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R C Williamson

Publications and source records attributed to R C Williamson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Experimental models of pancreatitis.

Experimental animal models are helpful tools that have been employed to study pancreatitis for more than a century. Although not closely related to all aspects of the human disease, they have contributed greatly to our current understanding of the pathophysiology and cell biology of this disease. They have also become a standard means of testing innovative treatments against pancreatitis. This article reviews the experimental models of acute pancreatitis in common use, their severity, the criteria for the selection of an appropriate model, standards in monitoring and relevance to clinical disease. Despite their undoubted value in elucidating the mechanisms involved in the early cellular events and pathophysiology of acute pancreatitis, these models have not lent themselves to the development of effective new therapies. Models of chronic pancreatitis are also reviewed. The development of a reproducible model relevant to human chronic pancreatitis remains challenging. Experimental models of chronic pancreatitis have not yet added greatly to the understanding of the pathogenesis of this disease in man.

Animals↗
PubMed1998

Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer.

Overexpression of tissue factor (TF) is characteristically observed in advanced pancreatic cancer and has been associated with invasion and metastasis. Functional responses of TF activation are here investigated using as a model system the human pancreatic cancer cell lines SW979 (which overexpresses TF) and MIAPaCa2 (which does not express detectable levels). After stimulation of these cell lines with factor VIIa (FVIIa), the only known TF ligand, expression of urokinase receptor (uPAR) gene was up-regulated in SW979 cells in a dose-dependent manner but not in MIAPaCa2 cells. Interestingly, urokinase (uPA) and its specific inhibitor PAI-1 were not up-regulated. Exposure to functionally inactivated FVIIa did not show any effect on uPAR expression on SW979 cells despite binding to TF with higher efficiency. The neutralizing anti-TF antibody 5G9 blocked the FVIIa-induced up-regulation of uPAR completely, whereas hirudin failed to block this up-regulation. Treatment of SW979 cells with Factor Xa did not up-regulate the expression of uPAR gene, whereas treatment with FVII induced the same level of enhanced uPAR gene expression as that with FVIIa. In the matrigel invasion assay, enhanced invasion of SW979 cell line induced by FVIIa was completely inhibited by anti-TF antibody and alpha2-antiplasmin. Moreover, the endogenous levels of uPAR gene expression were significantly correlated with the level of TF gene expression in 19 human cancer cell lines (P < 0.05). These data suggest that up-regulation of uPAR expression by tumor cells leading to tumor invasion is induced through the TF-FVIIa pathway rather than TF-initiated thrombin generation. This is the first report that TF may be one of the key receptors that can up-regulate expression of the plasminogen activator receptor in human cancer cells to enhance tumor invasion and metastasis.

Breast Neoplasms↗
PubMed1998

Proliferation of parenchymal epithelial cells enhanced in chronic pancreatitis.

This study was performed to determine whether pancreatic parenchymal epithelial cells in human chronic pancreatitis tissues retain a biologically significant capability to proliferate and, if so, within which epithelial compartment proliferation occurs. The techniques of immediate per-operative in vitro labelling with bromodeoxyuridine (BrdU) and conventional immunohistochemistry for Ki-67 antigen expression were used to identify proliferating cells. Concordance between the two techniques was confirmed in all tissues examined. In normal pancreas, proliferation was restricted to acinar epithelial cells, with no activity in the ductules. In chronic pancreatitis of both chronic obstructive and chronic calcifying types, the number of proliferating cells in the acini was significantly increased. A small population of proliferating cells was also apparent within ductules in chronic calcifying pancreatitis, but not in chronic obstructive pancreatitis. This investigation has shown that loss of parenchymal epithelium occurring in chronic pancreatitis is not caused by a primary failure of pancreatic 'stem-cell' proliferation, but is due to disproportionate attrition of differentiated parenchymal epithelial cells by a mechanism, possibly stromal in origin, which remains hitherto unidentified. The presence of proliferating ductular cells in chronic calcifying pancreatitis, but not chronic obstructive pancreatitis, suggests that distinct pathogenic processes may be operating in the former condition, which is classically regarded as secondary to ductal obstruction by stones, and in this single respect might be considered to be identical to chronic obstructive pancreatitis. Preservation of 'stem-cell' function supports the belief that regeneration of pancreatic parenchymal tissue could be a feasible proposition if biologically appropriate management strategies were developed to treat chronic calcifying pancreatitis.

Adult↗
PubMed1998

Venous thromboembolism and cancer.

The association of thrombosis with malignant disease has been recognized for well over 100 years. Evidence from experimental and clinical studies indicates that the haemostatic system is involved in the growth, invasion and metastasis of tumours. Laboratory parameters of haemostasis are frequently deranged in patients with cancer and overt thrombosis is common spontaneously where it may be the first sign of malignancy or secondary to therapy. The mechanisms by which coagulation activation facilitates the malignant process remain to be completely elucidated, but it is clear that cells and proteins of the coagulation and fibrinolytic systems are involved at many steps in the processes of tumour growth and dissemination. The low-molecular-weight heparins with their well-proven safety and efficacy profiles offer unique modalities for the prevention and treatment of cancer-associated thrombosis. They may also play a role in overall mortality reduction in patients with malignant disease.

Antineoplastic Agents↗
PubMed1998

Increased nitric oxide activity in a rat model of acute pancreatitis.

BACKGROUND: Overproduction of nitric oxide (NO) via induction of the inducible NO synthase (iNOS) is an important factor in the haemodynamic disturbances of several inflammatory states. AIMS: To identify the role of NO in a caerulein induced model of acute pancreatitis in the rat. METHODS: Arterial blood pressure and plasma NO metabolites were measured at zero and seven hours in adult male Wistar rats administered caerulein (n=10) or saline (n=10). Pancreatic activity of NOS (inducible and constitutive) was assayed biochemically. The pancreatic expression and cellular localisation of NOS and nitrotyrosine (a marker of peroxynitrite induced oxidative tissue damage) were characterised immunohistochemically. RESULTS: Compared with controls at seven hours, the pancreatitis group displayed raised plasma NO metabolites (mean (SEM) 70.2 (5.9) versus 22.7 (2.2) micromol/l, p<0.0001) and reduced mean arterial blood pressure (88.7 (4.6) versus 112.8 (4.1) mm Hg, p=0.008). There was notable iNOS activity in the pancreatitis group (3.1 (0.34) versus 0.1 (0.01) pmol/mg protein/min, p<0.0001) with reduced constitutive NOS activity (0.62 (0.12) versus 0.96 (0.08) pmol/mg protein/min, p=0.031). The increased expression of iNOS was mainly localised within vascular smooth muscle cells (p=0.003 versus controls), with positive perivascular staining for nitrotyrosine (p=0.0012 versus controls). CONCLUSIONS: In this experimental model of acute pancreatitis, iNOS induction and oxidative tissue damage in the pancreas is associated with raised systemic NO and arterial hypotension. Excess production of NO arising from the inducible NO synthase may be an important factor in the systemic and local haemodynamic disturbances associated with acute pancreatitis.

Acute Disease↗
PubMed1998

Collagen variation during experimental acute obstruction of the left colon.

BACKGROUND/AIMS: The colonic response to obstruction is poorly understood. Thickening of the proximal bowel following colonic stricture may be due to increased protein synthesis. We have investigated the colonic morphology and collagen concentration during the development of left-sided colonic obstruction in an animal model. METHODS: Twelve male Wistar rats received either a silk ligature obstruction of the colon 2.5 cm above the peritoneal reflection (n = 6) or manipulation of the left colon (controls, n = 6). Twenty-four hours later, three colonic specimens from the ligature zone and from 1 cm proximal and distal to this site, or from equivalent regions in controls, were assayed for hydroxyproline concentration. RESULTS: In controls there was no difference in hydroxyproline concentration between colonic sites. In obstructed rats, the hydroxyproline concentration was greater both at the ligature and distally, when compared with the proximal region. The hydroxyproline concentration was higher (p < 0.05) than corresponding control values at the ligature site (14.95 +/- 2.76 vs. 10.97 +/- 1.95 microgram/mg of dry tissue mean +/- s.d.) but not on either side. CONCLUSION: The colonic collagen concentration is equivalent or raised near an obstruction, demonstrating that obstructed colon may possess an enhanced capacity to hold sutures.

Animals↗
PubMed1998

Thromboprophylaxis in the cancer patient.

Thrombosis is a common complication in patients with malignant disease resulting from tumour elaboration of procoagulants and subsequent activation of intravascular coagulation. Cancer therapies (operation, chemotherapy and the use of central venous lines) further heighten the risk of thrombosis. The risk of thrombosis in cancer operations is of sufficient magnitude to necessitate routine thromboprophylaxis, for which low-dose unfractionated heparin or the low-molecular-weight heparins (LMWHs) have been proven effective and safe. Thrombotic complications with chemotherapy have been extensively described in women receiving either adjuvant or palliative cytotoxic or hormonal therapy for breast carcinoma. The problems are common, but of all the suitable prophylactic modalities available, only oral anticoagulants have been evaluated for this indication. Thrombosis complicates the use of central venous catheters in the cancer patient and both low-dose warfarin and LMWHs are effective in protecting against line-associated thrombi. Recent evidence from the retrospective analyses of randomized studies comparing unfractionated heparin and LMWH in the treatment of deep vein thrombosis have shown a striking mortality reduction among cancer patients who received LMWH. The use of LMWHs to prolong survival in patients with advanced malignant disease is currently the subject of a prospective, randomized, placebo-controlled study.

Administration, Oral↗
PubMed1998

Three-dimensional spiral CT angiography in pancreatic surgical planning using non-tailored protocols: comparison with conventional angiography.

The aim of this study was to investigate three-dimensional spiral computed tomography (3DCT) as an adjunct to routine pancreatic CT scanning, with particular regard to the identification of surgically important hepatic arterial anomalies, correlated with conventional visceral angiography. 32 patients underwent spiral CT scans prior to pancreatic surgery using established protocols. Oral contrast medium was used throughout. 150 ml of intravenous contrast medium was given at 3 ml s-1 with a 24 s spiral CT sequence starting 35 s after the start of infusion. Two protocols were employed, both with a pitch of 1:3 mm table feed/collimation (n = 17) and 5 mm table feed/collimation (n = 15). Overlapping (1 mm minimum) axial reformats were reconstructed. 3DCT shaded-surface displays of the visceral arteries were assessed for visceral arterial anomalies. Visceral angiography (n = 23) was independently correlated. Satisfactory 3D angiograms were performed in all but one patient, in whom the coeliac axis was missed. (i) 3 mm protocol: 3DCT (n = 17) showed three anomalous right hepatic arteries (ARHA), one trifurcation anomaly and one splenic artery with an aortic origin. Angiography (n = 11) confirmed these findings, although one patient with an ARHA did not have angiography. A left gastric arterial supply to the left liver was not detected. (ii) 5 mm protocol: 3DCT (n = 15) showed two cases of ARHA. While confirming these findings, angiography (n = 12) showed a third case of ARHA, in which the coeliac and superior mesenteric artery had very close origins. A left gastric supply to the left liver was also missed. It is concluded that satisfactory 3DCT is possible without changing existing scanning protocols, although narrow sections are required for the confident assessment of right hepatic arterial anomalies, and any left hepatic supply via the left gastric artery was poorly assessed in this series.

Adolescent↗
PubMed1997

Spiral CT and the pre-operative assessment of pancreatic adenocarcinoma.

AIM: To determine the value of spiral computed tomography (CT) in the pre-operative assessment of pancreatic carcinoma. PATIENTS AND METHODS: Fifty patients with proven pancreatic carcinoma referred for pancreatoduodenectomy underwent pre-operative spiral CT using a dedicated pancreatic protocol to determine tumour resectability. Twenty-eight patients subsequently underwent surgical exploration. RESULTS: Pre-operative imaging suggested that 15 tumours were resectable, and macroscopic clearance was complete in 13 giving a positive predictive value (PPV) of 87%. PPV of irresectability was 92%. CT underestimated locally advanced disease (n = 2), missed small hepatic metastases (n = 1), and lymphadenopathy (n = 1). CT overestimated SMV encasement in 1 case, otherwise prediction of vascular patency and compromise was correct. The conspicuity of small resectable carcinomas was improved by spiral scanning. CONCLUSION: The optimised pancreatic parenchymal enhancement and vascular opacification achieved by spiral CT improves tumour detection of small carcinomas, allows accurate assessment of peripancreatic vessels, and reliably predicts both resectable and irresectable disease. CT remains inherently limited in the prediction of early extrapancreatic non-vascular spread and of lymphatic metastases.

Adenocarcinoma↗
PubMed1997

Effect of intraoperative nutritional solutions on perianastomotic colonic mucosa in experimental large bowel obstruction.

We investigated the effect of intraoperative lavage with various solutions on the morphology of the mucosa adjacent to the anastomosis performed in left-sided colonic obstruction. After 24 hr of ligature obstruction to the pelvic colon, 108 male Wistar rats underwent colonic resection followed by primary anastomosis and were randomized for lavage with one of four different solutions: saline, povidone-iodine, 10% hypertonic glucose (HG), and short-chain fatty acids (SCFA). A control group had no lavage. The anastomotic region was studied both macroscopically and with light microscopy after three or six days. At day 3, lavaged animals, especially those with SCFA, had significantly smaller ulcers than controls, and at day 6 only rats lavaged with SCFA and HG were free of large ulcers. At day 3, median (interquartile range) crypt depth was higher in SCFA [360 (286-374) microm] and HG animals [306 (279-315) microm] when compared with controls [243 (225-252) microm; P < 0.05], and SCFA [67 (53-89)] rats showed more cells per crypt than controls [48 (39-52); P < 0.05]. No differences occurred on the sixth day. We conclude that intraoperative lavage with nutrient solutions, particularly with SCFA, has a trophic effect on the colonic mucosa. The suture line gap in the mucosa may be filled more quickly, thus contributing to improve the healing of a colonic anastomosis.

Anastomosis, Surgical↗
PubMed1997

Chronic pancreatitis and neoplasia: correlation or coincidence.

Any link between pancreatic carcinoma and chronic pancreatitis could reflect the malignant potential of a chronic inflammatory process. Four patients with ductal adenocarcinomas had a long history of pancreatic pain (median duration 5 years) and showed clear-cut evidence of chronic pancreatitis "downstream" of the tumour. Four were alcoholics and two heavy smokers. These four cases arose within a surgical series of approximately 250 patients with chronic pancreatitis, giving an incidence of 1.6 per cent. The incidence and anatomical distribution of carcinoma and chronic pancreatitis could possibly be consistent with a casual relationship.

Adenocarcinoma↗
PubMed1997

Prevention of venous thromboembolism in cancer using low-molecular-weight heparins.

Patients with cancer are at increased risk for venous and arterial thromboembolism and the principal interventions in such patients--surgical operation, chemotherapy or venous catheterization--heighten this risk. Thromboprophylaxis is indicated in cancer patients undergoing surgical operation and there is also evidence that thrombopropylaxis appears beneficial during chemotherapy, particularly for breast cancer, and possibly for ovarian and pancreatic carcinoma. Low-molecular-weight heparins (LMWHs) have shown promise as a thromboprophylactic agent in oncology patients, and offer significant benefits over standard heparin because of their improved safety profile and ease of use. There is emerging evidence that LMWHs may also favourably influence survival, possibly as a result of direct anti-tumour effects.

Heparin↗
PubMed1996

Proximal pancreatoduodenectomy for chronic pancreatitis.

A personal series is reported of 52 patients who underwent proximal pancreatoduodenectomy for severe chronic pancreatitis between 1979 and 1994. There were 13 women and 39 men of median age 42.2 (range 12-70) years. Disease predominantly affected the head of pancreas, with calcification present in 37 patients. Indications for operation were chronic pain (47 patients), obstructive jaundice (19) and duodenal stenosis (six); cancer was suspected in 12. In addition, 14 patients had a pseudocyst, two pancreatic endocrine failure and 20 exocrine failure. Aetiology was chronic alcohol abuse in 34, recurrent acute pancreatitis in five and unknown in 13. Pylorus-preserving proximal pancreatoduodenectomy was performed in 45 patients, while the remaining seven had partial gastrectomy. Drainage of a dilated distal pancreatic duct by side-to-side pancreaticojejunal anastomosis was included in 15 patients. Mean operating time was 6.2 (range 4.5-9.5) h and mean blood loss was 2.7 (range 0.2-13.0) litres. There were no hospital deaths, but three patients required a second operation and five had percutaneous drainage of infected collections. During a median follow-up of 54 months, six patients required completion distal pancreatectomy for renewed pain and four others had persistent pain. Four patients required intervention for stricture at the biliary-enteric anastomosis. Ten patients have died from causes not directly related to chronic pancreatitis. Proximal pancreatoduodenectomy is a relatively safe procedure, effectively palliating pain in 80 per cent of patients with chronic pancreatitis.

Abdominal Pain↗
PubMed1996

External beam and intraluminal radiotherapy for locally advanced bile duct cancer: role and tolerability.

BACKGROUND AND PURPOSE: Cholangiocarcinoma is rare but carries a poor prognosis. Radiotherapy has been used either as an adjuvant treatment following surgical resection of tumour or for palliation. The purpose of this study was to assess the feasibility and morbidity of accelerated external beam radiotherapy with or without intraluminal radiotherapy in the treatment of locally advanced bile duct cancer. MATERIALS AND METHODS: Thirty eight patients were treated. Surgical procedures performed prior to radiotherapy were extended hepatectomy (3), hepaticojejunostomy with tumour resection (6), palliative biliary-enteric bypass (6), biopsy (4), Whipple's procedure (1), gastrojejunostomy (1) and cholecystectomy (1). Twenty patients received external beam radiotherapy (ERT). Six patients received one Phase of ERT and 12 received two Phases, separated by a 2-week gap. Dose per Phase was 22.5 Gy in 10 twice daily fractions. After 1989, dose per Phase was increased to 27.5 Gy. One patient received Phase I ERT (30.0 Gy) using conventional fractionation and one patient received an uninterrupted, conventionally fractionate course of treatment (50.0 Gy). Fourteen patients received both ERT and intraluminal radiotherapy (IRT) using iridium-192 (192Ir) wire passed through a percutaneous, transhepatic catheter (median dose, ERT 23.8 Gy + IRT 40.0 Gy). In addition, four patients received IRT alone (median dose 45.0 Gy at 1 cm radius). Patients were followed for at least 42 months. RESULTS: Median overall survival was 15 months. Overall survival for the whole group at 1,2 and 3 years was 59.6%, 32.5% and 16.2%. Thirty four patients died of disease. Radiotherapy caused acute toxicity in seven patients. According to RTOG/EORTC criteria toxicity was Grade 1 in four cases, Grade 2 in two cases and Grade 3 in one case. Two patients developed gastrointestinal bleeding as a late complication of radiotherapy. CONCLUSIONS: Accelerated external beam radiotherapy with or without intraluminal radiotherapy is feasible and associated with acceptable toxicity when used in the management of advance cholangiocarcinoma.

Bile Duct Neoplasms↗