Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein.

Mucin 1 (MUC1) is a large complex glycoprotein that is highly expressed in breast cancer, and as such could be a target for immunotherapy. In mice, human MUC1 is highly immunogenic, particularly when conjugated to mannan, where a high frequency of CD8(+) MHC-restricted cytotoxic T lymphocytes is induced, accompanied by tumor protection. On this basis, a clinical trial was performed in which 25 patients with advanced metastatic carcinoma of breast, colon, stomach, or rectum received mannan-MUC1 in increasing doses. After 4 to 8 injections, large amounts of IgG1 anti-MUC1 antibodies were produced in 13 out of 25 patients (with antibody titers by ELISA of 1/320-1/20,480). Most of the antibodies reacted to the epitopes STAPPAHG and PAPGSTAP. In addition, T cell proliferation was found in 4 out of 15 patients, and CTL responses were seen in 2 out of 10 patients. Mannan-MUC1 can immunize patients, particularly for antibody formation, and to a lesser extent, cellular responses. It remains to be seen whether such responses have antitumor activity.

Correlation of histopathologic characteristics of primary tumor and uninvolved regional lymph nodes in Dukes' class C colonic carcinoma with prognosis.

Ninety-two patients with Dukes' class C colonic carcinoma, divided equally into those who survived 5 years or more and those surviving less than 5 years after resection for cure, underwent evaluation of multiple histopathologic characteristics of the primary tumor and the uninvolved regional lymph nodes. These characteristics were analyzed by the chi-square test for correlation with survival. A statistically significant correlation (P less than 0.05) in the group who survived 5 years or more was observed for Broders' grades 1 and 2, tumor not involving serosa, and a pushing tumor margin. Of the 14 patients who had a pushing tumor margin and tumor not involving serosa, 12 (86%) survived 5 years or more. Seven patients had an infiltrating tumor margin and peritumor venous invasion, and of this group, only one (14%) survived 5 years or more. Histopathologic characteristics of host immune reaction at the tumor or in the uninvolved regional lymph nodes did not correlate with survival.

Serum markers casa, cea, cyfra-21-1, msa, nse, tpa and tps in lung-cancer.

Serum CASA, CEA, CYFRA 21-1, NSE, MSA, TPA, and TPS were determined in patients with lung cancer (LC), benign lung disease (BL), and healthy control (HC) donors. Using predefined cutpoints, the cytokeratin-related markers TPA, TPS, and CYFRA showed the highest sensitivity in non-small cell lung cancer (TPA 69%, TPS 63%, CYFRA 54%), while NSE gave the highest sensitivity in small cell lung cancer (50%), indicating that these markers may be most appropriate in monitoring the course of disease and the patients response to therapy. Receiver-operator analysis was performed to compare assays at the same specificity. At high specificities (greater than or equal to 95%), CYFRA was significantly better than all assays except CASA in the LC vs. HC and LC vs. non-infectious BL comparisons (p<0.05), while CEA was the only assay which was not significantly different to CYFRA in the LC vs. BL comparison. CASA was of particular value when used in combination with these markers, as the sensitivity was increased. In addition, pretreatment CASA was the best indicator of patient survival (one year survival of 83% for patients with CASA <5 units/ml and 10% for patients with CASA greater than or equal to 5 units/ml).

Plasma carcinoembryonic antigen and erythrocyte sedimentation rate in patients with colorectal carcinoma.

Preoperative and postoperative plasma carcinoembryonic antigen (CEA) levels in patients with colorectal carcinoma have been reported to correlate with tumour mass and prognosis. The erythrocyte sedimentation rate (ESR) has previously been reported to be elevated in most patients with metastatic carcinoma. In this study of 17 patients with advanced colorectal carcinoma and of nine patients who were disease-free more than three years after resection of their tumour, the plasma CEA and ESR levels demonstrated a close correlation, both in frequency and in degree of elevation, with the disease status. Of nine patients who were disease-free more than three years after resection of their colorectal carcinoma, all except one had plasma CEA levels of less than 20 ng/ml and an ESR less than 20 mm in one hour respectively. The incidence of plasma CEA more than 20 ng/ml and ESR more than 20 mm in one hour in the locally advanced and distant metastases groups, as compared with those patients in the more than three years group, was increased at a level of statistical significance (P less than 0.05). This study showed that the ESR, an inexpensive and simple estimation, may be as effective as the estimation of plasma level of CEA in monitoring the disease status of patients with colorectal carcinoma.

Tumour stimulation by anti-oestrogens.

Two women who developed tumour progression while taking anti-oestrogens are described and some of the possible mechanisms for this action are discussed.

In situ intraduct carcinoma of the breast: a long term follow-up study.

Twenty-eight patients with in situ intraduct carcinoma of the breast are reviewed. Two patients had bilateral tumours. The numbers of patients treated by wide local excision, simple mastectomy and mastectomy with axillary dissection were approximately equal; none of these patients died of carcinoma. The conclusions regarding prognosis and treatment of in situ intraduct carcinoma of the breast are discussed.

Perforation of the sigmoid colon by an orthopedic nail: report of a case.

Clinical features and radiographs are presented of a patient whose sigmoid colon was perforated by an orthopedic nail entering the peritoneal cavity via the left acetabulum. The patient was successfully treated by extraction of the nail and closure of the colonic defect.

Malignant fibrous histiocytoma.

Seven cases of malignant fibrous histiocytoma are reported. Two patients had tumour involving the scrotum and small-gut mesentery, which are unusual primary sites, while three others with pulmonary metastases are alive five years since the appearance of these metastases. A review of the histogenesis, biological behaviour and the treatment of these uncommon tumours suggests that the prognosis is good even in the presence of advanced local or metastatic disease. Radiotherapy controlled the primary lesion in one patient and was effective in treating pulmonary metastases in three, suggesting that these tumours do show a response to radiotherapy. The prophylactic use of radiotherapy and chemotherapy awaits further evaluation.

A phase I study of a multi-modal schedule with Corynebacterium parvum.

A Phase I study of an immuno-chemotherapy regime was carried out using C. parvum as an immune-modulator. 14 women were studied. All received doses of C. parvum ranging from 2.5 mg to 21 mg administered in 1 litre of dextrose saline over 4 h. No evidence of tumour enhancement was observed.

The preoperative carcinoembryonic antigen test in the diagnosis, staging, and prognosis of colorectal cancer.

A study of preoperative carcinoembryonic antigen (CEA) levels was conducted in 319 patients with surgically treated colorectal cancer, 272 of whom had disease resectable with curative intent. Only three patients could not be completely followed. All of the remaining 316 patients have been followed for a minimum of 5 years or until death. From the standpoint of diagnosis, the CEA test was more frequently positive (greater than 5 ng/ml) in patients with advanced stage disease, with larger primary tumors, and with more differentiated histopathologic characteristics. It was grossly insensitive in diagnosis of resectable cancer (26%) and was only reasonably reliable (72%) in patients with unresectable and metastatic disease. In relationship to surgical pathology of colorectal cancer, CEA levels were significantly correlated with stage of disease and with size of the primary tumor in Dukes' B lesions, but not with extent of nodal metastasis in Dukes' C lesions. In advanced stage lesions, CEA was inversely correlated with degree of anaplasia. In the overall patient group, and also among resectable patients, the preoperative CEA level was strongly associated with survival after adjustment for the effects of a number of other prognostic factors. Within stages of resectable disease, however, CEA was not significantly associated with survival among patients with Dukes' A and B lesions or Dukes' C lesions with one to three nodes involved. CEA was found to be a significant and independent prognostic determinant only in patients with Dukes' C lesions who had four or more metastatically involved lymph nodes. Under these circumstances, a preoperative CEA level could perhaps be of some value for stratification of Dukes' C patients in randomized colorectal cancer surgical adjuvant trials. The value of this test as a prognostic guide in clinical practice, however, would seem to be limited because of a lack of sensitivity in identifying individual poor prognosis patients.

A prospective evaluation of the leukocyte adherence inhibition test in colorectal cancer and its correlation with carcinoembryonic antigen levels.

Fifty-four patients from the surgical gastroenterology service and 22 healthy controls have been prospectively evaluated in a single-blind protocol by the LAI tube method. The LAI correctly identified 25 of 33 early colorectal patients staged as Dukes' B and C at surgery but none of the Dukes' D patients. An inverse relationship was seen between the results of the non-adherence index (NAI) and CEA levels which was most pronounced in those with advanced colorectal cancer. The majority of Dukes' B and C patients having a "false negative" LAI had a CEA level greater than 2.5 ng/ml, suggesting that more advanced disease than that seen at surgery may be present. Two of 22 normal controls gave a borderline positive NAI. Some technical problems, including the relatively short life of the tumor extracts, are discussed.

Mannan mucin-1 peptide immunization: influence of cyclophosphamide and the route of injection.

The mucin MUC1 is greatly increased in breast cancer and is a potential target for immunotherapy. In mice, MUCI conjugated to oxidized mannan (MUC1-mannan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this basis, three phase I trials were performed in patients with adenocarcinoma to evaluate the toxicity and the immunologic responses to mannan MUCI. Forty-one patients with metastatic or locally advanced carcinoma of the breast (trial 1), colon (trial 2), and various adenocarcinomas (trial 3) received increasing doses of M-FP (1 to 300 microg). The immunizations were given at weekly intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide (to increase cellular immunity) was given on weeks 1 and 4. M-FP was given intramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effects occurred, and delayed-type hypersensitivity responses were present only as a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with the intraperitoneal route yielding approximately 10-fold higher responses. Cellular responses (proliferation, cytotoxic T cells, or CD8 T cells secreting tumor necrosis factor-alpha alphand interferon-gamma in response to MUC1 stimulation in vitro) were found in 28% of the patients, which was similar to that seen without cyclophosphamide. In most patients, disease progressed, but in five it remained stable. In addition, there were no objective responses. M-FP is not toxic and induces immune responses that were amplified by the intraperitoneal route of immunization. Cyclophosphamide was of no benefit.