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Biomedical subjects

J D Hardcastle

Publications and source records attributed to J D Hardcastle.

At least 19 recordsLinked to original sources
PubMed1992

An idiotypic replica of carcinoembryonic antigen inducing cellular and humoral responses directed against human colorectal tumours.

A monoclonal anti-idiotypic antibody (anti-Id MAb) 708 (IgG2b), which inhibited the binding of NCRC23 (IgG1) MAb to CEA and prevented radiolabelled CEA from binding to MAb NCRC23, was produced. No recognition of 3 other anti-CEA antibodies, 3 other IgG1 or 2 IgM MAbs was observed with this anti-idiotypic antibody. When an immunoblotting technique was used, 708 anti-Id MAb failed to bind to isolated heavy or light chains of MAb NCRC23, whereas binding was observed with intact antibody. Mouse, rat and human lymphocytes (in vitro) were immunized with 708 anti-Id MAb and the resultant Ab3 antibodies all inhibited binding of labelled 708 anti-Id MAb to MAb NCRC23 and also reacted with CEA, showing that 708 anti-Id MAb induced anti-CEA antibody responses. Similarly, mice immunized with 708 anti-Id MAb could be restimulated in vitro with either CEA or tumour cells expressing CEA which induced specific T-cell proliferative responses. Human tumour-infiltrating lymphocytes isolated from colorectal tumours or peripheral blood T cells from cancer patients were stimulated in vitro with 708 anti-Id MAb or an irrelevant IgG2b antibody. Six days later both sets of lymphocytes were restimulated with CEA, and lymphocytes primed to 708 anti-Id MAb proliferated in response to CEA. These results suggest that 708 anti-Id MAb can act as an idiotypic replica of CEA and stimulate cellular and humoral anti-CEA immune responses. It is therefore of great interest as an idiotypic vaccine against colorectal cancer.

Animals↗
PubMed1992

Predeposit autologous blood transfusion in patients with colorectal cancer: a feasibility study.

Over a 2-year period, a predeposit autologous blood transfusion service was provided for all patients undergoing elective surgery for left-sided colonic or rectal cancer in one hospital. Of 129 such patients, 28 were suitable for autologous donation. Eight of these received autologous blood only, 13 required no transfusion, and seven needed additional homologous blood. Thus, although predeposit autologous transfusion for patients with colorectal cancer is possible, only a very small proportion are likely to derive any benefit which it might confer.

Aged↗
PubMed1992

Screening for colorectal carcinoma: an analysis of the sensitivity of haemoccult.

The sensitivity of Haemoccult for asymptomatic colorectal carcinoma has been estimated in a large randomized controlled trial of mass population screening, with a minimum follow-up of 2 years. A total of 111 cancers were diagnosed in those who completed the screening tests; of these, 36 appear to have been missed by Haemoccult and 75 were detected by the test, giving an overall sensitivity of 67.6 per cent. Haemoccult was shown to be significantly more sensitive for carcinoma of the sigmoid and descending colon than for rectal or right-sided cancers (81 versus 45 and 47 per cent, respectively). The sensitivity was higher when tests were completed over 6 rather than 3 days (74 versus 65 per cent), but this difference was not statistically significant. There was no evidence for a detrimental effect on tumour stage of a false-negative Haemoccult test; indeed, a higher proportion of the interval cancers were Dukes' A tumours than cancers in the control group.

Aged↗
PubMed1992

Cost savings in mass population screening for colorectal cancer resulting from the early detection and excision of adenomas.

The widely-accepted hypothesis of a development sequence from colorectal adenoma to carcinoma is felt by clinicians to legitimate adenoma excision during routine colonoscopic investigation. Using published data on adenoma development, and adenoma prevalence data derived from the Nottingham colorectal cancer screening trial, the number of carcinomas prevented by early excision as a result of screening is predicted. The cost-effectiveness of early excision is then evaluated with reference to the expected treatment costs saved. These cost savings are found to represent a discount on the overall costs of mass population screening for colorectal cancer.

Adenoma↗
PubMed1992

Inhibition of gastrin-stimulated growth of gastrointestinal tumour cells by octreotide and the gastrin/cholecystokinin receptor antagonists, proglumide and lorglumide.

The rat pancreatic cell line, AR42J possessed high-affinity gastrin and somatostatin receptors and its growth was stimulated by physiological gastrin-17 concentrations between 5 x 10(-11) mol/l and 10(-9) mol/l as measured by [75Se]selenomethionine uptake. The somatostatin analogue, octreotide (2 x 10(-7) to 2 x 10(-11) mol/l), reduced this stimulated growth. Gastrin-stimulated AR42J growth was also inhibited by proglumide (3 x 10(-4) mol/l) and lorglumide (3 x 10(-5) mol/l) at maximal G17 concentrations of 5 x 10(-11) and 10(-10) mol/l, respectively, and the analogues competed with [125I] gastrin-17 (5 x 10(-10) mol/l) for binding to gastrin receptors on AR42J (50% inhibitory concentrations, less than or equal to 10(-3) mol/l and 4 x 10(-6) mol/l, respectively. Octreotide reduced the basal growth of the human gastric cell line, MKN45G, (which is associated with intracellular gastrin immunoreactivity) in serum-free medium to 73% of control at a concentration of 2 x 10(-8) mol/l, which was reversed by gastrin-17 (10(-10) mol/l). Lorglumide (3 x 10(-5) mol/l) also reduced the basal growth to 30% of control, which was reversed to 78% by 10(-5) mol/l gastrin. Proglumide had no effect on the basal growth of MKN45G.

Animals↗
PubMed1992

Chemical and immunological testing for faecel occult blood: a comparison of two tests in symptomatic patients.

An established chemical faecal occult blood test (Haemoccult prepared without rehydration) has been compared with a new immunological test (Hemeselect) in patients referred for investigation of lower gastro-intestinal symptoms. Hemeselect was shown to have a higher sensitivity for colorectal carcinoma (94.0% compared with 58.0%), the greatest difference in sensitivity between the two tests being for rectal cancers. Similarly Hemeselect was more sensitive than Haemoccult for colorectal adenomas (66.6% vs 33.3%), and for inflammatory bowel disease (88.9% vs 33.3%). However the enhanced sensitivity of Hemeselect for colorectal neoplasia and inflammatory bowel disease was accompanied by a significant increase in the overall rate of positive reactions (32.8% of patients had a positive Hemeselect reaction compared with 14.8% who had a positive Haemoccult test), and a reduction in specificity (84.1% for Hemeselect vs 96.0% for Haemoccult). Hemeselect is a more sensitive indicator of colorectal neoplasia in symptomatic subjects, trials of its use as a screening test for asymptomatic neoplasia appear justified.

Adenoma↗
PubMed1992

Therapeutic effect of the gastrin receptor antagonist, CR2093 on gastrointestinal tumour cell growth.

The gastrin receptor antagonist, CR2093, competed with 125I-gastrin-17 (5 x 10(-10) M) for binding to gastrin receptors on the rat pancreatic adenocarcinoma, AR42J (CR2093 concentration inducing 50% of 125I-gastrin-17 binding (IC50) was 8 x 10(-5) M), on the human gastric adenocarcinoma, MKN45 (IC50 5.5 x 10(-5) M) and the human colo-rectal adenocarcinoma C523 (IC50 greater than 10(-4) M). Intravenous administration of CR2093 (40 mg kg-1 day-1) reduced the gastrin-17 stimulated growth of AR42J xenografts in nude mice to below that of the original basal growth (P = 0.0166 from basal and P = 0.0109 from gastrin stimulated growth). CR2093 administration also reduced the gastrin-stimulated growth of MKN45 xenografts (P = 0.045) but failed to inhibit the gastrin enhanced proliferation of C523 xenografts. This may be related to the affinity (Kd) of the gastrin receptors present on the xenograft lines as the Kds of the two xenografts inhibited by CR2093 were 4.6 x 10(-10) M (AR42J) and 1.2 x 10(-9) M (MKN45) respectively whereas the Kd of C523 was of higher affinity (2.2 x 10(-10) M). GR antagonists may be a viable therapeutic option for gastrin receptor positive, gastro-intestinal tumours.

Amino Acids↗
PubMed1992

Assessment of proliferation of squamous, Barrett's and gastric mucosa in patients with columnar lined Barrett's oesophagus.

There is no satisfactory biomarker yet available for predicting the likelihood of premalignant changes or carcinoma developing in Barrett's or columnar lined oesophagus. In this study we have evaluated the proliferation of squamous epithelium, columnar epithelium from columnar lined oesophagus and gastric columnar epithelium from 23 Barrett's patients using positive immunoreactivity with the mouse monoclonal antibody Ki67 (which recognises an antigen associated with proliferative cells) with a view to using this parameter as a biomarker. Squamous epithelium had significantly higher Ki67 immunostaining as compared with columnar epithelium from columnar lined oesophagus (when examining the tissue with greater than 15% cells staining positive for Ki67, Fisher's exact test p = 0.004) but there was no difference found between the epithelium from the columnar lined oesophagus and gastric columnar epithelium. There was no correlation between histological inflammation and Ki67 immunoreactivity of Barrett's mucosa, and the Ki67 immunostaining of two patients with dysplasia was no different from the rest of the group. There was, however, a significant correlation between the Ki67 immunoreactivity of columnar epithelium from columnar lined oesophagus and columnar epithelium from the stomach (correlation coefficient = 0.44, p = 0.03) suggesting that epithelium from columnar lined oesophagus behaves in a similar fashion to gastric epithelium.

Adult↗
PubMed1992

Length of Barrett's oesophagus: an important factor in the development of dysplasia and adenocarcinoma.

In a 15 year prospective study of endoscopic surveillance of columnar lined oesophagus, 102 patients with a mean follow up of 54 (12.5) months and total follow up of 462 years have been evaluated. Of all the sets of biopsies taken, 59 in 21 patients were found to exhibit dysplasia or carcinoma. Four male patients had carcinoma of the oesophagus, indicating a 30 times increased risk of development of adenocarcinoma in columnar lined oesophagus. The length of columnar lined oesophagus in subjects with dysplasia was significantly longer as compared with the whole group (p = 0.01) and when compared with the patients without dysplasia (p = 0.005). None of the patients with dysplasia had a columnar lined oesophagus of less than 8 cm. Length of columnar lined oesophagus therefore seems to be a significant risk factor in the development of dysplasia and subsequent carcinoma and intensive follow up of patients with columnar lined oesophagus greater than 8 cm in length is recommended.

Adenocarcinoma↗
PubMed1992

Effect of subject age on costs of screening for colorectal cancer.

STUDY OBJECTIVE: The aim was to estimate costs and yields of faecal occult blood screening and rescreening for colorectal cancer, for differing age cohorts. DESIGN: Cost and clinical data were used as the basis for modelling the expected costs, and cost savings, resulting from the treatment of screen detected cancers, as compared with cancers detected by symptomatic presentation. SETTING: Data were derived from the MRC screening trial currently in progress in Nottingham. PARTICIPANTS: Approximately 140,000 subjects, age 50-79 years, were randomly allocated to a test (screened) and a control (unscreened) group. MAIN RESULTS: The net costs of detecting and treating a cancer following colorectal screening fall as the age of the target population increases, owing principally to the increasing incidence of the disease with age. Generally, the marginal detection and treatment costs falls for all age groups with the first screening round, but rises considerably with the second. If allowance is made for cancers prevented as a result of early detection and excision of adenomas, the costs of screening are substantially reduced for all age groups. CONCLUSIONS: Assuming a cost per QALY (quality adjusted life year gained) equivalent to that derived for the breast cancer screening programme, and a QALY gain from colorectal screening of one year, three screens, each separated by two years, appear economically justified for populations aged 60 years and above. Expected gains from cancer prevention make two screens justifiable for those between 45 and 59 years of age.

Age Factors↗
PubMed1992

Cost-effective screening strategies for colorectal cancer.

This paper models a range of feasible strategies for mass population screening for colorectal cancer. It uses both clinical and economic data derived from the major colorectal cancer screening trial currently under way in Nottingham, supplemented by data from concurrent Scandinavian trials. Costs and yields for 12 strategies are modelled, and optima are identified according to a number of evaluation criteria. The cost-effectiveness condition for the desirability of introducing a programme of colorectal screening is also established.

Aged↗
PubMed1991

Antitumor immune response and interleukin 2 production induced in colorectal cancer patients by immunization with human monoclonal anti-idiotypic antibody.

The immunogenicity of human anti-idiotypic antibody has been investigated using a human monoclonal anti-idiotypic antibody (105AD7) which interacts with the binding site of 791T/36, a mouse monoclonal antibody against gp72 antigen. This antigen is frequently expressed in gastrointestinal cancer, therefore, six patients with advanced colorectal cancer have been immunized with 105AD7 as an aluminum hydroxide gel precipitate in a phase I clinical study. Cryopreserved blood mononuclear cells were tested for in vitro proliferative responses by [3H]thymidine incorporation; plasma samples were tested by enzyme-linked immunosorbent assay for anti-anti-idiotypic and antitumor antibodies, and for interleukin 2. Proliferative responses to gp72 positive tumor cells were seen in four of five patients tested; parallel in vitro responses to 105AD7 anti-idiotypic antibody were seen in most of these patients. Interleukin 2 was detected in the plasma of four of six patients after 105AD7 immunization, with peak levels up to 7 units/ml. No toxicity related to anti-idiotype immunization and no antitumor or anti-anti-idiotype antibodies were seen. This study shows that human monoclonal anti-idiotype 105AD7 is immunogenic in cancer patients, inducing cellular antitumor responses and interleukin 2 production. This suggests that human monoclonal anti-idiotype antibodies may have considerable potential for immunotherapy of human cancer.

Adult↗
PubMed1991

A prospective evaluation of the effect of tumor cell DNA content on recurrence in colorectal cancer.

Tumor cell DNA (ploidy) content was measured prospectively in samples from 320 patients resected for colorectal cancer with a minimum follow-up time of 2 years. All patients were followed and those with recurrence were investigated carefully. There was no correlation between tumors with an abnormal cellular DNA content (aneuploid or tetraploid) and patient age, sex, tumor site, pathologic stage, or histologic grade. In 236 patients who underwent potentially curative operations, 75 (32%) had local and/or distant recurrence. The recurrence rate was significantly higher (test statistic, 4.3; P = 0.04) for those patients with aneuploid tumors (52 of 142, 37%) compared with those with diploid tumors (23 of 94, 24%). The subgroups of patients where ploidy exerted an effect were in patients with Stage B tumors or mobile tumors and in patients over 65 years of age. Further analysis showed that there was a twofold increase in local recurrence and a threefold increase in distant recurrence in patients with aneuploid tumors, but no excess of patients who had both local and distant recurrence. Measurement of DNA ploidy can identify a group of patients undergoing curative surgery for colorectal cancer at high risk for recurrence. In combination with clinicopathologic factors, DNA ploidy may be useful in analyzing the results of trials and in planning adjuvant therapy.

Aged↗
PubMed1991

Detection of colorectal liver metastases using intraoperative ultrasonography.

Intraoperative ultrasonography of the liver has been carried out in 99 patients undergoing surgery for colorectal cancer. Palpation of the liver, preoperative abdominal ultrasonography and computed tomography scanning were also performed in all patients. Metastases were identified in 26 of the 99 patients (26 per cent). Intraoperative ultrasonography diagnosed more metastases than palpation, abdominal ultrasonography or CT scanning, identifying metastases in 24 of the 26 patients, including six patients in whom the metastases were not detected by any other technique. Identification and localization of impalpable liver metastases is therefore possible using intraoperative ultrasonography.

Colorectal Neoplasms↗
PubMed1991

The hospital costs of diagnostic procedures for colorectal cancer.

Diagnosis for colorectal cancer is commonly made using either colonoscopy or double contrast barium enema techniques. To data, little attention has been paid to the comparative costs of these two procedures and the paper presents estimates of hospital costs for each, using data from the colorectal study being undertaken in Nottingham, U.K. Consideration is also given to procedure sensitivity and the frequency of referral to the alternative technique in cases of incomplete diagnosis. The paper presents the conditions under which a given technique may be considered cost-superior to its alternative but concludes that the absence of conclusive clinical trial data and other considerations precludes the identification of a definitively optimum technique from the economic point of view.

Barium Sulfate↗
PubMed1991

Failure of CA19-9 to detect asymptomatic colorectal carcinoma.

Serum CA19-9 levels have been measured in 34 patients with asymptomatic colorectal cancer, 39 age and sex matched subjects with healthy colons (as assessed at full colonoscopy) and 55 patients known to have liver metastases from primary colorectal cancers. In subjects with asymptomatic cancer the median CA19-9 was 12.75 U ml-1 (0.0-280.7 U ml-1), in the healthy controls the median CA19-9 was 12.80 U ml-1 (0.0-88.9 U ml-1) and in those with liver metastases was 62.5 U ml-1 (4.8-458.0 U ml-1). Levels were significantly higher in patients with metastatic disease than in patients with asymptomatic tumours or the healthy controls, however there was no significant difference between the asymptomatic group and the controls. Using an upper limit of normal of 37 U ml-1, the sensitivity of CA19-9 was 60.3% for the detection of colorectal cancer with liver metastases but only 17.6% for asymptomatic cancer. Serum CA19-9 estimation is of no value as a means of screening for asymptomatic colorectal cancer.

Adult↗