Biomedical subjects
Publications and source records attributed to R C Williamson.
We present a case of a vascular anomaly with Dieulafoy's disease in a young man. The diagnosis was made by coeliac and selective left gastric angiography after endoscopy, laparotomy and angiography had failed to detect the lesion. The patient was treated successfully by laparotomy and resection of the bleeding area in the stomach. This is the second report of a vascular anomaly with Dieulafoy's disease.
Since compensatory hyperplasia promotes experimental carcinogenesis in the gut, we tested the ability of two surgical models of pancreatic growth to promote pancreatic carcinogenesis. Male Wistar rats (n = 60) weighing 250-300 g underwent pancreatobiliary diversion (PBD), 90% small bowel resection (PSBR) or triple transection and reanastomosis of the small intestine (controls). Postoperatively, each group received azaserine (20 mg kg-1 wk-1 i.p.) for 6 weeks. Surviving rats were killed at 6 months, pancreatic wet weight was measured and histological sections were examined for atypical acinar cell foci (AACF), the putative precursor of carcinoma. Median relative pancreatic weight (mg pancreas/g body weight) was 2.20 for controls (n = 18), 4.08 for PSBR (n = 11) (P less than 0.001) and 6.86 for PBD (n = 16) (P less than 0.001). PSBR did not affect the development of acidophilic AACF, but PBD produced an enormous increase in their number per cm3 (median 96 vs. 0; P less than 0.001) and a 7-fold increase in their volume (P less than 0.001). Both operations cause pancreatic growth, but only PBD promotes carcinogenesis, possibly because of its unique hormonal effect.
Sterculic acid, a delta-9-desaturase inhibitor, administered to rats caused a rise in the stearic:oleic acid ratio of total lipids in peripheral red cells, serum and liver (P less than 0.001). As a reduction in the stearic:oleic acid ratio has been described in cancer cells, we investigated the effect of sterculic acid on tumour growth. Female F344 rats were injected subcutaneously with two different doses of sterculic acid for 4 weeks prior to, and 4 weeks following, implantation of a nitrosomethylurea-induced mammary tumour. Tumour growth was inhibited equally by the two doses of sterculic acid (P less than 0.001). A rise in the stearic:oleic acid ratio of tumours was observed in rats treated for only 16 days with sterculic acid. Manipulation of the tissue stearic:oleic acid ratio inhibits transplanted mammary tumour growth in rats.
The tumour suppressor gene p53 has been found to be mutated or inactivated at high frequency in several common human tumours. We have examined a series of exocrine pancreatic carcinomas for over-expression of mutant forms of p53 by immunohistochemistry with a panel of specific antibodies. We found immunodetectable p53 in 13 of 22 (60%) frozen pancreatic cancers and seven of 13 pancreatic cell lines. One of the antibodies, CM1, recognises p53 in formalin-fixed, paraffin-embedded archival material and using this reagent we found immunodetectable p53 in 28 of 124 (23%) pancreatic cancers. We have successfully demonstrated the presence of point mutations by direct sequencing of genomic DNA extracted from archival tissue showing CM1 immunoreactivity. We conclude that p53 activation is an important event in human pancreatic tumorigenesis and that the CM1 antibody can detect a proportion of cases of overexpression of mutant p53 in archival pathological material.
Dietary supplementation with calcium may prevent the development of colorectal cancer. This mechanism may be related to fatty acid and bile salt chelation in the small bowel forming non-toxic calcium-soap compounds. Calcium may also act locally or systemically on the colonic mucosa. Faecal concentrations of free fatty acids and free bile acids were measured in 17 Sprague-Dawley rats (weighing 472 (39 g)) whose daily calcium intake had been trebled by enriching the chow and adding calcium lactate (24 g/l) to the drinking water. Mean (SEM) faecal concentrations of free bile acids were 33% less than in 19 controls (1.23 (0.15) v 1.82 (0.20) mg/g; p less than 0.001), whereas free fatty acid concentrations were 117% higher (14.68 (3.59) v 6.76 (2.41) mg/g; p less than 0.02). The 'direct' effect of calcium was assessed by organ culture of rat colonic explants in three different concentrations of calcium. Crypt cell production rate (measured by a stathmokinetic technique), which was (mean (SEM)) 4.80 (0.23) cells/crypt/h in control medium (Ca2+ = 2.14 mmol/l), fell by 43% when calcium concentration was doubled (p less than 0.05) and by a further 43% when the concentration was trebled (p less than 0.02). Calcium binds free fatty acids but not free bile acids intraluminally. Calcium has a direct antitropic action on colonic crypts.
Morphological and immunohistological appearances of liver biopsy specimens are described in a personal series of 52 patients undergoing operation for chronic pancreatitis. The findings are compared with those in a series of 10 histologically normal liver biopsy specimens from patients without pancreatitis. Alcohol was the prime aetiological agent in 40 of the 52 patients (77%). No obvious damage to hepatic parenchymal cells or biliary structures was observed but minor morphological changes of alcohol associated liver disease were seen in 42% of specimens. The most consistent finding, present in 48 specimens (92%), was a chronic inflammatory cell infiltration of portal tracts. In all but one case, T lymphocytes predominated, but a few B cells were present. In four biopsy specimens, T cells spilled over into adjacent hepatic parenchyma, but there was no evidence of T cell mediated cytotoxic damage to the parenchymal cells or biliary epithelium. It is suggested that these inflammatory cells are in transit from the pancreas through the liver via the portal circulation and may reflect the underlying pathogenesis of chronic pancreatitis rather than alcoholic liver disease.
Valuable information on intestinal adaptation can be gained by using the technique of organ culture to measure the crypt cell production rate. It is not known, however, whether the production rate in organ culture accurately represent that in vivo. Colonic crypt cell production rate, determined by a standard method in vivo, was compared with that in vitro in organ culture in 56 rats. Extensive jejunoileal bypass was used to stimulate colonic hyperplasia, and colonic defunction (by transverse colostomy) led to hypoplasia. There were no differences in crypt cell production rates between in vivo and in vitro groups in normal colon (4.62 (0.39) v 4.80 (0.23) cells/crypt/hour), after 80% jejuno-ileal bypass (7.81 (0.71) v 6.75 (0.72) cells/crypt/hour), or after defunction (2.11 (0.39) v 1.81 (0.35) cells/crypt/hour). Adapting colonic mucosa does not undergo appreciable readaptation in vitro in short term organ culture (10-24 hours). Crypt cell production rate results obtained in man probably reflect in vivo values.
Since pancreatobiliary diversion probably stimulates pancreatic growth by increasing cholecystokinin secretion, the effect of the cholecystokinin antagonist CR-1409 on this adaptive response was tested. Male Wistar rats (n = 108) weighing 220-250g were randomised to receive either pancreatobiliary diversion (n = 60) or sham diversion (n = 48) and thereafter to receive either saline injections or CR-1409 (10 mg/kg/day, subcutaneously). Rats were killed at four, seven, and 14 days postoperatively, when blood was obtained for cholecystokinin assay and the pancreas was assessed for proliferative activity by three techniques: nucleic acid and protein assay, bromodeoxyuridine labelling, and metaphase arrest after vincristine administration (1 mg/kg, intraperitoneally). Pancreatobiliary diversion increased plasma cholecystokinin concentrations by 91% at seven days and 137% at 14 days, irrespective of CR-1409 treatment. Total pancreatic RNA content was doubled by pancreatobiliary diversion at four days (2.15 v 1.07 mg/100 g body weight: p less than 0.001) and at seven days (3.43 v 1.76 mg/100 g: p less than 0.001), and trebled at 14 days (4.27 v 1.32 mg/100 g: p less than 0.001). Pancreatobiliary diversion increased bromodeoxyuridine labelling index from 1.1 to 3.7% at seven days and the cell birth rate from 0.09 to 0.06%. CR-1409 completely abolished this proliferative response and partly prevented the rise in RNA. The results confirm pancreatic hypertrophy and increased acinar cell proliferation after pancreatobiliary diversion. CR-1409 prevents this adaptive growth, probably by blocking cholecystokinin receptors. Bromodeoxyuridine labelling and the metaphase arrest technique may be used to assess pancreatic cell kinetics.
CEA, CA19-9 and CA50 are tumour associated antigens defined by monoclonal antibodies which have been raised against adenocarcinoma cell lines. The aim of this study was to determine whether their combined use could improve diagnostic accuracy in patients with primary and secondary liver tumours. An immunoradiometric assay was used for the detection of CEA and CA19-9 and the Delfia system for CA50. Serum was collected from 65 normal subjects, 40 with hepatobiliary carcinoma (26 primary, 14 secondary) and 17 with benign hepatobiliary disease. The cut-off levels were calculated as the mean of the control group plus 2 standard deviations. All three antibodies contributed to improving the correct classification of secondary liver tumours (multivariant discriminant analysis p less than 0.05), but only CA19-9 and CA50 contributed to the diagnosis of primary liver tumours (multivariant analysis p less than 0.05). The diagnostic accuracy versus benign disease was 81% for primary carcinoma and 91% for secondary carcinoma. Combined use of CEA, CA19-9 and CA50 helps to differentiate benign from malignant hepatobiliary disease.
A 32-year-old woman with a choledochal cyst (Todani type I) developed recurrent acute pancreatitis leading to calcific chronic pancreatitis. She had previously been treated with two cyst drainage procedures and subtotal cyst excision. This association between choledochal cyst and chronic pancreatitis has not been previously reported. Severe continuing symptoms led to pylorus-preserving proximal pancreatoduodenectomy, which was undertaken to prevent future carcinoma in the cyst remnant and progression of the chronic pancreatitis.
Diets enriched with fat, especially unsaturated fat, promote experimental pancreatic carcinogenesis, but little is known of the effects of individual fatty acids. The effect of stearic and oleic acid on pancreatic fatty acids and atypical acinar cell nodules (preneoplastic lesions) was studied in 14-day-old weanling male Leeds strain rats (n = 60) given the carcinogen azaserine. Rats were allocated to one of six groups: untreated controls (n = 10), 20% stearic acid diet (n = 10), 20% oleic acid diet (n = 10), carcinogen alone (n = 10), carcinogen plus 20% stearic acid diet (n = 10) or carcinogen plus 20% oleic acid diet (n = 10). Azaserine was administered by intraperitoneal injection in a dose of 30 mg/kg at 2, 3 and 4 weeks of age. When total lipid extracts of pancreas were examined, there was an increase in stearic acid in the stearic acid fed group and an increase in oleic acid in the oleic acid fed group, irrespective of carcinogen treatment. The relative content of all other pancreatic fatty acids was suppressed by feeding oleic acid. At 26 weeks, the number and volumetric indices of pancreatic atypical acinar cell nodules was increased only in rats given azaserine and oleic acid. The enhancing effect of oleic acid on pancreatic carcinogenesis may be associated with pancreatic fatty acid changes.
CEA, CA19-9 and CA50 are tumour-associated antigens defined by monoclonal antibodies that have been raised against adenocarcinoma cell lines, but no single antibody is specific for the detection of pancreatic malignancy. The aim of this study was to determine whether the combined use of CEA, CA19-9 and CA50 would improve diagnostic accuracy. An immunoradiometric assay was used for the detection of CEA and CA19-9 and the Delfia system for CA50. Serum was collected from 65 normal subjects, 16 with pancreatitis and 28 with pancreatic carcinoma. Of the 28 cancer patients, 24 (85%) had a CA19-9 level above 46 mu/ml, 26 (92%) had a CA50 level above 21 mu/ml and 10 (37%) had a CEA level above 7 ng/ml. Multivariant discriminant analysis on the combined antibodies showed that 96% of the malignant group, 13% of the pancreatitis group and 11% of the normal group were positive, with an overall correct classification of 91% into the three groups (multivariant discriminant analysis P less than 0.05). Thus the combined use of CEA, CA19-9 and CA50 improves diagnostic accuracy in differentiating benign from malignant disease of the pancreas.
This review examines the lack of improvement in terms of mortality and outcome in patients with acute pancreatitis. Energetic fluid replacement is the only treatment of proven value. There is a strong case for identification of patients with severe disease who may benefit from early operative intervention. Eradication of gallstones may prevent further attacks in patients with gallstone pancreatitis. The benefits of pancreatic resection and necrosectomy still require full evaluation.
An intestinal suture line potentiates experimental carcinogenesis in its vicinity, probably due to adaptive hyperplasia. By contrast, a defunctioning colostomy causes distal hypoplasia, and fewer tumours develop. Male Sprague-Dawley rats (n = 160) were used to study adaptation (assessed by a stathmokinetic technique) and carcinogenesis (induced by azoxymethane) at an end-to-end anastomosis that was raised in either functioning or defunctioned left colon. Controls had no procedure and other rats had proximal colostomy alone. Defunction had a profound antitropic effect on the colon, reducing bowel length and weight and crypt cell production rate (CCPR) by 22-56 per cent. Anastomotic CCPR was increased by a factor of 2.6 over controls: mean(s.e.m.) values of 12.71(2.85) versus 4.87(0.41) cells/crypt/h (P less than 0.01), but defunction reduced this by 76 per cent to a mean(s.e.m.) value of 3.00(0.52) cells/crypt/h below that in the intact colon. In the left colon, 39-50 per cent of tumours were sited at the anastomosis. Compared with controls there were 77 per cent fewer tumours in defunctioned colon, but they still favoured the site of anastomosis. Neoplasms at the colostomy site accounted for 74-77 per cent of all right-sided tumours. Anastomosis and defunction have powerful but contrasting effects on colonic adaptation and carcinogenesis; when combined they tend to cancel each other out.
Peptic ulcer surgery may predispose to the subsequent development of colorectal cancer. This experimental study has investigated the effects of gastric operations on colonic cell proliferation, bile acid excretion and carcinogenesis. Male Sprague-Dawley rats (n = 105) underwent sham operation, Pólya partial gastrectomy or vagotomy and pyloroplasty. The carcinogen azoxymethane was administered weekly for 6 weeks thereafter (total dose 60 mg kg-1). When the animals were killed 24 weeks after operation, colons were examined for mucosal mass, crypt cell production rate (CCPR) and tumour yield; faeces were assayed for contents of neutral steroids and bile acids (both total and individual). Morphometric indices and mucosal DNA content were similar in all three groups. Pólya gastrectomy reduced: (1) CCPR throughout the colon (by 42-65 per cent, P less than 0.002); (2) the number of rats with colorectal tumours (26 per cent versus 63 per cent, P less than 0.05); (3) faecal levels of neutral steroids and bile acids, notably hyodeoxycholic acid (P less than 0.01). Although vagotomy and pyloroplasty increased caecal CCPR, there were no consistent differences in faecal steroids and no alteration in tumour yield after the operation. These results fail to support clinical studies suggesting that gastric surgery predisposes to colonic carcinogenesis. Indeed, Pólya partial gastrectomy exerts a protective effect, probably by inhibiting colonic cell proliferation.
Fifty-four patients have undergone abdominocervical oesophagectomy for oesophageal carcinoma as an alternative to a conventional transthoracic approach. Their median age was 69 years, with a range of 38-90 years, and 39 per cent of patients had chronic cardiorespiratory disease. Lymph node metastases were found in 80 per cent of patients and transmural tumour spread in 91 per cent. Median duration of operation was 2.2 h (range 1.75-6.0 h), and median transfusion requirement was 2.5 units (range 0-8 units). Respiratory complications were common (41 per cent) and caused all six postoperative deaths (11 per cent). Other complications were atrial fibrillation (26 per cent), transient recurrent laryngeal nerve palsy (11 per cent), cardiac failure (2 per cent), stroke (2 per cent), subphrenic abscess (2 per cent) and empyema (2 per cent). There were two anastomotic leaks (4 per cent), clinically manifest as temporary salivary fistulae. There have been 32 deaths from recurrent carcinoma, with a median duration of survival of 14 months (range 4-53 months). Fifteen patients are still alive, with a median survival of 16.5 months (range 3-49 months); the current 3-year survival rate is 10 per cent. All patients resumed normal swallowing after operation, but 11 of them developed anastomotic strictures requiring a median of three dilatations. Avoidance of formal thoracotomy by the abdominocervical approach may allow more rapid oesophagectomy without increasing the risk of postoperative death and gives a quality of palliation at least equivalent to that of conventional transthoracic oesophageal excision.
We describe our experience with 124 on-table pancreatograms performed during 117 operative procedures on 112 patients in a wide variety of clinical settings. Endoscopic retrograde cholangiopancreatography (ERCP) was performed on 84 occasions with a 73 per cent success rate for visualization of the main pancreatic duct. On-table pancreatography (OTP) was performed by one of five different techniques: retrograde, prograde or ambigrade ductography, cystography and ascending loopography after pancreaticojejunostomy. OTP provided important information about the main pancreatic duct when endoscopic visualization was unsuccessful (n = 23), incomplete (n = 17) or not performed (n = 33); there was a failure rate of 4 per cent. In 35 patients either the additional information or discrepancies between ERCP and OTP findings resulted in a change of operative plan (19 extra procedures, 16 altered procedures). Complete ductography was especially helpful in the 63 patients with chronic pancreatitis. OTP is technically simple, free from complications and invaluable for planning operative strategy.
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