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ABSTRACT: Livers from donation after circulatory determination-of-death (DCD) donors suffer ischemic injury during a preextraction period of cardiac arrest and are infrequently used for transplantation; they have the potential, however, to considerably expand the donor pool. We aimed to determine whether hypothermic oxygenated machine perfusion would improve or further deteriorate the quality of these livers using a clinically relevant porcine model.
Donor livers were subjected to 90 min of cardiac arrest and preserved at 4°C with either static cold storage using University of Wisconsin solution (CS, n=6) or oxygenated machine perfusion using University of Wisconsin machine perfusion solution and 25% physiological perfusion pressures (HMP, n=5). After 4 hr of preservation, livers were transplanted into recipient pigs, which were followed intensively for up to 5 days.
Five-day survival was 0 in CS and 20% in HMP. Immediately after reperfusion, hepatocellular injury and function were improved in HMP versus CS. However, HMP grafts also demonstrated significant endothelial and Kupffer cell injury, and a progressive lesion developed 24 to 48 hr after reperfusion that led to death in all but one of the recipient animals.
Although hypothermic oxygenated machine perfusion performed using subphysiological perfusion pressures seems to offer some advantages over cold storage in the preservation of ischemically damaged livers, it simultaneously conditions endothelial and Kupffer cell injury that may ultimately lead to the failure of these grafts.
Transplantation 06/2012; 94(1):22-9. · 4.00 Impact Factor
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ABSTRACT: Recently, considerable focus has been placed on the use of hypothermic perfusion ex vivo in abdominal organ transplant. Herein, we discuss the appropriateness of using this modality to preserve livers, in particular those of suboptimal quality, and whether perfusing at warmer temperatures in this context may, in fact, be better.
Hypothermic perfusion (0-4°C) appears to improve the hepatocellular energy charge and achieve adequate results in normal livers. However, its use for the preservation of suboptimal grafts may lead to significant endothelial and Kupffer cell injury that is incompatible with survival. Studies on the perfusion of suboptimal livers at higher temperatures, on the contrary, indicate that results improve as temperatures approach 37°C, provided that the oxygen supply during perfusion is adequate.
Normothermic perfusion provides oxygen and other metabolic substrates under physiological conditions; in liver transplant, it appears to be the best option to improve the viability of suboptimal organs.
Current opinion in organ transplantation 01/2012; 17(2):143-7. · 1.22 Impact Factor
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ABSTRACT: Unexpected donation after cardiac death (DCD) donors suffer cardiac arrest suddenly and are maintained with normothermic extracorporeal membrane oxygenation (NECMO) while consent for donation is obtained. The objective of this study was to determine whether ex vivo normothermic machine perfusion (NMP) improves upon the benefits of NECMO in a large-animal model of unexpected DCD liver transplant.
Donor pigs underwent 90-minute cardiac arrest and were divided in to 3 groups. In the first, livers were preserved immediately with cold storage (CS, n = 6). In the other 2 groups, donors underwent 60-minute NECMO followed by CS (NECMO+CS, n = 6) or NMP (NECMO+NMP, n = 6). After 4-hour preservation, livers were transplanted into recipient pigs.
Five-day survival was 0 in CS, 83% in NECMO+CS, and 100% in NECMO+NMP. After reperfusion, injury, and inflammatory markers rose significantly among CS grafts, all of which developed primary nonfunction. Sixty minutes of NECMO, however, resulted in only 1 death, whereas NECMO followed by NMP led to no deaths and significant improvements in injury, inflammation, and synthetic function in comparison to NECMO and CS.
Although 60 minutes recuperative NECMO is better than CS alone, NMP improves further on NECMO and may have a role in preserving DCD livers in the clinical setting.
Annals of surgery 08/2011; 254(6):1000-7. · 7.90 Impact Factor
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ABSTRACT: In partial liver transplant, a reduction in the intrahepatic vascular bed produces a rise in the portal vein flow and the portal venous pressure gradient, leading to endothelial and, thereby, hepatocellular injury and death in a process known as "small-for-size" (SFS) syndrome.
To demonstrate that a calibrated portocaval shunt prevents superfluous inflow in a porcine model of SFS transplant.
Donor pigs (15-20 kg) underwent 70% hepatectomy. In 2 groups, a 6 mm (S6) (n = 6) or 12 mm (S12) (n = 6) Gore-Tex shunt was placed between the portal vein and infrahepatic inferior vena cava. In a third group, no portocaval shunt was placed (SFS) (n = 17). Grafts were stored for 5 hours at 4°C and then transplanted into recipients (30-35 kg).
Five-day survival was 29% in SFS, 100% in S6, and 0 in S12. Postreperfusion portal vein flow was 4-, 2-, and 1-times flow at baseline in SFS, S6, and S12, respectively. With respect to portal venous pressure gradient, both the 6- and 12-mm shunts effectively decompressed the portal bed. Aspartate aminotransferase and bilirubin rose and the Quick prothrombin time fell in all animals after reperfusion but improved significantly by day 5 in S6. Serum levels of endothelin-1 remained elevated in SFS and S12 but returned to baseline by 12 hours in S6: 2.76 (2.05-4.08) and 2.04 (1.97-2.12) versus 0.43 (0.26-0.50) pg/mL, respectively (P < 0.05 for both comparisons).
A calibrated portocaval shunt that maintains portal vein flow about twice its baseline value produces a favorable outcome after SFS liver transplantation, avoiding endothelial injury due to portal hyperperfusion or to hypoperfusion because of excess shunting.
Annals of surgery 06/2011; 253(6):1201-10. · 7.90 Impact Factor
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ABSTRACT: Based on similar anatomy, physiology, and size to humans, pigs provide an excellent means for studying new therapies related to orthotopic liver transplant (OLT). Techniques that have been described to date, however, are unnecessarily complex and increase the likelihood of morbidity and adverse outcome.
Male outbred weanling pigs underwent OLT according to our procedure, with a short anhepatic time (<20 min) and without veno-venous bypass or vasoactive substances during the anhepatic phase. Vascular anastomoses were performed identical to the clinical setting, and a simple stented choledochocholedochostomy was created.
The authors have performed this procedure 130 times using four transplant models: standard, whole-liver (n = 10), small-for-size (n = 48), donor after cardiac death (n = 44), and donor adenoviral gene transfection (n = 28). The average cold ischemic and anhepatic times were 302 ± 43 and 17 ± 3 min, respectively. Hypotension was successfully treated with intravenous fluids. In all cases, the recipient survived the operation and was extubated. Survival to the end follow-up varied according to the model and was 56% (73/130) for all cases. At autopsy or euthanasia, no vascular thrombosis or outflow obstruction was found. Survival was 100% for pigs transplanted with standard, whole-liver grafts (n = 10). In this group, AST and bilirubin rose during the first 24 h after graft reperfusion, while the Quick prothrombin time (QPT) fell. By the fifth postoperative day, these parameters had returned to baseline.
This model is straightforward and reproducible and offers surgeons and researchers the opportunity to perform OLT studies under clinically relevant conditions.
Journal of Surgical Research 02/2011; 167(1):e39-45. · 2.25 Impact Factor
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ABSTRACT: Recent studies have identified cases of hepatocellular carcinoma (HCC) arising in cryptogenic cirrhosis and proposed that many of them may be attributable to nonalcoholic fatty liver disease (NAFLD).
To evaluate the prevalence of NAFLD-associated metabolic risk factors among HCC patients to determine whether NAFLD could have played a role in the development of HCC.
Patients with HCC in the setting of hepatic cirrhosis and age-matched, sex-matched, and Child-Pugh-matched cirrhotic patients were included in this study. A verbal interview regarding family and personal history of metabolic risk factors; a complete physical examination, including morphometric measurements; and a blood analysis evaluating liver function and cirrhosis etiology were conducted with each patient.
Seventy HCC patients and 64 tumor-free cirrhotics were included. Sixty-six patients (49%) were overweight and 37 (28%) obese, with a median body mass index of 27.6 (range: 19-41). Fifty-six patients (42%) had central adiposity, 62 (46%) had hypertension, 46 (34%) had type 2 diabetes, seven (5%) had coronary artery disease, and 48 (36%) had dyslipidemia. There were no significant differences in the distribution of metabolic risk factors between the groups. The main cause of cirrhosis was HCV in 83 patients (62%). In only two patients (1.4%), no cirrhosis etiology could be determined; both of them had HCC and metabolic risk factors.
Metabolic risk factors are a major health issue in patients with liver disease, regardless of the presence of HCC. Metabolic factors may have been risk factors for the development of liver disease and cirrhosis, even when other established causes of cirrhosis were present.
European journal of gastroenterology & hepatology 10/2010; 22(10):1239-44. · 1.66 Impact Factor
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ABSTRACT: Understanding the pathogenesis of small-for-size (SFS) syndrome is critical to expanding the applicability of partial liver transplantation. We aimed to characterize its acute presentation and association with alterations in hepatic hemodynamics, microstructure, and regeneration in a porcine model. Eighteen SFS liver transplants were performed. Donors underwent 70% hepatectomy. Partial grafts were implanted into larger recipients. Whole liver transplants were also performed (n = 6). Recipients were followed until death or for 5 days. Hemodynamics were measured, and tissue was sampled intraoperatively and at the study end. Serum was sampled regularly during follow-up. Seventeen SFS transplants and 6 whole liver transplants were included. SFS grafts represented 23.2% (19.3%-25.3%) of the recipients' standard liver volume. The survival rate was 29% and 100% in the SFS and whole liver groups, respectively. The portal venous flow, pressure gradient, and resistance were significantly higher in recipients of SFS grafts versus whole livers after portal and arterial reperfusion. Arterial flow as a percentage of the total liver blood flow was significantly lower after reperfusion in SFS grafts and remained so when measured again after 5 days. Markers of endothelial cell injury increased soon after reperfusion, and those of hepatocellular injury increased later; both predicted the appearance of either graft failure or histological recovery. Proliferative activity peaked earlier and higher among nonsurvivors in the SFS group. Surviving grafts demonstrated a slower but maintained rise in regenerative activity, although metabolic activity failed to improve. In SFS transplantation in the acute setting, portal hyperperfusion is a stimulus for regeneration but may simultaneously cause irreparable endothelial injury. This porcine model not only helps to elucidate the inciting factors in SFS pathogenesis but also offers a clinically relevant means to study its prevention.
Liver Transplantation 03/2010; 16(3):364-74. · 3.39 Impact Factor
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ABSTRACT: In liver transplantation, macrovesicular steatosis is a major determinant of graft outcome. Visual assessment of steatosis by the donor surgeon is highly inaccurate, whereas hepatic biopsy is user dependent and cumbersome. Our objective was to validate a novel bioelectrical impedance sensor as a means of objectively quantifying macrovesicular hepatic steatosis and to correlate the results with another surrogate measure of macrosteatosis, hepatic microcirculation.
Fatty (n=36) and lean (n=18) male Zucker rats, 250 to 450 g, were used to achieve varying degrees of steatosis. After a bilateral subcostal incision, hepatic microcirculation was measured using laser Doppler microflowmetry. Low-frequency bioelectrical impedance (LF-BEI) was measured at 1 kHz using a custom-made sensor and instrumentation system. Complete hepatectomy was performed. Hepatic tissue was preserved and stained with hematoxylin-eosin for histology.
Both microflow and LF-BEI correlated well with macrosteatosis and each other: Pearson correlation coefficients -0.71, 0.73, and -0.81, respectively. Livers were grouped according to the degree of macrosteatosis: mild (<30%), moderate (30%-60%), and severe (>60%). Both LF-BEI and microflow varied significantly among groups on one-way analysis of variance, although only LF-BEI was capable of discriminating between mild and moderate macrosteatosis on post hoc analysis. Regarding their individual capacities to detect the presence of severe macrosteatosis, both tests were excellent classifiers: receiver operating curve area under the curve 0.885 and 0.9 for LF-BEI and microflow, respectively. However, the bioimpedance apparatus is more rapid and less susceptible to local factors and background noise and could more easily be used in the clinical liver transplantation setting.
Transplantation 09/2009; 88(5):716-22. · 4.00 Impact Factor
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ABSTRACT: Evaluation of response to treatment is a key aspect in cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) are used in most oncology trials, but those criteria evaluate only unidimensional tumor measurements and disregard the extent of necrosis, which is the target of all effective locoregional therapies. Therefore, the European Association for the Study of the Liver (EASL) guidelines recommended that assessment of tumor response should incorporate the reduction in viable tumor burden. The current report provides an assessment of the agreement/concordance between both RECIST and the EASL guidelines for the evaluation of response to therapy.
The authors evaluated a cohort of 55 patients within prospective studies, including 24 patients with hepatocellular carcinoma who underwent transarterial chemoembolization (TACE) with drug eluting beads (DEB-TACE) and 31 patients who underwent percutaneous ablation (percutaneous ethanol injection [PEI]/radiofrequency [RF]). Triphasic helical computed tomography scans were performed at baseline, at 1 month, and at 3 months after procedure, and 2 independent radiologists evaluated tumor response.
Evaluating response according to RECIST criteria, no patients achieved a complete response (CR), 21.8% of patients achieved a partial response (PR) (none in the PEI/RF group), 47.3% of patients had stable disease (SD), and 30.9% of patients had progressive disease (PD). When response was evaluated according to the EASL guidelines, 54.5% of patients achieved a CR, 27.3% of patients achieved a PR, 3.6% of patients had SD, and 14.5% had PD. The kappa coefficient was 0.193 (95% confidence interval, 0.0893-0.2967; P < .0001).
RECIST missed all CRs and underestimated the extent of partial tumor response because of tissue necrosis, wrongly assessing the therapeutic efficacy of locoregional therapies. This evaluation should incorporate the reduction in viable tumor burden as recognized by nonenhanced areas on dynamic imaging studies.
Cancer 01/2009; 115(3):616-23. · 4.77 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third cause of cancer-related death. Despite therapeutic advances, the overall survival of patients with HCC has not significantly improved in the last two decades. In the majority of the cases there is underlying cirrhosis, so the prognosis of HCC depends on not only tumor stage but also liver function. There is not a widely accepted HCC staging system. In our group we have developed a new staging classification that stratifies HCC patients into four major categories and simultaneously links staging with treatment. Patients at an early stage are those who present with an asymptomatic single HCC with a maximum diameter of 5cm or up to three nodules each less than 3cm. They will benefit from curative therapies, including resection, liver transplantation (LT), and percutaneous ablation. Patients exceeding these limits, but who are free of cancer-related symptoms and vascular invasion or extrahepatic spread fit into the intermediate stage and may benefit from palliation with chemoembolization. The patients with mild cancer-related symptoms and/or vascular invasion or extrahepatic spread are included in the advanced stage. In this stage there is not effective therapy, and these patients may profit from new therapies in the setting of randomized controlled trials (RCTs). Finally, the patients with severe cancer-related symptoms or great tumor burden belong to the terminal stage and only benefit from symptomatic treatment.
Critical Reviews in Oncology/Hematology 12/2006; 60(2):89-98. · 4.41 Impact Factor
