Role of bone marrow transplantation in 90Y antibody therapy of colon cancer xenografts in nude mice.

The efficacy of bone marrow transplantation (BMT) for the prevention of 90Y toxicity and extension of survival in nude mice with i.p. LS174T carcinomatosis was evaluated. 90Y-labeled monoclonal antibody (MAB) directed against carcinoembryonic antigen (90Y-anti-CEA MAB) at a dose of 120 microCi caused no deaths due to treatment toxicity and increased the duration of animal survival. No long term cures were obtained in these mice. At doses of 160 microCi or more 90Y-anti-CEA MAB led to hematological deaths. Nude mice were given i.p. injections of 10(6) LS174T tumor cells on day 0. On day 7 the mice received 90Y-anti-CEA MAB i.p. at doses of 120-225 microCi. Syngeneic bone marrow cells (10(7) cells) were then injected i.v. into the mice at 1, 3, 5, 7, 10, or 14 days following 90Y treatment. In the absence of BMT, toxic deaths for animals given 175 microCi 90Y were 11 of 24 (46%) with a median survival of 17 days and 13 of 20 (65%) for animals given 225 microCi 90Y with a median survival of 14 days. Animals receiving the same two doses of 90Y and given BMT 5 days following the 90Y treatment showed 0 of 24 (0%) and 0 of 54 (0%) toxicity deaths, respectively. The optimal time of BMT in relation to 90Y therapy was dependent upon the dose of 90Y-anti-CEA MAB (225 microCi, 3-5 days; 175 microCi, 5-14 days). The mean survival in tumor bearing animals was extended from 31.7 +/- 1.2 (SE) to 45.3 +/- 2.0 days by treatment with 120 microCi of 90Y-anti-CEA MAB. By increasing the dose of 90Y-anti-CEA MAB to 225 microCi and undertaking BMT 5 days later the mean survival was further extended to 63.2 +/- 3.6 days (P less than 0.005). BMT administered at the optimal times can prevent toxic deaths and facilitates higher, more effective doses of tumor specific 90Y-MAB.

Presurgical imaging with indium-labeled anti-carcinoembryonic antigen for colon cancer staging.

Over a 4-year period, 108 patients with known or suspected colorectal cancer were studied by radioimmunoconjugate scintigraphy prior to operative procedures. Study subjects received 0.2 to 40 mg i.v. of murine anti-carcinoembryonic antigen monoclonal antibody labeled with 2-5 mCi of 111In (Indacea). Resected tissues were analyzed for 111In and carcinoembryonic antigen content. Tumor, liver, and draining lymph nodes had over 10% injected dose/kg compared to less than 2.5% injected dose/kg for other normal tissues. Primary tumors that were successfully imaged were significantly larger and had higher 111In and carcinoembryonic antigen content. In 54 patients, primary tumors were visualized with a sensitivity of 78%. Hepatic metastases (58 patients) were visualized as negative filling defects (sensitivity, 45%). Extrahepatic (intraabdominal) metastases (25 patients) were visualized (sensitivity, 48%) as areas of increased uptake. Extraabdominal metastases were uncommon (10 patients; sensitivity, 80%). Of 56 patients with known or suspected hepatic metastases who presented with no evidence of extrahepatic disease by conventional tests (X-ray, computerized tomographic scan), 20 (36%) were documented to have extrahepatic metastases at exploratory surgery and 10 of these (50%) had the extrahepatic disease localized by the Indacea scan. The management of these 10 patients was, or could have been, modified by the scan findings and unnecessary surgery eliminated.

Impact of radiolabeled antibody imaging on management of colon cancer.

One hundred patients with known or suspected colorectal cancer were studied by radioimmunoconjugate scintigraphy prior to operation. Study subjects received murine monoclonal anticarcinoembryonic antigen labeled with indium 111 (Indacea). Sensitivity of imaging was 76 percent for primary tumors, 44 percent for hepatic metastases, 38 percent for extrahepatic abdominal metastases, and 78 percent for extraabdominal metastases. Seventeen of 46 patients (37 percent) with known or suspected hepatic metastases and no evidence of extrahepatic disease by conventional imaging methods had extrahepatic metastases at exploratory surgery. Nine of the 17 patients had disease accurately predicted by the Indacea scanning. The management of each of these nine patients was, or could have been, modified by the scan findings and unnecessary surgery eliminated. A number of patients without post-operative disease had an unexplained increase in plasma carcinoembryonic antigen level due to production of human antimouse antibody. The addition of excess mouse immunoglobulin to the plasma prior to assay blocked this artifactual increase.

Artifactual CEA elevation due to human anti-mouse antibodies.

Retrospective analysis of 108 patients who received indium 111-labeled murine monoclonal antibodies for imaging of cancer was performed. Most patients had operative procedures for colorectal carcinoma following completion of scintiscanning. Eleven patients had markedly elevated carcinoembryonic antigen (CEA) levels postoperatively without evidence of residual or recurrent disease. The laboratory method of measuring CEA levels was a commercially available double mouse monoclonal antibody enzyme immunoassay. It was postulated that the unexplained elevation of CEA was a reflection of the presence of human anti-mouse antibody (HAMA) induced by the administration of radiolabeled mouse antibody. A competitive assay for HAMA was undertaken by incubation of these patients' sera with a high dose of nonspecific mouse immunoglobulin prior to CEA determinations, and subsequent CEA levels were normal. The presence of HAMA was confirmed by a noncompetitive solid-phase enzyme immunoassay in 73% of tested patients who received murine monoclonal antibodies for imaging. Identification of artifactual CEA elevations is important in the treatment of cancer patients.

Brains--a computer advisor system to aid in CT scan interpretation and cerebral disease diagnosis.

This paper describes a prototype system to aid in the radiological interpretation of CT scan images of patients with cerebral disease. The system is able to provide guidance, both on diagnosis and the need for enhancement.

An unusual presentation of colon cancer.

A rare case of asymptomatic cancer of the ascending colon presenting as a subcutaneous groin mass is reported. At the time of right hemicolectomy with resection of the groin mass there was no sign of incontinuity spread or lymph blockage. Sequential determination of carcinoembryonic antigen levels (CEA) in serum reflected the reduction in tumor mass after surgery as well as subsequent recurrences of disease in the groin and in the lung after 2 years. Immunoperoxidase staining of the primary tumor and the metastases showed strong positivity for CEA confirming the origin of the serum CEA. There have been no signs of liver involvement. The route of spread of this unusual metastasis is not known.

Monoclonal antibody-defined phenotypes of regional lymph node and peripheral blood lymphocyte subpopulations in early breast cancer.

Lymphocyte subset phenotypes in peripheral blood and axillary lymph node cell isolated from 28 patients undergoing surgery for breast cancer were determined by two-color immunofluorescence with monoclonal antibodies and flow cytometric analysis. Lymphocyte subpopulation proportions were determined with combinations of monoclonal antibodies directed against the Leu 2, Leu 3, Leu 7, Leu 8, Leu 11, Leu 12, Leu 15, Leu M3, and HLA-DR surface markers. Patients were staged according to the postsurgical-pathological modification of the Tumor-Node-Metastases staging system, for analysis of tissue source (lymph node versus peripheral blood) and stage of disease as factors influencing lymphocyte subset size. Activated Leu 2+DR+ and Leu 3+DR+T-cells were elevated in stage 2 carcinoma compared to Stage 1. Elevation of Leu 2+8+ circulating T-cells and a reciprocal depression of Leu 2+8- T-cells were also seen in Stage 2 patients when compared to Stage 1. Total T-cells, B-cells, Leu 2+, and Leu 3+ T-cell subsets and natural killer phenotypes defined by Leu 7 and Leu 11 were unchanged in the peripheral blood of Stages 1 and 2 breast cancer. Regional lymph nodes from Stage 1 were found to contain a high frequency of Leu 3+ cells which dropped significantly in Stage 2 patients; this was found to be numerically due to a sharp decrease in the Leu 3+8- subpopulation in Stage 2 patients. Elevated B-cells (Leu 12+), activated T-cells (Leu 2+DR+ and Leu 3+DR+), total Leu 2+ cells, and Leu 7-11+ natural killer cells were demonstrated in Stage 2 lymph nodes when compared to Stage 1. Generally, no differences in subpopulations were seen when level 1 (low axillary) lymph node cells were compared to level 3 (high axillary) lymph node cells at each stage of the disease. These findings demonstrate substantial differences in the profile of lymphocyte phenotypes between Stage 1 and Stage 2 breast carcinoma, especially in the ipsilateral regional nodes. The findings presented in this study suggest that changes in local-regional immunocompetent cell subsets may be related to metastasis of tumor to the regional nodes and progression of disease without being fully reflected in the systemic circulation.

Computer assistance for C.T. scan interpretation and cerebral disease diagnosis.

This paper describes the development and use of a system to aid in the radiological interpretation of C.T. scan images of patients with cerebral disease. The system is able to provide guidance, both on diagnosis and the need for further scan investigations. Explanation and help facilities, similar to those found in certain rule-based expert systems, are available on demand. Diagnostic and other advice is, however, based on hard statistical data. The scan interpretation and diagnostic system offers important benefits in the training of less experienced radiologists.

Statistical modelling and diagnostic aids.

This paper considers the problems involved in constructing operational aids for diagnosis. A collaborative approach is proposed which involves utilisation of the expertise of clinician and statistician, working jointly on the analysis of hard data for a particular diagnostic application. The application of this approach to a problem involving cerebral disease diagnosis based on CT scan data is described.