Phenol sulphotransferase SULT1A1*1 genotype is associated with reduced risk of colorectal cancer.

Sulphation is an important detoxification pathway for numerous xenobiotics; however, it also plays an important role in the metabolism and bioactivation of many dietary and environmental mutagens, including heterocyclic amines implicated in the pathogenesis of colorectal and other cancers. A major sulphotransferase (SULT) enzyme in humans, SULT1A1, is polymorphic with the most common variant allele, SULT1A1*2, occurring at a frequency of about 32% in the Caucasian population. This allele codes for an allozyme with low enzyme activity and stability compared to the wild-type (SULT1A1*1) enzyme, and therefore SULT1A1 genotype may influence susceptibility to mutagenicity following exposure to heterocyclic amines and other environmental toxins. Previously, a significant association of SULT1A1*1 genotype with old age has been observed, suggesting a 'chemoprotective' role for the high-activity phenotype. Here we have compared the frequencies of the most common SULT1A1 alleles in 226 colorectal cancer patients and 293 previously described control patients. We also assessed whether SULT1A1 genotype was related to various clinical parameters in the patient group, including Duke's classification, differentiation, site, nodal involvement and survival. There was no significant difference in allele frequency between the control and cancer patient populations, nor was there a significant association with any of the clinical parameters studied. However, when the age-related difference in allele frequency was considered, a significantly reduced risk of colorectal cancer (odds ratio = 0.47; 95% confidence interval = 0.27-0.83; P = 0.009), was associated with homozygosity for SULT1A1*1 in subjects under the age of 80 years. These results suggest that the high activity SULT1A1*1 allozyme protects against dietary and/or environmental chemicals involved in the pathogenesis of colorectal cancer.

Radiosurgery for the treatment of recurrent central neurocytomas.

OBJECTIVE: Central neurocytomas are benign neoplasms with neuronal differentiation typically located in the lateral ventricles of young adults. Although the treatment of choice is complete surgical excision, patients may experience local recurrence. Adjuvant therapy for patients with residual or recurrent tumor has included reoperation, radiotherapy, or chemotherapy. To avoid the side effects of conventional radiotherapy in young patients, we present a series of patients with clear evidence of tumor progression who were treated with gamma knife radiosurgery. METHODS: Four patients (ages 20-49 yr; mean, 28 yr) who presented with an intraventricular mass on magnetic resonance imaging scans and underwent craniotomy for tumor resection were reviewed retrospectively. Histopathological analysis confirmed central neurocytoma in all cases. Each patient was followed up clinically and radiographically with serial magnetic resonance imaging. When radiographic signs of tumor progression were evident, patients were treated with radiosurgery. RESULTS: Complete radiographic tumor resection was achieved in all patients. There were no major postoperative complications. Local tumor progression was detected on magnetic resonance imaging scans 9 to 25 months after surgery (median, 17.5 mo). All patients achieved complete response to radiosurgery with reduction in tumor size. There have been no complications from radiosurgery. Follow-up ranged from 12 to 28 months (mean, 16.5 mo) after radiosurgery, and from 24 to 84 months (mean, 54.5 mo) after initial presentation. CONCLUSION: Radiosurgery with the gamma knife unit provides safe and effective adjuvant therapy after surgical resection of central neurocytomas. Radiosurgery may eliminate the need for reoperation and avoid the possible long-term side effects from conventional radiotherapy in young patients.

Screening for colorectal cancer: present, past and future.

Colorectal cancer results in 18,000 deaths annually in England and Wales, with 24,000 new cases diagnosed each year. Despite a better understanding of the genetics, and advancement in surgical and anaesthetic techniques, there has been little reduction in mortality and morbidity from this disease over the past 25 years. Colorectal cancer fits recognized criteria for a disease that should be screened in asymptomatic individuals. The putative duration of the adenoma to carcinoma sequence gives an ample window of opportunity to detect and treat colorectal cancer. In this article we have reviewed the strategies involved in screening for colorectal cancer in an asymptomatic population. We have presented trials and arguments for and against the different screening methods and discussed cost effectiveness of screening. In the USA and Canada, major professional organizations and societies now endorse screening; in the UK it is still far from being accepted. We feel that the available evidence shows that colorectal cancer screening has the potential to reduce the morbidity and mortality from this disease and that funding for a mass screening and public education programme should be sought.

Hereditary non-polyposis colorectal cancer: an updated review.

INTRODUCTION: Colorectal cancer is the commonest cause of death due to malignancy in non-smokers in the western countries. The two main hereditary types of colorectal cancer are familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), constituting approximately 10% of all cases of colorectal cancer. The main aim of this review is to reappraise the current advances in the genetics and diagnosis of HNPCC. METHODS: A Medline search was carried out to identify papers published from 1970 to 1999 on HNPCC. Embase and Cochrane databases were also searched. Reference lists of retrieved articles were carefully searched for additional articles. RESULTS AND CONCLUSIONS: Recent technological advances in the genetics of HNPCC have refined the criteria for diagnosis and management of HNPCC, however current policies regarding the testing of pedigrees are not clearly established. We believe that with the rapid development in this area definitive clinical guidelines will need to be available in future for the management of HNPCC.

A histopathological assessment of the response of rectal adenocarcinoma to combination chemo-radiotherapy: relationship to apoptotic activity, p53 and bcl-2 expression.

AIMS: To investigate the use of pre-operative chemo-irradiation in downstaging advanced rectal cancer prior to surgical resection. METHODS: We examined the pathological effects of chemo-irradiation on 24 rectal tumours and correlated the efficacy of treatment with the level of apoptosis, mitosis, P53 and bcl-2 protein expression on pre-treatment biopsies. RESULTS: All tumours were resectable following chemo-irradiation. Six cancers showed complete regression with no viable tumour in the resection specimen. A significant correlation was found between spontaneous tumour apoptosis and tumour regression. CONCLUSIONS: Our results suggest that in rectal cancer the apoptotic rate in untreated tumour tissue may predict sensitivity to radiation and cytotoxic agents. No relationship was found between regression and mitotic rate, p53 or bcl-2 expression.

Helicobacter pylori transmission: evidence from a comparison with hepatitis A virus.

OBJECTIVE: To assess the possibility that faecal-oral contact might play a role in the transmission of Helicobacter pylori. DESIGN: A cross-sectional comparison of the patterns of hepatitis A and H. pylori seropositivity. METHODS: At interview, blood samples and questionnaire data were collected from a group of 467 male volunteers, aged 18-65, from Stoke-on-Trent, UK. Serum samples from each subject were then analysed for anti-H. pylori and anti-hepatitis A antibodies. RESULTS: Overall, 100 of 175 H. pylori seropositive subjects (57.1%) and 113 of 292 H. pylori seronegative subjects (38.7%) were hepatitis A seropositive (chi 2 = 15.0, P < 0.001). This difference was not statistically significant after adjustment for age group and father's occupation, as a surrogate for socioeconomic status in childhood (P = 0.15). The seroprevalence of hepatitis A increased with age at a rate of 2.3% per year, compared to only 1.0% per year for H. pylori (P = 0.015). CONCLUSION: These data suggest that the case for faecal-oral transmission of H. pylori, in a manner similar to the spread of hepatitis A, is not proven and that other modes of transmission, for instance through oral-oral contact, should also be considered.

Recent experimental and clinical studies on the pharmacology of colloidal bismuth subcitrate.

Recent experimental and clinical pharmacological studies on colloidal bismuth subcitrate (CBS) are reviewed. CBS combines with mucus to produce a marked retardation of the movement of hydrogen ions. CBS has potent anti-ulcer and anti-erosive action in various experimental models in animals, and is able to stimulate the generation of gastric mucosal prostaglandins. CBS is thought to be a cytoprotective agent. The type of mucosal cell repair in the vicinity of the ulcer is favourably affected in man. CBS also exhibits anti-pepsin and bile acid-binding properties. Pyloric campylobacter are inhibited in vitro and in vivo. The recent pharmacological findings are discussed in the light of the clinical efficacy of CBS and new indications.

Intragastric PCO2 in man and calculated gastric bicarbonate concentrations: effect of carbenoxolone sodium.

In six normal subjects, ten patients with either gastric or duodenal ulcer or combined duodenal and gastric ulcers and in one with gastric carcinoma, the fasting intragastric PCO2 was measured using a new silicon-coated teflon intragastric catheter connected to a mass spectrometer. PCO2 values ranged from 9 to 38 mm Hg in normal subjects and from 23 to 75 mm Hg in patients. In some patients sharp peaks up to 170 mm Hg were obtained. The pH of the resting juice was measured and the intragastric HCO-3 concentration calculated using the Henderson-Hasselbach equation. Intragastric HCO-3 concentration was 5--136 nmol per litre in normals and 12 nmol-960 mumol per litre in those with dyspepsia, and 6.05 mmol per litre in the patient with gastric carcinoma. Five dyspeptic patients and the one with stomach cancer were given 100 mg carbenoxolone t.d.s. for 72 hours. The fasting PCO2 decreased from a mean of 34.6 +/- 4.89 to 26.6 +/- 2.24 Se mmHg (p less than 0.05) with corresponding changes in HCO-3 concentration. These results suggest that carbenoxolone increased the thickness of the unstirred layer of mucus, making it more resistant to H+ penetration and thus reducing H+ and HCO-3 interaction with consequent lowering of PCO2.

Surgical suppression of gastric acid secretion. Lessons from long-term follow-up studies.

This paper reviews data from case controls studies, cohort studies, and long-term follow-up papers of over 30,000 patients following surgical reduction of gastric acid secretion 20-40 years postoperatively. There is an increase in gastric cancer which becomes highly significant 20 years after Billroth II resection and rises thereafter, many studies showing a three- or four-fold increase compared with a non-operative control or contrast population. There is little doubt that surgical depression of gastric acid secretion is associated with the development of carcinoma of the stomach. The mechanisms by which this development may occur are discussed.

Glutathione S-transferase T1 polymorphisms are associated with outcome in colorectal cancer.

Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22-2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (<70 versus > or =70 years at diagnosis), in the patients diagnosed <70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31-0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12-3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.

Surgical treatment of duodenal ulcer.

This paper reviews the pathophysiology of peptic ulcer disease, the role of the vagus and gastrin in the control of gastric acid secretion and motility and the rationale for modern operations for peptic ulcer. The importance of arriving at a balanced decision before recommending surgery for a peptic ulcer is discussed. The indications for surgery in elective and emergency cases are defined and the results reviewed critically and compared with medical treatment. Novel operative procedures are mentioned but still await validation follow-up studies before their final assessment. Well tried operations should not be dismissed lightly and the importance of prospective randomized trials to evaluate new procedures is emphasized.

Gastric-acid output, pepsin output, and lean body mass in normal and duodenal-ulcer subjects.

Gastric-acid output bears a significant relationship to parietal cell mass and to lean body mass. The relationships of pepsin output to gastric-acid output and to lean body mass have been investigated in 13 normal subjects and 40 duodenal-ulcer patients. Peak pepsin output (P.P.O[I]) was stimulated by insulin-induced hypoglycaemia and the enzyme was assayed by Piper's method. Peak acid output to pentagastrin (P.A.O.[Pg] was obtained at a separate test. P.P.O.(I) correlated significantly with P.A.O.(Pg) in normal subjects (r equals 0-889, P less than 0-0001). P.P.O.(I) also showed good correlation with lean body mass (L.B.M.) (r equals 0-714, P less than 0-01), suggesting that P.P.O.(I) reflects peptic cell mass in normal subjects. In 40 duodenal-ulcer subjects there was no significant overall correlation of P.P.O.(I) with P.A.O(Pg) or with L.B.M. However, expressing the results as output of pepsin per milliequivalent of acid per kilogramme of lean body mass allowed separation of the ulcer patients into two groups whose ratios appeared to correlate with their symptomatic state at the time of testing: thus mean P.P.O(I) per meq. acid per kg. L.B.M. for duodenal-ulcer patients in relapse was significantly greater than the ratios for the patients in remission and for the normal group (P less than 0-001), suggesting either the presence of an increased sensitivity to insulin stimulation or a lack of pepsin inhibitor substance during a relapse of ulcer symptoms.

Effect of gonadectomy on epidermal growth factor values in the gastrointestinal tract of male and female CD-1 mice.

The effects of gonadectomy on the epidermal growth factor (EGF) concentrations in the gastrointestinal tract of CD-1 mice were studied. The EGF concentrations in the gastrointestinal tissues were always higher in males than in females. Gonadectomy led to a decrease in the EGF concentration in males, and an increase in females. Gonadectomy with sialoadenectomy led to a decrease in the EGF concentrations in the gastrointestinal tract of both sexes; the most significant effect being observed in the stomach. Orchidectomy led to a decrease in total body weight, and to a significant decrease in the weight and the protein concentration (ng.g-1 wet weight of tissue) of the submandibular gland, but had no significant effect on the other tissues of the gastrointestinal tract of male mice. Body, tissue weights, and protein concentrations did not change with oophorectomy. This study shows that male and female gonads have a profound effect on the EGF content of the tissues of the gastrointestinal tract and suggests that the submandibular gland also influences the EGF concentration in gastrointestinal tissues in mice.

Transforming growth factor alpha and epidermal growth factor levels in normal human gastrointestinal mucosa.

Acid soluble proteins from 23 samples of normal human gastrointestinal mucosa derived from four normal adult organ donors were extracted and subjected to specific radiommunoassays for transforming growth factor alpha (TGF alpha) and urogastrone epidermal growth factor (URO-EGF). All tissues were found to contain immunoreactive TGF alpha and levels ranged from 57 to 4,776 pg-1 wet weight of tissue. Although levels varied between tissue donors, the distribution of TGF alpha throughout the gastrointestinal tract appeared similar in all cases. URO-EGF levels were much lower (0-216 pg g-1 wet weight). TGF alpha levels in extracts of gastrointestinal mucosa from a 7-year-old female donor were higher and the observed distribution was markedly different from adult levels. URO-EGF was not detected in mucosal or submucosal tissue extracts from this patient. Further studies in juveniles are indicated.

Studies of a gastric fundic mucosal factor which affects absorption from the antrum and jejunum in the rat.

1. A rat bio-assay has been developed in which the tracer ion technetium 99 m (99mTc) was used to monitor absorption from both the antrum and the jejunum of the rat. 2. Evidence has been obtained for the release of a humoral substance from the rat gastric fundus after alkalinization of the mucosa at pH 8, and this fundic factor has been shown to reduce the absorption of the tracer ion 99mTc from both the lumen of the antrum and of the jejunum in the rat. 3. Intravenous infusion of a neutral extract of porcine fundic mucosa, distension of the rat fundus with air or exposure of the fundic mucosa to alkaline buffer all decreased absorption of the tracer ion virtually to the same extent from the lumen of the antrum (P less than 0.001) and to a lesser extent from the lumen of the jejunum (P less than 0.05). This effect does not appear to be due to histamine. 4. Preliminary biochemical data have indicted that the biological activity in the mucosal extract is protein in nature and has a molecular weight of less than 10,000.