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ABSTRACT: Numerous techniques developed in medicine require careful evaluation to determine their indications, limitations and potential side effects prior to their clinical use. At present this generally involves the use of animal models which is undesirable from an ethical standpoint, requires complex and time-consuming authorization, and is very expensive. This process is exemplified in the development of hepatic ablation techniques, starting experiments on explanted livers and progressing to safety and efficacy studies in living animals prior to clinical studies. The two main approaches used are ex vivo isolated non-perfused liver models and in vivo animal models. Ex vivo non perfused models are less expensive, easier to obtain but not suitable to study the heat sink effect or experiments requiring several hours. In vivo animal models closely resemble clinical subjects but often are expensive and have small sample sizes due to ethical guidelines. Isolated perfused ex vivo liver models have been used to study drug toxicity, liver failure, organ transplantation and hepatic ablation and combine advantages of both previous models.
World Journal of Gastroenterology 01/2013; 19(2):147-54. · 2.47 Impact Factor
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ABSTRACT: Ex vivo perfused porcine livers have been used for temporary support during acute liver failure. The aim of this study was to assess both the histological changes and temporal pattern of the changes that occur during extracorporeal liver perfusions and to correlate these with factors that may influence them. Five porcine livers were harvested, preserved in cold ice and reperfused for 6 h in an extracorporeal circuit using autologous normothermic blood. Tissue biopsies were collected hourly. The Ishak score was used to quantify hepatic necrosis, and immunohistochemistry was used to evaluate apoptosis and regeneration. Liver weight, perfusion parameters, arterial blood gases and blood samples were also collected. The Ishak score peaked immediately before and 4 h after the start of reperfusion. Scattered necrosis, microvesicular steatotic vacuolization, sinusoidal dilatation and red cell extravasation were present. Anion gap acidosis was associated with the Ishak score. An inverse correlation was present between liver regeneration and necrosis, and between liver weight and regeneration. No changes were observed for apoptosis. Among the inflammatory cytokines evaluated, interleukin-6 and -8 levels increased significantly during the perfusions. Hepatic necrosis was always present during the extracorporeal perfusions, followed a definite pattern and was inversely correlated with regeneration. Apoptosis did not increase over baseline levels. The meaning of these findings and their correlation with clinical outcomes during acute hepatic failures deserve further investigation.
Journal of Artificial Organs 11/2012; · 1.59 Impact Factor
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ABSTRACT: The ex vivo porcine liver perfused model isolates the organ from extrinsic regulatory mechanisms, facilitating an improved understanding of the organ physiology and reaction to various conditions. We have assessed the influence of the addition of a porcine kidney to the circuit.
Eight livers were harvested and perfused for 6 hours. In 5 additional experiments a kidney also was connected in parallel. Hourly arterial blood gases were collected to analyze glucose, acid base, and renal parameters. The primary end point was an evaluation of the influence of the kidney on glucose, pH, and electrolyte levels.
In the combined porcine liver-kidney circuit all the parameters significantly improved compared with the liver circuit alone. This was particularly evident for glucose values because normoglycemia was reached by the end of the perfusion, and for pH and electrolyte values that were maintained at initial levels.
The addition of a porcine kidney to the perfusion circuit improves the biochemical milieu. This might produce more consistent and reliable results, particularly during studies requiring a steady-state environment.
American journal of surgery 10/2012; 204(4):518-26. · 2.36 Impact Factor
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ABSTRACT: Electrolytic ablation (EA) destroys the liver by releasing toxic radicles and producing modifications in the local pH without increasing the tissue temperature. We assessed the histological changes produced by EA using an ex-vivo perfused model. Five porcine livers were harvested, preserved in ice and reperfused for six hours in an extracorporeal circuit using autologous normothermic blood. One hour after reperfusion EA was performed and liver biopsies collected at the end of the experiments. The main necrotic zone consisted of coagulative necrosis, sinusoidal dilatation and haemorrhage with an unusual morphological pattern. The coagulative necrosis and haemorrhage affected mainly the peripheral area of the lobule with relative sparing of the area surrounding the centrilobular vein. Contrasting with this sinusoidal dilatation appeared to be more prominent in the centrilobular area. EA produces patterns of tissue destruction that have not been observed with the more commonly used thermal techniques. Further studies should obtain more information about the influence of adjacent biliary and vascular structures so that appropriate clinical trials can be designed.
Pathology & Oncology Research 06/2012; 18(4):1085-9. · 1.37 Impact Factor
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ABSTRACT: The addition of a kidney to the ex vivo liver perfused model may facilitate the circuit homeostatic balance of important biochemical parameters (i.e. pH changes, urea and creatinine, or glucose levels) but might also increase the inflammatory reaction produced. In this study, we compared the production of various cytokines between liver-kidney and liver-alone circuits. Seven livers were harvested from female pigs and perfused for 6 h. In five additional experiments, a kidney was also harvested and connected in parallel. Blood samples for interleukins (IL) 1, 2, 4, 6, 8, 10, and 12, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were collected before perfusion and at hours 1, 2, 4 and 6 postperfusion. In the combined liver-kidney circuit, a significant increase was present only for IL-6 and IL-8, but this did not differ significantly from those recorded in the liver-alone circuit. All other cytokines were not modified from baseline levels. The addition of a kidney to the perfusion circuit does not stimulate a greater inflammatory reaction than that of the liver alone and therefore further confirms the safety of the experimental setups in view of more delicate experiments requiring strict homeostatic conditions.
Journal of Artificial Organs 04/2012; 15(3):290-4. · 1.59 Impact Factor
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ABSTRACT: Variations in the porcine hepatic vasculature may contribute to the outcome of experiments based on liver perfusion models. We studied the hepatic artery (HA), variations of its branches, and the correlation with the resultant perfusion.
Nineteen animals were used. After 6 h of perfusion, dissection of the HA and its branches was conducted up to the insertion in the liver parenchyma. Data about the macroscopic appearance of lobes and the pattern of branching were recorded.
In all cases, the HA bifurcated into two constant branches, one for the LL/LM lobes (further divided in two vessels for each lobe) and one for the RM lobe. Five main patterns were identified involving vessels for the RL and the CL lobes. Two variations produced complete and uniform perfusion of the entire liver in all cases, while in the remaining cases, only part of them were completely perfused.
Some variants of the porcine HA and its branches are associated with the risk of incomplete perfusion if the perfusion cannula placement does not take the individual hepatic arterial anatomy into account. Understanding of the hepatic arteries branching patterns is essential when ex vivo perfusion models are being established.
Journal of Surgical Research 06/2011; 168(1):56-61. · 2.25 Impact Factor
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ABSTRACT: Islet autotransplantation requires access to the portal vein or tributaries. We originally infused islets into the liver via the middle or right colic veins, but since 2005 we have used the recanalised umbilical vein. Here, we describe the technique, the advantages and the early results achieved.
After removal of the pancreas and restoration of the biliary and enteric continuity, the ligamentum teres is transected. The obliterated umbilical vein is identified and recanalised with Bakes dilators giving access to the left portal vein. A Vygon® Nutricath 'S' 11-Fr catheter is inserted and used for the islet infusion. If the ligamentum teres is to be exteriorised for postoperative measurements or subsequent access, it is pulled through a 10-mm laparoscopic port in the epigastrium, sutured to the skin and covered with a dressing.
We have used this approach in 17 patients and exteriorised the falciform ligament in 4. There have been no intra- or postoperative complications.
The recanalised umbilical approach is safe and allows for venous sampling and postoperative measurements of the portal pressure. Under local anaesthetic, the umbilical vein can be approached above the umbilicus and exteriorised if repeated transplants are required for allograft patients. and IAP.
Pancreatology 05/2011; 11(2):233-9. · 1.99 Impact Factor
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ABSTRACT: The aim of this review is to summarize the available evidence for changes in bile composition following liver surgery and assess their use in predicting post-operative complications.
A literature search was undertaken for all studies focusing on bile composition, bile volume and analysis. Articles were selected from MEDLINE, Embase and the Cochrane Central Register of Controlled Trials databases up to May 2009.
Low values of pre-operative bilirubin diglucuronide predict reduced post-operative liver function and the occurrence of jaundice. Low concentrations of hepatocyte growth factor and interleukin-6 in bile following surgery are associated with the subsequent development of liver failure and are probably surrogate markers for situations where the resultant hepatic regeneration is inadequate.
Analysis of the composition and quality of bile is probably underused as a tool for the pre-operative screening and early post-operative monitoring of patients at high risk of developing liver failure following major hepatobiliary procedures.
Digestive surgery 11/2010; 27(6):450-60. · 1.37 Impact Factor
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ANZ Journal of Surgery 10/2010; 80(10):679-80. · 1.25 Impact Factor
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ABSTRACT: BackgroundElectrolytic ablation (EA) destroys tissues through extreme pH changes in the local microenvironment. An ex vivo perfused liver model was used to assess the systemic effects of EA on the acid–base balance without the influence of compensatory organs (lungs and kidneys).MethodsEleven pigs were perfused extracorporeally at 39°C with autologous blood; 4 also underwent EA after 1 hour of reperfusion. Arterial blood samples were obtained hourly.ResultspH and CO2 levels did not change throughout the experiments. A significant increase of HCO3-, anion gap, base excess, and lactate was present after the third hour. No differences were observed between EA experiments and controls.ConclusionsEA does not alter the acid–base balance even when the confounding influence of compensatory organs is removed. Such findings should be considered when planning ablations in patients with renal failure or respiratory diseases in which EA could avoid undesirable metabolic changes.
American journal of surgery 05/2010; · 2.36 Impact Factor
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ANZ Journal of Surgery 05/2010; 80(5):368-9. · 1.25 Impact Factor
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ABSTRACT: Radiology reports provide specialist interpretation of images and relate these findings to the patient's symptoms and signs. This study compared ultrasound (USS) reports generated by radiologists and sonographers to determine if any significant or clinically relevant differences existed.
A retrospective analysis of 624 consecutive USS reports was carried out. The reports were assessed for the presence of a 'disclaimer' or 'caveat' pertaining to the quality of the images and were analysed with respect to the clarity of their wording and ability to answer the clinical request.
The majority of sonographer USS reports contained a disclaimer regarding the quality of the USS images (57.1%) compared with a smaller proportion of radiologist scans (9.9%) (P < 0.001). Overall, radiologists performed significantly better in providing a clear negative or positive diagnosis to the clinical question on the request form, when compared with sonographers (88.5% vs. 65.4%, P < 0.001).
'Disclaimer' comments and 'hedging' must be avoided in radiology reporting. While feedback as to the accuracy of the radiology images is important, overuse of such terms undermines the validity of the radiology report.
Journal of Evaluation in Clinical Practice 02/2010; 16(1):97-9. · 1.23 Impact Factor
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ABSTRACT: Surgery has become heavily dependent on accurate imaging in the assessment and treatment of suspected or confirmed intra-abdominal malignancy. Positron emission tomography-computed tomography (PET-CT) fuses uptake of a radiotracer combined with CT images to assess both functional tissue activity and anatomical detail. Since its introduction it has offered new ways of treating gastrointestinal cancers.
The review analyses the present literature regarding the use of PET-CT in the assessment, diagnosis, staging and treatment of hepatobiliary malignancies.
PET-CT is widely used in pre-operative tumours staging for colorectal liver metastases. There is convincing data that it may also be applicable for neuroendocrine tumours, assessment of indeterminate pancreas lesions and clinical drug trials. PET-CT is of limited value in hepatocellular cancers, although new techniques in dual-tracer PET-CT may change this.
Knowledge of the strengths and limitations of PET-CT is important for all surgeons managing cancer of the hepatobiliary system. More clinical data are required on PET-CT, particularly its effect on long-term survival in PET-CT-staged patients undergoing resection.
HPB 02/2009; 11(1):4-17. · 1.60 Impact Factor
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ABSTRACT: Early Warning Scores (EWS) is a widely used scoring system monitoring patient progress, which we have previously shown to predict outcome from acute pancreatitis. This study examined EWS from a larger group of patients to confirm if this predictive value held true.
The EWS scores were compared with the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, modified organ dysfunction scores, Imrie scores, computed tomography grading scores, and Ranson criteria for 181 admissions with acute pancreatitis. The accuracy of EWS in predicting outcome was determined by receiver operator characteristics.
A total of 181 patients were identified with acute pancreatitis. On day 1 of admission, APACHE II scores were the most accurate predictor of mortality with an area under curve (AUC) values of 0.876, closely followed by EWS (AUC, 0.827). By day 2 and 3 after admission, the EWS was the most accurate predictor of mortality (AUC, 0.910 and 0.934, respectively). The APACHE II was the second most accurate scoring system at 48 and 72 hours (AUC, 0.892 and 0.911, respectively).
The EWSs on days 2 and 3 after admission are sensitive and specific in predicting mortality from acute pancreatitis. It is as accurate as the APACHE II scores and easier to implement in daily practice.
Pancreas 11/2008; 37(3):e54-61. · 2.39 Impact Factor
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ABSTRACT: Ablation of liver tissue produces in situ tumoural antigens and elicits specific immune responses. The aim of this review is to examine the available data about the local and systemic responses produced and to compare differences between the methods available. A literature search was undertaken for all papers focusing on immune responses following ablative therapy of the liver, including experimental and clinical studies. Following ablative procedures, the cellular response is elicited by the presentation of antigens by dendritic cells to specific CD4(+) T cells, which in turn stimulate natural killer or CD8(+) cytotoxic cells. The local release of intracellular debris activates Kupffer cells to produce cytokines, which, in the immediate vicinity, activate monocytes/macrophages or specific T cells that respond and produce systemic reactions such as fever, thrombocytopaenia or shock. The immune responses elicited by cryotherapy, both cellular and cytokine, seem far greater than those produced by radiofrequency or microwave ablation, probably as a consequence of the peculiar mechanism of cell death of the former (disruptive necrosis). This mechanism is considered central to the pathogenesis of cryoshock. Ablative techniques stimulate the immune system and provide an easy way to achieve in vivo vaccination against tumoural antigens. Immunomodulatory approaches have the potential to augment the initial immune stimulation and this combined approach could pave the way to a more selective and specific method of treating liver tumours.
Liver international: official journal of the International Association for the Study of the Liver 11/2008; 29(1):18-24. · 3.82 Impact Factor
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ABSTRACT: The liver has a complex hormonal and nervous control mechanism leading to difficulty in the interpretations of its responses to chronic hypoxia. Theoretically an ex vivo perfused model of the liver should, by dissociating the organ from the extrinsic regulatory mechanisms, allow a better and unequivocal analysis of changes obtained.
Twelve livers were harvested from female pigs and perfused for 6 h. Hypoxia was produced by means of isovolemic hemodilution with hemoglobin and hematocrit reduced to 40% of the baseline value. The extracorporeal circuit included a centrifugal pump, heat exchanger, and oxygenator. Every hour, physiological parameters (arterial/portal venous pressures and flows) were measured and blood samples were collected for the analysis of hemoglobin, red blood cells, hematocrit, lactate, glucose, albumin, alanine aminotransferase, alkaline phosphatase, and total bilirubin, arterial and venous blood gases. The arterio-venous oxygen and carbon dioxide differences, and the hepatic metabolic rate for oxygen, were also calculated. Primary endpoint of the study was the glucose response of the liver to acute hypoxia. Secondary endpoints were eventual changes of markers for hepatic viability and functionality.
Most parameters showed significant variability during the first h of perfusion but subsequently normalized and remained stable at baseline values for the following 5 h. A strong and significant hyperglycemic response was present throughout the experiment (P < 0.001). Lactate rose steadily throughout the study period and after 6 h of perfusion there was a significant deviation from initial values (P < 0.05). Albumin did not change significantly throughout the study although a trend towards decreasing values was observed (Friedman test, P = NS). After an initial rise in levels of alanine transaminase and alkaline phosphatase following perfusion (P < 0.01), values remained constant without any further increase.
Following reperfusion in an ex vivo model, the liver reacts to low oxygen concentrations mobilizing glycogen deposits. This mechanism depends on an intrinsic sensibility of hepatocytes to hypoxia, as demonstrated by the ex vivo liver perfusion. These findings improve our knowledge in organ preservation for liver transplantation.
Journal of Surgical Research 11/2008; 160(1):73-80. · 2.25 Impact Factor
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ABSTRACT: Solitary fibrous tumour (SFT) is an uncommon neoplasm of mesenchymal origin that primarily affects the pleura and mediastinum. SFTs may occur elsewhere in the body including the liver, peritoneum, orbit and other soft tissues. Recent advances in immunohistochemical analysis have allowed greater identification of SFTs. Nevertheless, radiologically it remains difficult to distinguish SFTs of the liver from other solitary tumours as they have many common features. We report a case of SFT of the liver and highlight the potential inaccuracy of percutaneous biopsy in the diagnosis of large solitary liver tumours.
Asian Journal of Surgery 11/2008; 31(4):195-8. · 0.57 Impact Factor
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ABSTRACT: The inflammatory response following hepatic ablation depends on different factors including the method used, the duration and intensity of the treatment and the presence or absence of ischemia. Debate continues about the use of different modalities and whether some aspects of the response may be advantageous by releasing immunological active substances. Little data have been published concerning the cytokine response elicited by hepatic electrolytic ablation (EA). Study of an ex vivo liver model could allow for the evaluation of this response without the influence of confounding systemic factors.
Livers explanted from 11 pigs were perfused extracorporeally with normothermic autologous blood. Four of them underwent EA after 1 h of reperfusion. Serum samples were obtained up to 6 h after the reperfusion and assayed for IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFN-gamma, TNF-alpha.
Significant changes in the control group were observed for IL-6 after the second hour and IL-8 after the first hour compared with baseline levels (P < 0.001). In the EA group, IL-6 and IL-12 were raised after the second hour and IL-8 and IL-10 after the first hour (P < 0.001). The comparison between groups showed significant differences for IL-2, IL-4 (decreased in the EA group compared with controls), IL-10 and TNF-alpha (EA group increased compared with controls; P < 0.001).
The ex vivo perfused liver model demonstrated changes in levels of IL-2, IL-4, IL-10 and TNF-alpha following hepatic EA.
ANZ Journal of Surgery 80(7-8):537-41. · 1.25 Impact Factor
