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B R Davidson

Publications and source records attributed to B R Davidson.

At least 37 records · Page 2Linked to original sources
PubMed2003

Arterialization of the portal vein improves hepatic microcirculation and tissue oxygenation in experimental cirrhosis.

BACKGROUND: Arterialization of the portal vein (APV) has shown beneficial effects on liver regeneration and function in selected patients undergoing liver resection and transplantation. Whether APV improves liver perfusion and function in cirrhosis is unclear. This study investigated the effect of APV on hepatic haemodynamics and liver function in a rat model of cirrhosis. METHODS: Male Sprague-Dawley rats (250-300 g) were divided into three groups: normal controls (n = 7), cirrhosis with sham laparotomy (sham; n = 7) and cirrhosis with APV (APV; n = 9). Portal venous blood flow, portal vein pressure and hepatic parenchymal microcirculation (HPM) were measured before and after APV. Hepatic parenchymal oxygenation was assessed by near-infrared spectroscopy and hepatocellular injury by standard liver function tests. Measurements were taken at baseline, after APV and 7 days after surgery. RESULTS: APV increased portal blood flow and pressure in cirrhotic rats without altering intrahepatic portal resistance. APV increased the HPM in cirrhotic rats by a mean(s.e.m.) of 28.5(0.1) per cent on day 0 and 54.6(0.1) per cent by day 7 (P = 0.001). Liver tissue oxygenation was increased by APV and the plasma gamma-glutamyltranspeptidase level was reduced (mean(s.e.m.) 6.0(0.5) versus 3.8(0.3) units/l before and after APV respectively; P = 0.006) at day 7. CONCLUSION: APV increases portal blood flow, tissue perfusion and oxygenation in cirrhosis.

Animals↗
PubMed2003

Management of colorectal liver metastases.

Hepatic metastases occur in 60% of patients following resection for colorectal cancer. Liver resection is the only curative option, with one third of resected patients alive at five years. In those developing recurrence in the liver following resection, further liver surgery may be curative, with similar 5 years survival rates of about 30%. Until recently surgery was feasible in only 15-25% of patients with colorectal liver metastases. New strategies, such as downstaging chemotherapy, portal vein embolization and two-stage hepatectomy, may increase the resectability rate by 15%. Earlier detection of liver metastases would increase resectability, although good follow-up trials are lacking. Once suspected, colorectal liver metastases are staged by spiral CT, CT portography and MRI, which have similar overall accuracies. Mortality following liver resection is less than 5% in major centres, with a morbidity rate of 20% to 50%. Prognostic scoring systems can be used to predict the likely cure rate with resection. Pulmonary metastases occur in 10-25% of patients with resected colorectal cancer, but are limited to the lung in only 2% of cases. In these selected cases surgery provides long-term survival in 20-40%, and repeat lung resection has shown similar rates. For patients with unresectable disease, chemotherapy and ablation techniques have been demonstrated to prolong survival, although chemotherapy alone has been shown to improve quality of life.

Antimetabolites, Antineoplastic↗
PubMed2002

Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer.

PURPOSE: The prognosis for advanced pancreatic cancer remains poor. Gastrin acts as a growth factor for pancreatic cancer. We describe the first study of the antigastrin immunogen G17DT in pancreatic cancer. Our aims were to determine the antibody response, safety, tolerability, and preliminary evidence of efficacy of G17DT in advanced pancreatic cancer. PATIENTS AND METHODS: Thirty patients with advanced pancreatic cancer were immunized with three doses of either 100 micro g or 250 micro g of G17DT. RESULTS: In the whole group, 20 (67%) of 30 patients produced an antibody response. The 250- micro g dose resulted in a significantly greater response rate of 82% compared with 46% for the 100- micro g group (P =.018). The most significant side effects, seen in three patients, were local abscess and/or fever. The median survival for the whole group from the date of the first immunization was 187 days; median survival was 217 days for the antibody responders and 121 days for the antibody nonresponders. The difference in survival between the antibody responders and nonresponders was significant (P =.0023). CONCLUSION: Patients with advanced pancreatic cancer are able to mount an adequate antibody response to G17DT. The 250- micro g dose is superior to the 100- micro g dose, and it appears to be generally well tolerated. Antibody responders demonstrate significantly greater survival than antibody nonresponders. Phase III studies are currently underway in order to determine efficacy.

Adult↗
PubMed2002

Prognostic significance of intratumoural microvessel density (IMD) in resected pancreatic and ampullary cancers to standard histopathological variables and survival.

AIM: Angiogenesis is required for tumour growth. Its evaluation, by intratumoural microvessel density (IMD), has prognostic significance in many solid tumours. There is controversy regarding its use in pancreatic cancer and little is known about its role in ampullary tumours. The aim is to study IMD as a prognostic marker in resected ductal adenocarcinomas of head of pancreas and cancers of the ampullary region. METHODS: Forty-seven patients (23 pancreatic and 24 ampullary, mean age 62.0 years) surviving a potentially curative (R0/R1) resection were analysed. Paraffin-embedded sections of these tumours were immunohistochemically stained for CD-34 and IMD was determined (magnification x200). This was correlated with histopathological data and survival using Cox's multivariate analysis. RESULTS: Mean survival for the pancreatic cancer group was 18.4 months (SE=2.7) and 81.2 months (SE=9.9) for the ampullary cancer group. In the pancreatic cancer group, IMD was found to have independent prognostic significance to survival on multivariate analysis (P=0.002, Hazard Ratio (HR) 13.60) along with microscopic resection margin involvement (P=0.003, HR 15.18). For ampullary cancers, IMD was higher in those with lymph node metastasis (P=0.02, Mann-Whitney U -test). CONCLUSION: IMD in resected pancreatic cancers correlates with survival.

Adenocarcinoma↗
PubMed2002

Pk11195, a mitochondrial benzodiazepine receptor antagonist, reduces apoptosis threshold in Bcl-X(L) and Mcl-1 expressing human cholangiocarcinoma cells.

BACKGROUND: Cholangiocarcinoma cells express high levels of the antiapoptotic proteins Bcl-X(L) and Mcl-1 and are markedly chemo- and radioresistant. Mitochondria have emerged as central players in apoptosis. Antiapoptotic members of the Bcl-2 protein family localise to the outer mitochondrial membrane and regulate mitochondrial release of apoptogenic proteins. Mitochondrial benzodiazepine receptor (mBzR) ligands have been shown to reverse Bcl-2 action and facilitate apoptosis. AIM: We evaluated the ability of the mBzR antagonist Pk11195 to overcome preapoptotic mitochondrial dysfunction in Egi-1 and Tfk-1, two human cholangiocarcinoma cell lines expressing high levels of Bcl-X(L) and Mcl-1. MATERIALS AND METHODS: Cells growing in culture were used to perform in vitro experiments over 48-96 hours following treatment. The cytotoxic agents used were 5 fluorouracil 10 microM and etoposide (Vp16) 10 microM, together with ultraviolet and 0.5-1 Gy x ray irradiation with or without 75 microM Pk11195. Apoptosis and mitochondrial dysfunction were measured at single cell resolution by flow cytometry using the mitochondrial fluorochrome DiOC6(3). Severe combined immunodeficient non-obese diabetic (SCID-NOD) mice with subcutaneous xenografts using the Egi-1 and Tfk-1 cell lines were treated with etoposide with or without addition of Pk11195 over a 72 hour period during which time the xenograft growth patterns were monitored. RESULTS: In vitro, the effect of Pk11195 on induction of apoptosis in cholangiocarcinoma cells following stimulation by chemotherapy or radiotherapy was found to be both time and dose dependent, with Pk11195 increasing rates of apoptosis by 50-95%. Intraperitoneal administration of Pk11195 in combination with Vp16 was found to increase the growth inhibiting effects of Vp16 on xenografts during the treatment phase. PK11195 75 microM on its own had no intrinsic cytotoxic efficacy. CONCLUSION: This is the first study to demonstrate that functional antagonism of coexpressed Bcl-X(L) and Mcl-1 proteins using the mBzR antagonist Pk11195 can facilitate apoptosis in cholangiocarcinoma following chemotherapy and radiotherapy.

Antineoplastic Agents↗
PubMed2001

Assessment of hepatic ischaemia reperfusion injury by measuring intracellular tissue oxygenation using near infrared spectroscopy.

AIMS/BACKGROUND: Hepatic ischaemia/reperfusion (I/R) injury is a major cause of liver damage during liver surgery and transplantation. The relationship between the severity of I/R injury and the degree of intracellular hypoxia has not been investigated. METHODS: New Zealand white rabbits were used in 4 groups (n=6 each). At laparotomy, left lobe hepatic ischaemia was produced for 30, 45, or 60 min followed by 60 min reperfusion and compared with controls. Liver function, bile flow, and flow in the hepatic microcirculation (HM) were measured. Near infrared spectroscopy (NIRS) was used to monitor hepatic oxyhaemoglobin (HbO2), deoxyhaemoglobin (Hb), and cytochrome oxidase (Cyt Ox). RESULTS: I/R injury produced deranged liver function tests, reduced bile flow, and reduced flow in the microcirculation in comparison with controls. During ischaemia, HbO2 and Cyt Ox were significantly reduced in comparison with controls. After reperfusion, a biphasic change in tissue oxygenation was observed, with an initial increase in HbO2 and Cyt Ox followed by a progressive reduction. The reduction in tissue oxygenation with ischaemia and reperfusion paralleled the ischaemia time. After I/R, the changes in Cyt Ox (intracellular oxygenation) significantly correlated with the parameters of hepatocellular injury to a higher degree than HbO2 (extracellular oxygenation). CONCLUSION: This study shows the potential of monitoring the degree of I/R injury by measuring hepatic tissue intracellular oxygenation.

Animals↗
PubMed2001

Effect of graded hypoxia on the rat hepatic tissue oxygenation and energy metabolism monitored by near-infrared and 31P nuclear magnetic resonance spectroscopy.

Alteration in hepatic cellular adenosine triphosphate (ATP) levels has been shown to be a sensitive index for hypoxic damage. Hepatic ATP metabolism can be monitored by 31P nuclear magnetic resonance (NMR). Near-infrared spectroscopy (NIRS) can measure tissue oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and cytochrome oxidase (Cyt Ox), which reflect ATP production. In this study, hepatic oxygenation parameters have been correlated with ATP metabolism under graded hypoxia. Sprague-Dawley rats underwent laparotomy for liver exposure. NIRS probes and an NMR coil were placed on the liver and the animal was positioned in the NMR magnet. Graded hypoxia was achieved by a stepwise reduction of the fraction of inspired oxygen (FiO2) from 15 to 4%. Recovery between the hypoxic periods was achieved using 30% oxygen. Hepatic tissue oxygenation parameters were measured continuously by NIRS; 31P-NMR spectra obtained at 1 min intervals from energy metabolites and intracellular pH were calculated. All the hypoxic grades produced an immediate reduction in HbO2 with a simultaneous increase in Hb. Cyt Ox was reduced significantly only with FiO2 of </= 10%. 31P-NMR spectra showed a significant decrease in cellular beta nucleoside triphosphate (beta-NTP) only with FiO2 of </= 10%. Significant correlation was seen between beta-NTP and HbO2 (r=0.85), Hb (r=-0.74), and Cyt Ox (r=0.81). Cyt Ox was reduced with intracellular hypoxia and correlated temporally with the reduction of cellular beta-NTP, and therefore could be used as an index for the changes in beta-NTP with hypoxia.

Adenosine Triphosphate↗
PubMed2001

Inadvertent diclofenac rechallenge from generic and non-generic prescribing, leading to liver transplantation for fulminant liver failure.

This case report describes fulminant hepatic failure in a 53-year-old female caused by inadvertent rechallenging with diclofenac, treated by orthotopic liver transplantation. The case also illustrates the hazards of using both generic and non-generic drug prescribing, with drugs that are known to be toxic. The literature on non-steroidal anti-inflammatory drugs and hepatoxicity is reviewed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Genomic homogeneity in fibrolamellar carcinomas.

BACKGROUND: Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC) with distinctive clinical and histological features. To date there have been few studies on the genotypic aspects of FLC and no previous attempts have been made to use the arbitrarily primed-polymerase chain reaction (AP-PCR) technique to detect genetic alterations in this disease. AIM: The aim of this study was to assess the degree of genomic heterogeneity of FLC using the AP-PCR technique. METHODS: A total of 50 tissue samples of primary and metastatic FLCs from seven patients were microdissected. AP-PCR amplification of each genomic DNA sample was carried out using two arbitrary primers. RESULTS: DNA fingerprints of the primary FLCs and all their metastatic lesions (both synchronous and metachronous disease) were identical in an individual patient. The fingerprints were different between tumours of different patients. No evidence of intratumour heterogeneity was observed. CONCLUSIONS: Such genomic homogeneity in FLCs may explain their indolent growth. The absence of clonal evolution, which is present in other tumours (particularly HCCs), may explain the distinct behaviour in this tumour. The tumorigenic pathway and degree of somatic genomic changes in this disease may be less complex than in HCC.

Carcinoma, Hepatocellular↗
PubMed2001

The expression of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1 in benign, dysplastic, and malignant biliary epithelium.

AIM: Cholangiocarcinoma can be cured by surgery, but only in a minority of cases. The activation of apoptosis is a major mode of action of chemotherapy and radiotherapy, which have limited benefit in the treatment of cholangiocarcinoma. The antiapoptotic members of the Bcl-2 protein family (Bcl-2, Bcl-X(L), and Mcl-1) are important inhibitors of apoptosis, but have not been investigated extensively in cholangiocarcinoma. METHODS: The expression of Bcl-2, Bcl-X(L), and Mcl-1 was investigated in normal biliary epithelium (17), biliary dysplasia (three), and invasive cholangiocarcinoma (51), in addition to three human cholangiocarcinoma cell lines, by immunohistochemistry and immunofluorescence. RESULTS: The expression of Bcl-2 was not detected in normal or malignant biliary tissue. In contrast, granular cytoplasmic Bcl-X(L) and Mcl-1 staining was found in 60-100% of cells in all normal, dysplastic, and malignant specimens, including the human cell lines examined in this study. CONCLUSION: These findings indicate that Mcl-1 and Bcl-X(L), but not Bcl-2, are involved in the survival of normal and neoplastic cells in the biliary tree. By prolonging survival through blocking apoptosis, these proteins might be reducing the efficacy of cytotoxic anticancer treatments in cholangiocarcinoma.

Apoptosis↗
PubMed2000

Liver transplantation complicated by embedded transjugular intrahepatic portosystemic shunt: a new method for portal anastomosis- a surgical salvage procedure.

A transjugular intrahepatic portosystemic shunt (TIPS) is an increasingly used method of treating variceal bleeding from portal hypertension. Many patients are subsequently listed for transplantation, which may be complicated by malposition of the inferior end of the TIPS stent. This report details such a case and offers a surgical technique to salvage this situation.

Adult↗
PubMed2000

Results of choledochojejunostomy in the treatment of biliary complications after liver transplantation in the era of nonsurgical therapies.

Advances in radiological and endoscopic techniques have allowed many biliary complications after orthotopic liver transplantation (OLT) to be managed without surgery. The influence of nonsurgical management on the outcome of patients requiring surgical revision has not been addressed. We reviewed our 10-year experience (October 1988 to January 1998) of Roux-en-Y choledochojejunostomy (CDJ) to treat biliary complications after OLT. Forty-six patients underwent CDJ for biliary complications (32 men, 14 women; age, 22 to 65 years; median, 60 years). Biliary reconstruction at the time of OLT was duct to duct in 41 patients, primary CDJ in 3 patients, and gall bladder conduit in 2 patients. T-tubes were used only in patients with gallbladder conduit. The indication for CDJ was biliary leak (23 patients), stricture (20 patients), biliary stones (2 patients), and biliary sludge (1 patient). Two patients (4.3%) had associated hepatic artery thrombosis. The bile leaks were diagnosed at a median of 29 days post-OLT (range, 2 to 65 days) and strictures at a median of 2 years (range, 33 days to 6.5 years) post-OLT. Before surgery, 25 patients (54%) underwent an attempt at radiological or endoscopic therapeutic intervention that failed. Median follow-up was 5 years (range, 9 months to 10 years). Early complications occurred in 12 patients (26%); the most common was chest infection (4 patients). There were 3 perioperative deaths (6%); 1 death was directly related to surgery. Late complications, mainly anastomotic strictures, occurred in 10 patients (22%), half of which were successfully treated by biliary balloon dilatation. The complication rate post-CDJ was less in those who underwent a failed nonsurgical approach than those proceeding straight to surgery (9 of 25 patients; 36% v 13 of 21 patients; 62%; P =.21, not significant). The procedure-related mortality for surgical revision of biliary complications after OLT is low, but early and late complications are common. A failed attempt at nonsurgical management does not increase the complications of reconstructive surgery. Strictures after CDJ should be considered for biliary balloon dilatation.

Adult↗
PubMed2000

Bioenergetic targeting during organ preservation: (31)P magnetic resonance spectroscopy investigations into the use of fructose to sustain hepatic ATP turnover during cold hypoxia in porcine livers.

During liver preservation, ATP supplies become depleted, leading to loss of cellular homeostatic controls and a cascade of ensuing harmful changes. Anaerobic glycolysis is unable to prolong ATP production for a significant period because of metabolic blockade. Our aim was to promote glycolysis during liver cold hypoxia by supplying fructose as an additional substrate, compared to supplementation with an equivalent concentration of glucose. Porcine livers (two groups; n = 5 in each) were retrieved by clinical harvesting techniques and subjected to two cycles of cold hypoxia and oxygenated hypothermic reperfusion. In the second cycle of reperfusion, the perfusate was supplemented with either 10 mmol/L glucose (Group 1) or 10 mmol/L fructose (Group 2). During reperfusion in both groups, similar levels of ATP were detected by phosphorus magnetic resonance spectroscopy ((31)P MRS). However, during subsequent hypoxia, ATP was detected for much longer periods in the fructose-perfused group. The rate of ATP loss was sevenfold slower during hypoxia in the presence of fructose than in the presence of glucose (ATP consumption of -7.2 x 10(-3)% total (31)P for Group 1 versus -1.0 x 10(-3)% total (31)P for Group 2; P < 0. 001). The changes in ATP were mirrored by differences in other MRS-detectable intermediates; e.g., inorganic phosphate was significantly higher during subsequent hypoxia in Group 1 (45.7 +/- 2.7% total (31)P) than in Group 2 (33.7 +/- 1.1% total (31)P; P < 0. 01). High-resolution MRS of liver tissue extracts demonstrated that fructose was metabolized mainly via fructose 1-phosphate. We conclude that fructose supplied by brief hypothermic perfusion may improve the bioenergetic status of cold hypoxic livers by sustaining anaerobic glycolysis via a point of entry into the pathway that is different from that for glucose.

Adenosine Triphosphate↗
PubMed2000

Non-invasive measurement of hepatic oxygenation by an oxygen electrode in human orthotopic liver transplantation.

Precise evaluation of graft reperfusion is difficult in clinical liver transplantation. The oxygen electrode (OE) is a novel technique to detect blood flow indirectly by measuring the quantity of oxygen which can diffuse from the hepatic tissue to the surface electrode. Application of the surface OE does not influence the liver blood flow or parenchymal perfusion. Adequate graft oxygenation is essential to the outcome of organ transplantation and has not previously been analysed intra-operatively in liver transplant recipients. The OE was applied to the surface of the graft intra-operatively in 22 human liver grafts after restoring portal vein and hepatic artery inflow. OE readings were compared with liver blood flow using an electromagnetic flowmeter (EMF). Intra-operative haemodynamics and donor organ parameters known to influence graft function were correlated with the OE readings. There was a significant correlation (r=0.89; p<0.001, n=14) between tissue oxygenation using the OE and total liver blood flow measured by EMF. The tissue oxygenation measurements were reproducible with a coefficient of variation of 5%. The hepatic tissue oxygenation increased significantly from baseline following venous reperfusion of the graft (282+/-23 vs 3107+/-288 (+/-SE) nA, p<0.001). Hepatic arterial revascularisation resulted in a significant (p<0.001) increase of 41+/-7% in liver oxygen perfusion. There was significant negative correlation (r=0.80, p<0.001, n=22) between cold ischaemic time and graft tissue oxygenation. The OE provides a reliable, cheap and non-invasive method of monitoring liver graft oxygenation and perfusion during transplantation.

Adult↗
PubMed2000

Effect of liver blood flow and function on hepatic indocyanine green clearance measured directly in a cirrhotic animal model.

BACKGROUND: Peripheral blood clearance of indocyanine green (ICG) has been used as a test of liver function but gives little information on biliary excretion. Hepatic ICG uptake and clearance can be measured directly by near-infrared spectroscopy (NIRS). Direct ICG measurement has not previously been correlated with liver blood flow and function in cirrhosis. METHODS: Two groups of New Zealand white rabbits (n = 12) underwent laparotomy for liver exposure. Cirrhosis was induced by feeding animals (n = 6) with a high-cholesterol (2 per cent) diet for 16 weeks. Hepatic blood flow and microcirculation were measured. Hepatic ICG concentration was measured directly using NIRS probes on the liver surface. From the ICG concentration-time curve, hepatic ICG uptake and excretion rates were calculated by a non-linear least square curve fitting method. RESULTS: There was a significant reduction in ICG uptake rate (mean(s.d.) 0.300(0.130) versus 2.040(0.420) min-1; P = 0.0001) and ICG excretion rate (0.007(0.009) versus 0.227(0.096) min-1; P = 0. 002) in cirrhotic animals. The hepatic ICG uptake rate correlated with hepatic blood flow and flow in the microcirculation (r = 0.81, P = 0.002; r = 0.92, P < 0.001, respectively). The hepatic ICG excretion rate was significantly associated with indicators of impaired liver function including bilirubin (r = - 0.86, P = 0.0004), aspartate aminotransferase (r = - 0.81, P = 0.001) and lactate dehydrogenase (r = - 0.83, P = 0.0008). CONCLUSION: ICG uptake measured directly by NIRS reflects the reduced liver blood flow and perfusion in cirrhosis and its excretion correlates with the degree of liver parenchymal dysfunction. This technique may allow a more accurate method of liver function assessment than peripheral blood ICG clearance.

Animals↗
PubMed2000

Experimental study of a novel fibrin sealant for achieving haemostasis following partial hepatectomy.

BACKGROUND: Ensuring adequate haemostasis is a major difficulty in the field of liver surgery. This study aimed to evaluate a novel fibrin sealant (Vivostat), designed for autologous preparation, in a porcine model of partial hepatectomy. METHODS: Thirty-six Large White Landrace pigs underwent partial left hepatectomy by finger fracture under portal vascular inflow occlusion. Animals were randomized to treatment of the resected surface with either fibrin sealant (Vivostat, n = 12) or regenerated oxidized cellulose gauze (Surgicel, n = 12), or were left untreated (controls, n = 12). Blood loss from the resection margin was measured at 2-min intervals for 10 min, and the time to haemostasis was recorded. Following complete haemostasis the animals recovered for 7 days. RESULTS: Median (range) blood loss in the control group was 94.3 (17.3-467.0) g, and was significantly reduced with Vivostat (13.8 (5.5-150.9) g) and Surgicel (22.8 (5.8-67.3) g). Median (range) time to haemostasis in controls (31 (12-52) min) was also significantly reduced by Vivostat (8 (0-32) min) and Surgicel (10 (0-19) min) (both P < 0.001 versus controls, Kruskal-Wallis test). CONCLUSION: The novel fibrin sealant, Vivostat, is as effective as Surgicel cellulose gauze in achieving haemostasis after porcine partial hepatic lobectomy.

Animals↗