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Biomedical subjects

A R Dennison

Publications and source records attributed to A R Dennison.

At least 19 recordsLinked to original sources
PubMed2004

Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration.

Studies in vitro and in animal models of colorectal and hepatocellular cancers suggest that curcumin is an effective chemopreventive agent. In this pilot trial, we investigated whether oral administration of curcumin results in concentrations of the agent in normal and malignant human liver tissue, which are sufficient to elicit pharmacological activity. In total, 12 patients with hepatic metastases from colorectal cancer received 450-3600 mg of curcumin daily, for 1 week prior to surgery. Levels of curcumin and its metabolites were measured by HPLC in portal and peripheral blood, bile and liver tissue. Curcumin was poorly available, following oral administration, with low nanomolar levels of the parent compound and its glucuronide and sulphate conjugates found in the peripheral or portal circulation. While curcumin was not found in liver tissue, trace levels of products of its metabolic reduction were detected. In patients who had received curcumin, levels of malondialdehyde-DNA (M(1)G) adduct, which reflect oxidative DNA changes, were not decreased in post-treatment normal and malignant liver tissue when compared to pretreatment samples. The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.

Adenocarcinoma↗
PubMed2004

Angiogenesis of gastrointestinal tumours and their metastases--a target for intervention?

Angiogenesis is an obligatory event for the growth of tumours beyond 2 mm in diameter, above which simple oxygen diffusion can no longer support the rapid proliferation of malignant cells. Angiogenesis is a fine balance between inhibitory and stimulatory factors, the knowledge of which offers novel targets for the treatment of gastrointestinal neoplasia. A literature search of Pubmed and Medline databases was undertaken, using the keywords colorectal cancer, pancreatic cancer, gastrointestinal cancer, angiogenesis and anti-angiogenesis therapy. It was found that angiogenesis in primary tumours is a sequential and highly complex cascade of molecular events resulting in the rapid exponential growth of the tumour. Hepatic metastases of primary tumours may be less reliant on traditional angiogenic pathways, by co-opting pre-existing hepatic vasculature. Research into angiogenesis has revealed many different sites that can be targeted by agents such as tyrosine kinase inhibitors. Many anti-angiogenic agents are undergoing preclinical evaluation, with only a few entering phase I and phase III clinical trials. However, early results suggest that anti-angiogenic therapy could be an important adjunct to conventional chemotherapy treatment of gastrointestinal neoplasia.

Angiogenesis Inhibitors↗
PubMed2004

Two-stage liver resection and chemotherapy for bilobar colorectal liver metastases.

BACKGROUND: A significant number of patients with colorectal metastatic disease confined to the liver are inoperable at assessment. For these patients, the outlook is poor. Chemotherapy can 'down-stage' some tumours and render them operable. The authors present a series of patients with inoperable disease despite down-staging with chemotherapy, who underwent a two-stage resection to clear their metastatic disease. METHODS: The case-notes of 11 patients who were found to have inoperable hepatic metastatic disease were identified using computerised medical records and mean hospital stay, survival and long-term follow-up data was noted. RESULTS: The mean follow-up from initial resection was 13.5 months (range of 5-20 months). Three deaths were recorded in the follow-up interval. Causes of death included recurrence of hepatic disease following completion of two-stage resection, progression of original hepatic disease leading to inoperability at second stage operation and recurrence of original primary colorectal tumour. The mean survival in the patients who died was 17 months (range of 15-19 months). The remaining patients are alive to date with six patients showing no evidence of hepatic recurrence, follow-up period of 13 months (range of 8-20 months). One patient developed de novo prostate cancer and is awaiting his second liver resection, and one patient has stable hepatic disease with no evidence of progression. CONCLUSION: Two-stage liver resection can prolong survival when compared to chemotherapy alone, with a recurrence rate equivalent to ablation techniques. Longer-term studies are needed for further evaluation.

Adult↗
PubMed2004

Effect of patient, operative and isolation factors on subsequent yield and viability of human hepatocytes for research use.

It is widely accepted that the model of choice for pharmacotoxicological studies are human hepatocytes. There is therefore a demand for these cells, but quality must be maintained for their widespread use. We present a retrospective review of the isolation of hepatocytes from both surgically resected tissue and livers rejected for transplantation, and evaluated patient, operative and isolation variables to ascertain which may affect the viability and yield of cells. Seven clinically rejected whole livers and 60 surgically resected specimens (from two distinct operating centres) were isolated. For surgically resected tissue we found that decreasing age, securing the perfusing cannulae with suture rather than reforming Glissons capsule with glue and steatotic livers improved viability. No significant correlation could be found with pre-operative blood results, disease, type of operation, presence or absence of Pringle manoeuvre, weight of tissue isolated, time of digestion with collagenase and cold ischaemic time. There was a reduction in mean yield and viability when hepatocyte isolations were performed in livers rejected for transplant, compared to surgically resected tissue although this did not reach significance. Human hepatocytes can be successfully and consistently isolated from surgically resected tissue and appear to be superior to those isolated from rejected for transplant livers. From our study, there are few parameters that significantly affect the quality of isolated hepatocytes, which increases the possible pool of tissue that hepatocytes can be isolated from.

Adult↗
PubMed2003

Segmental nature of the porcine liver and its potential as a model for experimental partial hepatectomy.

BACKGROUND: In-depth knowledge of pig liver anatomy allows potential research into segmental liver resections and hepatic regeneration, as well as liver transplantation techniques. The segmental anatomy, however, remains largely unknown. This study aimed to delineate the segmental anatomy of the porcine liver in comparison with that of the human. METHODS: The segmental anatomy of the porcine liver was determined using acrylic injection casting of ex vivo pig livers, allowing the arterial, venous and biliary supply to be visualized directly. This was correlated using multi-slice computed tomography (CT) and three-dimensional reconstructions. RESULTS: Although the external morphology of the porcine liver differs from that of the human, the segmental anatomy is remarkably similar in term of its vascularity and biliary tree. CONCLUSION: Acrylic casting of the porcine liver accurately delineates the vascular and biliary anatomy, and is a useful tool for performing experimental liver surgery. The similarities between porcine and human segmental anatomy allow domestic swine to be used as a comparable model. Three-dimensional CT reconstructions can also accurately visualize the anatomy and may be used to perform virtual surgery, or to assess segmental volumes.

Animals↗
PubMed2002

Palliation of pancreatic cancer using electrolytic ablation.

BACKGROUND: Inoperable pancreatic cancer has a dismal prognosis. Palliation involves either stenting or surgical bypass. Stenting does not relieve gastric outlet obstruction, and surgical bypass is a major procedure. A minimally invasive procedure is needed that relieves both gastric outlet and biliary obstruction, with the potential for relieving pain. METHODS: In an experimental model, pancreatic electrolysis was investigated. The pancreatic duct was cannulated via a transduodenal approach with an electrode catheter. In 6 animals an electrolytic "lesion" was created using a direct current generator. Six animals were controls. The local and systemic effects of electrolysis were assessed using histological and biochemical parameters. RESULTS: The pancreatic duct was cannulated in all animals and treatment was uneventful. Electrolytic lesions comprised a central area of necrosis with a sharp demarcation between necrotic and viable pancreas. All animals developed transient hyperamylasemia after electrolysis. There was no significant difference between treatment and controls. Importantly, no animal had clinical, biochemical, or histological evidence of pancreatitis. CONCLUSIONS: This experimental study suggested that electrolytic palliation of inoperable pancreatic cancer via the gastrointestinal tract is potentially safe. In patients, this treatment could be performed during endoscopic retrograde cholangiopancreatography and may have therapeutic advantages when compared to stenting or biliary bypass.

Amylases↗
PubMed2002

Electrolytic ablation as an adjunct to liver resection: experimental studies of predictability and safety.

BACKGROUND: Combined liver resection and local ablation may offer the only chance of cure to patients with liver metastases who are presently deemed unresectable because of a single awkwardly placed metastasis. By definition, such a metastasis is often close to a major vein. An ablative technique is needed that is both predictable and safe in such a circumstance. METHODS: Electrolytic liver lesions were created in 21 pigs using platinum electrodes, connected to a direct current generator. Both electrolytic 'dose' and electrode separation were varied to produce different sized lesions. The 'dose' was correlated with the volume of necrosis and any vascular damage was determined histologically. RESULTS: There was a significant (P < 0.001) correlation between the electrolytic 'dose' and the volume of liver necrosis. For a given 'dose' the volume of necrosis was less when the electrodes were together, rather than separated. Liver enzymes were only transiently deranged. There were no significant vascular injuries. CONCLUSION: Predictable and reproducible necrosis is produced by electrolysis in the pig liver. The treatment appears to cause little or no damage to immediately adjacent liver or major vascular structures and, when combined with resection, may offer the chance of a cure to many patients who are currently unresectable.

Alanine Transaminase↗
PubMed2002

The mystery of liver regeneration.

BACKGROUND: Partial hepatectomy is the strongest stimulator of hepatic regeneration. The process of initiation and the control of the final size of the regenerated liver have been the subject of research for many years. A better understanding of this process and the effect of disease may allow better selection of patients for partial hepatectomy. It may also allow an insight into the possible application of clinical stimulation of regeneration. METHODS: Data were reviewed from the published literature using the Medline database. RESULTS: Most knowledge comes from in vitro studies and the study of resection in the rat model. A variety of cytokines, hormones and growth factors are involved in regeneration but very few have been found capable of stimulating regeneration in vitro. The exact interactions are not known, but there is probably a cascade involving different factors at differing stages of regeneration. CONCLUSION: Further in vivo research should allow greater understanding of liver regeneration, thereby providing a potential therapeutic tool in patients for whom regeneration has failed, or is likely to fail. Such research is also important in respect of liver support devices, which may inhibit liver regeneration by filtration of many of the factors involved.

Cytokines↗
PubMed2002

Idiopathic chronic ulcerative enteritis--the role of radical surgical resection.

Idiopathic chronic ulcerative enteritis is uncommon. It is a term that describes ulceration of the small bowel in the absence of a recognisable cause. Patients mainly present with a surgical abdomen and their management often proves to be a therapeutic challenge. Our series describes three such cases: the first patient presented with a tender left iliac fossa mass and rectal bleeding, the second with peritonitis and pneumoperitoneum, the third with severe acute colitis. All three patients needed urgent surgical intervention with further laparotomies due to recurrent ulceration, perforation and fistula formation in addition to intensive supportive measures such as inotropes and total parenteral nutrition. The importance and challenges of idiopathic chronic ulcerative enteritis are therefore discussed.

Adult↗
PubMed2001

Pancreas resection and islet autotransplantation for end-stage chronic pancreatitis.

OBJECTIVE: To assess the safety and efficacy of islet autotransplantation (IAT) combined with total pancreatectomy (TP) to prevent diabetes. SUMMARY BACKGROUND DATA: There have been recent concerns regarding the safety of TP and IAT. This is thought to be related to the infusion of large volumes of unpurified pancreatic digest into the portal vein. Minimizing the volume of islet tissue by purifying the pancreatic digest has not been previously evaluated in terms of the postoperative rate of death and complications, pain relief, and insulin independence. METHOD: During a 54-month period, 24 patients underwent pancreas resection with IAT. Islets were isolated using collagenase and a semiautomated method of pancreas digestion. Where possible, islets were purified on a density gradient and COBE processor. Islets were embolized into the portal vein, within the spleen and portal vein, or within the spleen alone. The total median volume of digest was 9.9 mL. RESULTS: The median number of islets transplanted was 140,419 international islet equivalents per kilogram. The median increase in portal pressure was 8 mmHg. Early complications included duodenal ischemia, a wedge splenic infarct, partial portal vein thrombosis, and splenic vein thrombosis. Intraabdominal adhesions were the main source of long-term problems. Eight patients developed transient insulin independence. Three patients were insulin-independent as of this writing. Patients had significantly decreased insulin requirements and glycosylated hemoglobin levels compared with patients undergoing TP alone. Of the patients alive and well as of this writing, four had failed to gain relief of their abdominal pain and were still opiate-dependent. CONCLUSION: Combined TP and IAT can be a safe surgical procedure. Unfortunately, almost all patients were still insulin-dependent, but they had decreased daily insulin requirements and glycosylated hemoglobin levels compared with patients undergoing TP alone. A prospective randomized study is therefore needed to assess the long-term benefit of TP and IAT on diabetic complications.

Adult↗
PubMed2000

Electrochemical lesions in the rat liver support its potential for treatment of liver tumors.

BACKGROUND: An effective therapy is needed for patients with surgically unresectable liver tumors who have very limited life expectancy. One possible treatment is electrochemical tumor necrosis. This study investigated the natural history of electrochemical lesions in the normal rat liver. MATERIALS AND METHODS: A direct current generator, connected to platinum electrodes, was used to create controlled areas of liver necrosis. Animals were sacrificed 2 days, 2 weeks, 2 months, and 6 months after treatment and the macroscopic and histological appearance of the necrotic lesions was followed. RESULTS: No animal died as a result of electrolysis; postoperatively, all gained weight normally. Liver enzymes were significantly (P < 0.001) elevated after treatment, but returned to normal after a week. Two days after electrolysis, histology confirmed an ellipsoidal area of coagulative necrosis at the site of the electrode tip and commonly a segment of peripheral necrosis. After 2 weeks there was histological evidence of healing. By 6 months, very little necrotic tissue remained within a small fibrous scar. CONCLUSIONS: Electrolysis is a safe method for creating defined areas of liver necrosis that heal well with no associated mortality. This study supports the potential of electrolysis for treating patients with unresectable liver tumors.

Animals↗
PubMed2000

The feasibility of spleen-preserving pancreatectomy for end-stage chronic pancreatitis.

BACKGROUND: It is considered difficult to preserve the spleen at the time of distal or total pancreas resection for chronic pancreatitis (CP). The aim of this study was to assess the feasibility of preserving the spleen in patients requiring total or completion pancreatectomy for CP. METHODS: All patients having total or completion pancreatectomy for CP were evaluated postoperatively in terms of morbidity, mortality, and pain relief. To assess splenic vascularity, all patients underwent abdominal ultrasound and power doppler imaging to assess splenic perfusion and the patency of the remaining splenic vessels. RESULTS: Of 35 patients having total pancreatectomy, the spleen was preserved in 30 patients (19 women, 11 men; median age 40 years). The etiology of CP was mainly idiopathic (n = 14) or alcohol related (n = 12). All patients presented with chronic abdominal pain (median 5 years) requiring opiate-derived analgesia for pain relief. Fifteen patients (50%) had undergone previous therapeutic intervention for pain relief. The spleen was preserved with either an intact splenic artery and vein in 19 patients and or the short gastric vessels (n = 11). The mean duration of the procedure was 7 hours (range 5 to 11) and mean blood loss was 1,090 mL. The 30-day mortality was 3.8% (n = 1). Five patients had splenic complications (17%). These included splenectomy (n = 2), intrasplenic collection (n = 2), and a wedge splenic infarct (n = 1). Two of these complications were related to intrasplenic islet autotransplants. Follow-up with abdominal ultrasound and power doppler scanning showed no other abnormalities; blood flow was demonstrable in all patients with intact splenic arteries and vein (n = 19). The mean hospital stay was 25 days. Of the 24 patients who were beyond 6 months' follow-up, 82% (n = 20) have complete relief of pain, and 4 still require opiate analgesia. CONCLUSIONS: Spleen-preserving pancreatectomy is a feasible procedure for chronic pancreatitis, providing complete pain relief in 80% of patients. When the splenic artery and vein cannot be preserved, there is a minimal risk of splenic complications that may require further treatment; but for the majority of patients, splenectomy is avoided.

Adult↗
PubMed2000

The safety of electrolytically induced hepatic necrosis in a pig model.

BACKGROUND: Electrolysis fulfils the criteria for an ideal treatment of patients with unresectable liver tumours. Previous studies in the rat and pig have shown that controlled necrosis can be safely produced by inserting platinum electrodes into normal liver' parenchyma and liver tumours. As with any new treatment it is mandatory to investigate the 'worst-case scenario' of inadvertent intravascular electrode placement in a large animal model before progressing to clinical trials. METHODS: Under ultrasound control in six pigs, electrodes were inserted into, or immediately adjacent to, an hepatic vein. An electrolytic 'dose' of 100 C was then administered and the evolution of the lesion was monitored using ultrasound. Venous blood was collected before and during the electrolysis to evaluate potential acid/base disturbances and animals were closely monitored during electrolysis and during their recovery until a full autopsy was performed 4-7 days after treatment. RESULTS: Gas bubbles were seen to enter the hepatic veins or interior vena cava during treatment in five of the six animals. There were no major complications as a consequence and all animals recovered and remained in a healthy state until they were killed. At autopsy one animal had complete thrombotic occlusion of the left hepatic vein. Otherwise, findings were normal. CONCLUSION: In the clinical setting, due to the use of ultrasound to guide electrode placement into the centre of a tumour, the electrodes should rarely juxtapose an hepatic vein. Nevertheless, in this extreme situation, electrolysis is surprisingly safe with only one major vascular occlusion and no morbidity or mortality.

Animals↗
PubMed2000

Electrolytic treatment of colorectal liver tumour deposits in a rat model: a technique with potential for patients with unresectable liver tumours.

BACKGROUND/AIMS: Patients with unresectable malignant liver tumours have a poor prognosis. A technique is needed which improves long-term survival. Previous studies in the rat have shown that electrolysis is a safe, predictable and reproducible method for creating areas of necrosis in the normal rat liver. This study examined the effects of electrolysis on colorectal liver 'metastases' in the rat. METHODS: Tumours of colorectal origin were implanted into the livers of Wistar-WAG rats. Two weeks after implantation the tumours were treated with electrolysis. A direct current generator, connected to 2 platinum intrahepatic electrodes was used to examine the effects of various electrode configurations on the extent of tumour necrosis. RESULTS: Significant (p<0.001) tumour ablation was achieved with all electrode configurations. Tumour necrosis was more complete (p<0.05) with the electrodes positioned on either side of the tumour than with both electrodes placed in the centre of the tumour. Liver enzymes (AST and ALT) were significantly (p<0.001) elevated after treatment, but returned towards normal by 2 days. CONCLUSIONS: This study has shown that colorectal liver 'metastasis' can be ablated by electrolysis in a rat model. Two separate mechanisms of tumour ablation were observed: With the electrodes directly in or adjacent to the tumour, necrosis resulted from the action of cytotoxic electrode products, whereas by positioning the electrodes proximal to the tumour, necrosis was induced by a 'secondary' ischaemic effect. The findings confirm the view that electrolysis has great potential for treating patients with unresectable malignant liver tumours.

Adenocarcinoma↗
PubMed2000

Intrahepatic biliary cystadenoma causing luminal common bile duct obstruction.

BACKGROUND: Biliary cystadenomas are rare cystic tumours that arise in the liver or less frequently in the extrahepatic biliary system. They are commoner in middle-aged women, their most favoured site is the right hepatic lobe. METHODS: Case report and review of the literature. RESULTS: We present only the second case of an intrahepatic cystadenoma causing luminal obstruction of the common bile duct. Clinical presentation is often non-specific and can prove to be a diagnostic challenge. CONCLUSION: Wide local excision of biliary cystadenomas is recommended, with regular radiological follow-up.

Adenoma, Bile Duct↗