health. Conventional MF analysis requires substantial tissue samples (>100 mg) obtained at open surgery. Here we report a method to assess MF using <3 mg of tissue obtained by a Tru-cut® biopsy needle making it suitable for percutaneous application. METHODS: An 18G Bard® Max-core® biopsy instrument was used to collect samples. The optimal Tru-cut® sample weight, stability in ice-cold University of Wisconsin solution, reproducibility and protocol utility was initially evaluated in Wistar rat livers then confirmed in human samples. MF was measured in saponin-permeabilized samples using high-resolution respirometry. RESULTS: The average mass of a single rat and human liver Tru-cut® biopsy was 5.60±0.30 and 5.16±0.15 mg, respectively (mean; standard error of mean). Two milligram of sample was found the lowest feasible mass for the MF assay. Tissue MF declined after 1 hour of cold storage. Six replicate measurements within rats and humans (nâ=â6 each) showed low coefficient of variation (<10%) in measurements of State-III respiration, electron transport chain (ETC) capacity and respiratory control ratio (RCR). Ischemic rat and human liver samples consistently showed lower State-III respiration, ETC capacity and RCR, compared to normal perfused liver samples. CONCLUSION: Consistent measurement of liver MF and detection of derangement in a disease state was successfully demonstrated using less than half the tissue from a single Tru-cut® biopsy. Using this technique outpatient assessment of liver MF is now feasible, providing a new assay for the evaluation of hepatic function.