Sequential analysis of urinary antigen(s) in patients with sarcoma.
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Biomedical subjects
Publications and source records attributed to D L Morton.
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Oncofetal antigen (OFA) has been defined with the use of human natural antibodies as a membrane antigen of human cancer cells that cross-reacts with human fetal brain tissues. The immunogen that elicits the antibody is unknown. The present study was undertaken to examine the immunogenicity of the OFA found on tumor cells. Postoperative melanoma patients were immunized with OFA-positive melanoma cells. Anti-OFA reactivities in the immunized sera were titrated by the immune adherence assay with the use of a known OFA-positive cultured melanoma cell line, M14, as target cell. Alloantibodies were excluded by absorption with lymphoblastoid cells autologous to M14. Anti-OFA antibody then was identified by absorption with fetal brain. In 6 months of immunization, 19 of 23 patients produced increased anti-OFA antibodies. The peak titers ranged from 1:16 to 1:2,048. Sera from 18 patients who were not immunized also were tested for 6 months postoperatively, and none had significant increases in antibody titers. The increase of anti-OFA antibody titer in response to the immunization with OFA-positive tumor cells suggests the immunogenic capability of tumor-related OFA in man.
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Peripheral blood lymphocytes and skin fibroblasts from 12 cancer patients were infected with Epstein-Barr virus (EBV) or SV40 virus. The EBV-transformed lymphoblasts and SV40-transformed fibroblasts were grown as continuous cell lines and expressed the same histocompatibility antigens as tumor cell lines established from the same cancer patients. Sera from 350 melanoma and 195 sarcoma patients were tested for antibody reactive with membrane antigens on three of these tumor cell lines (two melanomas and one sarcoma) by immune adherence (IA) and indirect immunofluorescence (IMI) assays. Antibodies to HLA and other non-tumor-related antigens were completely removed from the most reactive sera by quantitative absorption with 4 x 10(7) lymphoblasts or 10(7) transformed fibroblasts autologous to the tumor target cells. These paired cell lines were used to monitor humoral immune responses in melanoma and sarcoma patients receiving allogeneic tumor cell vaccines.
Adjuvant chemotherapy with adriamycin (ADR) and high-dose methotrexate (HDM) with citrovorum rescue appears to hold promise for preventing recurrence of sarcomas following surgery. However, the effect of prolonged treatment with these agents on both in vivo and in vitro cell-mediated immunity (CMI) is unknown. To assess in vitro CMI, cryopreserved lymphocytes from 18 patients, collected before and at monthly intervals following initiation of biweekly ADR and HDM therapy, were tested simultaneously for stimulation to phytohemagglutinin, poke-weed mitogen, Concanavalin A, and pooled allogeneic lymphocytes by a micro-test technique. In vivo CMI was determined by serial skin-testing with 2,4,-dinitrochlorobenzene (DNCB). No significant overall change was noted for any of the in vitro lymphocyte function tests. DNCB skin test ratings, peripheral leukocyte counts and absolute lymphocyte counts did not change significantly during the study. Lymphocytes from a second group of patients were tested before, at 24 and 48 hours after HDM therapy. In vitro lymphocyte function tests were significantly depressed 24 hours following treatment, but returned to pretreatment levels at 48 hours. Long-term adjuvant ADR and HDM therapy does not appear to alter in vivo and in vitro CMI, although transient depressions were noted. The preservation of intact CMI may account in part, for the effectiveness of these agents as surgical adjuvants.
Elevated membrane sialic acid (n-acetyl neuraminic acid) concentration may be a general phenomenon associated with malignant or transformed cells. In this study, sera from 30 normal persons and 25 melanoma patients were examined to determine first, if serum sialic acid elevations were associated with malignant melanoma, and second, if there was a relationship between tumor burden and serum sialic acid level. Significantly elevated sialic acid concentrations were found in the melanoma patients (p less than 0.005), and levels tended to be greater in those with a large tumor burden (p less than 0.05). Thus, increased serum sialic acid could prove to be a valuable clinical monitor of change in tumor burden as a result of therapy or change due to recurrence of disease following treatment.
This brief review of the more promising clinical trials suggests that immunotherapy is indeed beneficial for selected cancer patients. Because of its limited potency, it should not be used as primary treatment for malignant disease except as local immunotherapy for certain accessible tumors. It is effective for eradication of primary neoplasms of the skin as well as cutaneous metastases of malignant melanoma and breast carcinoma. The most important role for immunotherapy is in combination with other modalities. It may help control occult micrometastases that cause recurrence and death following surgical procedures or irradiation. Results of adjuvant immunotherapy appear promising for malignant melanoma, for carcinoma of the lung, breast, and colon, and for soft-tissue sarcomas. In combination with chemotherapy, immunotherapy appears to prolong remission and survival in acute myelogenous leukemia and in disseminated tumors of the lung and breast. Clearly, immunotherapy is not a panacea for malignant disease, but it could become an important arm in a multimodality attack on cancer.
Historically, the effectiveness of surgical therapy for cancer was thought to depend upon the successful removal of every last tumor cell from the patient's body. However, this view is not consistent with modern concepts of surgical oncology which suggest that successful cancer surgery depends upon how favorably it influences the patient's defenses against the cancer. Recent evidence suggests that the growing neoplasm is capable of evading immune attack by producing specific and nonspecific immunosuppression of the host's defenses to enhance tumor growth. The extent of the immunosuppression correlates with the tumor burden; immunosuppression is reversed by removing the neoplasm. Therefore, cancer surgery acts as immunotherapy because it removes the cancer cells that produce the immunodepression and allows the patient's immune response to recover.
A unique case of breast cancer presenting as renal colic due to ureteral obstruction is presented. Although antemortem diagnosis has been uncommon, ureteral metastases frequently are found in autopsy studies. Improvements in the management of patients with disseminated breast cancer may lead to more frequent recognition of this problem. Therapy should be directed against the tumor in general, and not specifically against the ureteral lesion unless renal function is jeopardized. Hormonal manipulation is the treatment of choice in patients with estrogen receptor-positive tumors. Ureteral catheterization or urinary diversion should be attempted only in combination with systemic injury.
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Human cell membranes acquired an antigenic substance from the bovine serum in culture medium. The antigen was named the heterologous membrane antigen (HM Ag). Cross-reactive antigen was found in sera of all mammals tested, except for man. The distribution of the HM Ag serologically distinguished man from other mammals.
This study evaluates the effect of adjuvant immunotherapy with BCG alone, or combined with melanoma cell vaccine, on the recurrence and survival rates of patients with metastatic melanoma in the regional lymph nodes who were treated by lymphadenectomy. Patients were prospectively randomized and stratified on the basis of age, sex, site of primary tumour, and clinical estimate of the regional nodes. During the past four years, 134 patients were entered into this trial, and to date, the incidence of recurrence among the two arms mentioned and the control arm is not significantly different; however, patients receiving BCG alone had longer survival than those in either the tumour cell vaccine or control groups. The improved survival in the BCG-only group was found to be due to the fact that patients survived longer with their recurrent disease than the patients in the other two groups. At the present time, these differences do not appear to be significant enough to justify routine adjuvant immunotherapy in patients with melanoma metastatic to regional nodes. Longer follow-up will be necessary to evaluate the role of adjuvant immunotherapy of Stage II melanoma.
Surgical therapy has been the accepted method for management of most soft tissue sarcomas of the extremities, although it has been associated frequently with local treatment failure. Even when local control was achieved, over 50% of the patients with soft tissue sarcomas eventually developed and succumbed to distant metastases of their disease. Therefore, single modality therapy for soft tissue sarcomas by operation alone results in an unacceptably high incidence of treatment failure. Fortunately, new adjuvant treatment techniques have been developed that seem to have activity against these neoplasms. It is the purpose of this article to discuss our experience with a number of these techniques.
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Seventeen consecutive patients with osteogenic sarcoma participated in a prospective study to ascertain first, whether postoperative adjuvant chemotherapy or chemoimmunotherapy could reduce the incidence of distant metastases and second, whether in situ tumor cell destruction could be achieved with preoperative chemotherapy and radiation therapy. To date 14 of 17 patients (85%) are alive and free of disease for a median survival time of 11 months. Three patients developed recurrent disease, one with local recurrence in the tibia and two with pulmonary metastases. Limb salvage was attained in 12 patients by cadaver allografts and in one patient by radiation alone at 6 months.
Because systemic spread occurs early in the growth of many malignancies, control of occult micrometastases must be an integral part of cancer treatment. For this reason, surgery and radiation therapy alone may fail to achieve a cure despite eradication of the primary tumor. Chemotherapy is potent and systemic in its effects but kills tumor cells by first-order kinetics so the last cancer cell may not be eliminated. An agent is needed that can selectively attack and destroy small numbers of tumor cells on a systemic basis without a significant increase in toxicity. Experimental observations indicate that immunotherapy could fill this role. Immunotherapy has been tested as an adjuvant to surgery, radiation therapy, and chemotherapy, and is clearly beneficial for selected cancer patients. There are many unresolved questions regarding the underlying mechanisms as well as the practical application of adjuvant immunotherapy, but the initial investigations indicate that it could play a vital part in the treatment of cancer. There is evidence that stimulation of host resistance can result in control of systemic micrometastases.