Radioimmunodetection of gastrointestinal neoplasms with antibodies to carcinoembryonic antigen.

Primary and secondary gastrointestinal tumors have been identified using sheep immunoglobulin G antibody to carcinoembryonic antigen radiolabeled with 131I. 99mTc-pertechnetate and 99mTc-human serum albumin were used to identify tissue spaces and blood pool and to facilitate external substraction imaging. In 13 patients with tumors, 4 of 5 primary sites and 8 of 11 secondary sites were successfully demonstrated. Two patients with benign disease had negative scans. Comparison with conventional methods of scanning showed good correlation.

Effect of dose, molecular size, affinity, and protein binding on tumor uptake of antibody or ligand: a biomathematical model.

A mathematical model has been developed to determine the best approach to improving tumor targeting with antibody. The amount of antibody in the tumor (tumor content) and the tumor:normal tissue antibody concentration ratio (uptake ratio) were calculated over 12 days from injection, using the computer program FACSIMILE to solve the stiff nonlinear differential equations describing the system. Results indicate that success requires an optimal combination of dose, size, and binding affinity of antibody. Increasing the dose to 100 times that presently used for scanning increased both the percentage of injected antibody in the tumor and the uptake ratio by up to 2 orders of magnitude to maximal values determined by affinity. This result could be achieved by coinjecting unlabeled antibody. Increasing affinity from Keq = 10(9) to 10(13)M-1 increased the uptake ratio from 5 to 100 for whole antibody and to 550 for a small ligand, at the calculated optimal dose, but had no effect at the current scanning dose. With decreasing molecular size at average affinity, the same maximum tumor content and uptake ratio were achieved but progressively earlier. At high affinity there was a substantial advantage for a small ligand compared with whole antibody in terms of uptake ratio (550 versus 100) and tumor:normal tissue integral dose ratio (330 versus 60). The uptake of a small ligand was not increased by binding to plasma protein but with increasing time the tumor content was higher than without protein binding.

Cancer-associated proteins in effusion fluids.

Two cancer-associated proteins, carcinoembryonic antigen (CEA) and pregnancy-associated alpha2 glycoprotein (PAG), together with 13 normal serum proteins were measured in the serum and effusion fluid of patients with ascites and pleural effusions. The results indicate that CEA measurement in effusion fluid is more effective than serum measurement in distinguishing cancerous from congestive or inflammatory effusions. Comparisons with the results of cytological examination suggest that fluid CEA estimation may prove a useful clinical tool. Serum PAG levels were higher in patients with cancer, but fluid determination offers no advantage in separating the disease groups. Similarly, the estimation of individual normal serum proteins in effusion fluids is unlikely to be of diagnostic value.

The effect of serum protein concentrations on the specificity of the radioimmunoassay of carcinoembryonic antigen in malignant neoplasia and non-neoplastic disease.

Carcinoembryonic antigen (CEA) has been measured in parallel with seven serum proteins and seromucoids in the sera of patients with malignant neoplasia and non-neoplastic disease. In the total group significant correlations were found between CEA and seromucoids and between CEA and several serum proteins. However, with two exceptions, when the individual disease groups were examined no correlation was seen. It is concluded that abnormal concentrations of the specific proteins measured do not consistently interfere in the CEA radioimmunoassay and do not explain the high CEA levels in patients with non-neoplastic diseases.

Measurement of whole body cellular and collagen nitrogen, potassium, and other elements by neutron activation and whole body counting.

Whole body nitrogen can be measured by neutron activation analysis with an acceptable radiation dose; it is an index of body protein which, in normal subjects, is 65% cellular protein and 35% extracellular connective collagen. Whole body potassium can be measured by whole body counting without irradiating the subject; it is an index of body cell mass. We measured whole body nitrogen, potassium, extracellular water, intracellular water, and fat-folds. The differences between 37 malnourished patients and five normal subjects suggested that the patients had 9 kg less cell mass than normal, but no difference in extracellular mass. Measurements were made on eight patients before and after 14 days of total parenteral nutrition; balance of nitrogen intake and excretion also was measured. The changes were consistent with mean increases of 3 kg of cellular mass and 3 kg of fat with no change of extracellular mass. The accuracy and sensitivity of the whole body measurements need further confirmation for use in patients with changing body composition. Where tissue wasting is largely from the cellular compartment, potassium could be a more sensitive index of wasting than nitrogen. Multielement analysis of nitrogen, potassium, chlorine, and carbon will probably be valuable in elucidating body composition in malnutrition.

Limitations to the killing of tumours using radiolabelled antibodies.

We have calculated the minimum requirements for effective therapy using intravenously administered, tumour-directed antibodies labelled with either iodine 131 or yttrium 90. A lethally large amount of either radionuclide would be required to achieve tumour destruction. At least a 10-fold increase in tumour uptake is necessary to combine tumour destruction with a survivable whole-body dose. The required improvement in specific uptake can be substantially reduced by accelerating the excretion of radioactivity outside the tumour. For all situations studied, yttrium 90 is superior to iodine 131 as a cytotoxic label.

Clinical evaluation of anti-alpha-fetoprotein radioimmunodetection.

Anti-alpha-fetoprotein (AFP) radioimmunodetection was performed in response to clinical requests in 16 patients. In two patients, assessment of a known tumour was required; the anti-AFP scans were accurate and provided useful clinical information in both cases. In the remaining 14 patients the request was for localisation of suspected recurrent tumour. Accurate information was provided in four of these patients. In this latter group, various conventional methods of investigation had failed to disclose the site of recurrence. However, of a total of 21 sites reported as positive in these 14 patients, eight proved to be false positives. Two false negative results also occurred in this group and nine could not be evaluated. Although occasionally patients were usefully scanned, improvements are necessary before consistently reliable information can be obtained using this technique.

Limitations in localising and killing tumours using radiolabelled antibodies.

Radiolabelled antibodies against tumours are being studied intensely for their use in tumour detection and tumour destruction. Although a host of different tumour types can be localised, results at present are no better than other scanning techniques. In addition no tumour has been eradicated using labelled antibodies. Dramatic improvements will depend upon a fuller understanding of tumour cell biology and optimising all the parameters involved.

A lethal complication of peripheral vein vasopressin infusion.

A patient bleeding from oesophageal varices in whom injection sclerotherapy failed to control bleeding required peripheral vein vasopressin infusion for a total of five days. Three days after stopping the infusion she collapsed and died. Post mortem examination showed the cause of death to be intestinal infarction resulting from superior mesenteric and portal vein thrombosis. This complication has not previously been described in association with vasopressin infusion into peripheral veins. The duration of each infusion should be minimised and blood volume should be carefully monitored throughout. The condition should be suspected in patients who develop unexplained abdominal pain or collapse following vasopressin treatment.

The therapeutic dilatation of enteric strictures due to Crohn's disease.

The use of dilatation as a treatment of strictures due to Crohn's disease has hitherto received little attention. We report dilatation of small and large bowel strictures in twelve patients with Crohn's disease. The technique appears to be safe when carried out either endoscopically or as part of a laparotomy. Short term follow-up suggests that the technique may have a part to play in the treatment of suitable strictures that can be reached endoscopically but early restenosis limits its value at laparotomy when strictureplasty may provide a more lasting relief of the stenosis.

The surgical treatment of gastroduodenal Crohn's disease.

Crohn's disease can affect any part of the gastrointestinal tract. Gastroduodenal involvement is uncommon and was not recognised until 1949 (1). Since then approximately 200 cases have been described in several series in the world literature. This paper describes the clinical presentation and surgical management of ten patients treated in the Birmingham General Hospital between 1970 and 1984.

The importance of laparotomy in the diagnosis and management of intestinal bleeding of obscure origin.

Thirty-seven patients who had had either a colonoscopy or a selective mesenteric angiogram while being investigated for severe or persistent gastrointestinal bleeding of obscure origin were reviewed. Failure to make a prompt diagnosis was partly responsible for the 16% hospital mortality in the series. Colonoscopy was diagnostic on 6 out of 38 examinations but detected 43% of lesions in the colon. Angiography achieved only 3 diagnoses in 17 examinations. Fourteen patients had an exploratory laparotomy which was diagnostic in 9. We believe that early laparotomy still has an important place in the diagnosis and treatment of intestinal bleeding of obscure origin.

Enterovesical fistulas in Crohn's disease.

A total of 19 enterovesical fistulas were recorded in a series of 799 patients with Crohn's disease (2.4%). The origin of the fistulas was: ileum (9), colon (6) and four were complex involving the small and large bowel. Only 13 patients presented with urinary symptoms: pneumaturia (9), haematuria (1) and urinary tract infection (3). Four fistulas were identified incidentally during contrast radiology, one fistula was identified during a laparotomy and one further fistula developed after a previous resection for Crohn's disease. Four patients were managed conservatively and all are asymptomatic, but it is not known whether the fistula has healed. Twelve fistulas were resected: 9 healed, 2 recurred and 1 patient died following resection for a malignant fistula complicating Crohn's disease. Early in the series three patients were managed by bypass or defunction of the fistula. In all cases the sepsis persisted resulting in mortality. Persistent symptomatic fistulas should be treated by resection of the affected segment of bowel with primary anastomosis if appropriate. The defect in the bladder should be closed over an indwelling catheter which should not be removed until there is radiological confirmation that the bladder defect has healed satisfactorily.