Carcinoma of unknown primary site--a complete and sustained response with interleukin-2, alpha interferon and 5-fluorouracil/leucovorin.
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Biomedical subjects
Publications and source records attributed to F P Avis.
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The purpose of this paper is to evaluate certain aspects of the present status of surgical oncology research. We have attempted to define the magnitude of the problem, characterize features unique to the surgical community, and formulate potential solutions. Demographic data concerning grant applications submitted to and funded by the National Cancer Institute (NCI) over the time period from 1980 to 1985 were analyzed. Departments of surgery submitted and were awarded substantially fewer grants over the study period than departments of medicine. Additionally, the number of applications submitted from departments of medicine increased during this time period while those from departments of surgery declined. This record is particularly worrisome because it occurred during a period of time of unprecedented scientific and educational opportunities and support mechanisms provided by the NCI. Further conclusions and potential solutions are discussed in this paper.
Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.
We studied the effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells plus interleukin-2 or therapy with high-dose interleukin-2 alone in 157 patients with metastatic cancer for whom standard therapy had proved ineffective or no standard effective treatment was available. One hundred eight patients were treated with 127 courses of LAK cells plus interleukin-2, and 49 patients were treated with 53 courses of high-dose interleukin-2 alone. Of 106 evaluable patients receiving LAK cells plus interleukin-2, 8 had complete responses, 15 had partial responses, and 10 had minor responses. The median duration of response was 10 months among those with complete responses and 6 months among those with partial responses; the patient with the longest complete response was still in remission 22 months after treatment. Of 46 evaluable patients treated with high-dose interleukin-2 alone, 1 had a complete response (remission greater than 4 months), 5 had partial responses (2, greater than 3, greater than 5, 7, and greater than 11 months), and 1 had a minor response. Seven of the total of nine complete responses still remain in remission. Hypotension, weight gain, oliguria, and elevation of bilirubin and creatinine levels were common, but these side effects resolved promptly after interleukin-2 administration was stopped. There have been four treatment-related deaths among these 157 patients. This immunotherapeutic approach can result in marked tumor regression in some patients for whom no other effective therapy is available at present. Determining its ultimate role in cancer therapy awaits further attempts to increase the therapeutic efficacy of treatment and decrease its toxicity and complexity.
A modification of Brook's prelabeling (75SE) selenomethionine assay was developed and evaluated for detection of complement-dependent antibody (CDA) in a human tumor system. CDA was indeed detected in some breast cancer patients' sera. To determine whether the assay was reliable and reproducible, xenoantibodies were raised in rabbits by immunization with a human breast cancer line, Sk-Br-3, and tested against that line and five other unrelated human cancer lines. Multiple tests were performed on separate days. It can be concluded from the data that the assay is reliable and reproducible. The assay has wide application in investigating the biologic role of complement-dependent antibody activity in human and experimental animal tumor systems.
To determine the significance of proteolysis and delayed freezing of tumor samples on estrogen receptor levels, values from 19 of 31 biopsy specimens were compared with that in remaining tumor at the completion of mastectomy. There was a 15-100% decrease in receptor content. Time-decay studies on selected postmastectomy samples showed a further decrease in estrogen receptor content inversely proportional to the time it was exposed to room temperature. Factors that govern the valid measurement of receptor levels include tumor cell concentration, tumor necrosis, and time between devascularization of the specimen to freezing. A carefully procured histologically confirmed sample of fresh tumor is necessary for reliable estrogen receptor values.
We reviewed 75 patients operated on for carcinoma of the pancreas during the period 1973 to 1978. The role of surgery was examined in terms of contributing toward diagnosis, palliation, and cure. Computerized tomography, ultrasonography, upper gastrointestinal series, and arteriography were used to determine the presence or absence of a pancreatic mass. Arteriography and CT scanning were very helpful. Histologic confirmation was most often provided in conjunction with celiotomy. Endoscopy with cytology and percutaneous needle biopsy was quite specific but was rarely done. Palliative decompression of the biliary tree was done in 63% and biopsy alone in 21%, with a collective morbidity of 20% and a mortality of 3%. Potentially curative resection was done in only 8% with no immediate postoperative deaths. Although pancreaticoduodenectomy will continue to offer the only chance of cure in small numbers of patients, it is evident the present role of surgery is largely for diagnosis and palliation. In view of the mortality and morbidity of operation, increased emphasis should be placed on noninvasive diagnostic tests (CT scan, endoscopy with cytology, and direct needle biopsy). The future role of surgical reduction of the tumor mass in conjunction with adjuvant therapy is at present ill defined.
We evaluated two renal carcinoma lines, CAKI-1 and CAKI-2, for the presence of certain cell surface antigens. CAKI-1 was from an individual with blood type O and CAKI-2 from an individual with blood type A. A modification of the standard Chromium-51 release assay was used to determine complement dependent antibody activity in the serum of test subjects against these lines. Seventy per cent of 77 sera contained complement dependent antibody activity against CAKI-2; none was reactive against CAKI-1. Eighty-three and 88 per cent of sera from subjects with blood type B and O were reactive against CAKI-2; only 25 and 26 per cent of the sera from A and AB subjects were reactive against this same line. Both cell lines were agglutinated by anti-H lectin but only CAKI-2 was agglutinated by anti-A lectin. Fourteen of 18 normal control sera and 8 of 9 sera from cancer patients were inhibited by A antigen. A Forssman antigen obtained from guinea pig kidney removed significant complement dependent antibody activity against CAKI-2 when the sera were previously absorbed with this antigen. It would thus seem that CAKI-2 has on its surface an antigen which is either a true blood group A antigen, a Forssman antigen, or a Forssman-like antigen. Of special interest is the long persistence of this antigen in culture, thus permitting further studies characterizing its nature.
Specific anti-breast cancer complement dependent antibody (CDA) was sequentially determined in the sera of patients before and after mastectomy or during progressive recurrent breast cancer. Several observations were made. (1) There appears to be a different pattern of antigenic cross-reactivity detected by cancer patients' anti-tumor CDA than by their anti-tumor cell-mediated immunity; the former being broader than the latter. (2) Patients can be classified into three categories: those with persistent anti-tumor CDA pre- and post-mastectomy; those with detectable CDA post-mastectomy but not pre-mastectomy; and those with only occasionally detectable CDA. (3) Some sera obtained from patients with clinically evident tumor inhibited anti-tumor CDA found in the sera of other cancer patients. The significance of these results are discussed.
Sera from 27 patients with renal cancer, 14 patients with transitional cell carcinoma of the bladder and 21 normal controls were tested against 2 renal cancer lines (CAKI-1 and CAKI-2) by the iodinated protein A assay. All sera tested against CAKI-2 were absorbed first with AB+ substance because CAKI-2 was found to have cell surface A antigen. Sera from 16 of 27 patients with renal cell carcinoma, 3 of 14 patients with transitional cell carcinoma of the bladder and 2 of 21 normal controls were reactive with CAKI-1. Sera from 11 of 27 patients with renal cell carcinoma, 2 of 14 patients with transitional cell carcinoma of the bladder and 3 of 21 normal controls were reactive with CAKI-2. There is a positive correlation between the number of counts obtained by the renal patients' sera tested against CAKI-1 and CAKI-2.
Nonadherent peripheral blood lymphocytes (PBL) from 110 normal individuals were evaluated for their capability to mediate antibody-dependent cellular cytotoxicity (ADCC) against rabbit antibody-sensitized chicken erythrocytes (CRBC). Titration of PBL against a constant number of chromium-51 labeled CRBC allowed for construction of dose response cytotoxicity curves where percent chromium release was plotted against the number of PBL. From these curves the maximum degree of lymphocyte-mediated cytotoxicity and the number of lymphoid cells required for 50% of the maximum lymphocyte-mediated cytotoxicity were determined. The results suggested that in this system the cytotoxic capability of PBL from normal individuals was independent of the age and sex of the donor. The cytotoxic capability of PBL was also found to be constant in individuals tested sequentially. However, significant differences were found to exist between different individuals in their capability of mediating ADCC in this system.
Cells derived from human prostates have been successfully transplanted from tissue culture and from primary surgical specimens into nude mice. Techniques of transplantation and results are discussed.
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