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A phase-I trial of UltrapureTM human leukocyte (alpha) interferon was performed, in which 15 patients were treated according to a dose-ranging protocol. Five patients were treated at each of these dosage levels: 2 X 10(6) IU/dose, 9 X 10(6) IU/dose, and 15 X 10(6) IU/dose. Doses were given on days 1-5 and 8-12 of a 28-day study period. Serial NK-cell assays were performed in all patients, and failed to show consistent effects referable to treatment. Serum interferon levels were assayed on one patient at the 9 X 10(6) IU and one patient at the 15 X 10(6) IU dose level. In both cases, a significant interferon titer (greater than or equal to 160) was detected in the serum, and this persisted for as long as 12 h. Fever, malaise, and myalgias were associated with therapy. The dose-limiting toxicity was a dose-related leukopenia, with median white blood cell nadirs of 6,500/mm3 (3 X 10(6) IU/dose), 3,200/mm3 (9 X 10(6) IU/dose), and 1,800/mm3 (15 X 10(6) IU/dose) being produced. One patient died in ventricular fibrillation while suffering chest pain after receiving 5 days of treatment at the 15 X 10(6) IU/dose level. Three patients showed minor responses, insufficient to be called partial responses, in association with interferon therapy. We conclude that dose-limiting leukopenia occurs with this schedule of administration of UltrapureTM human leukocyte interferon at 15 X 10(6) IU/dose.

Ten patients with disseminated renal cell carcinoma have been treated with transfer factor as an immunostimulant. In 5 patients with metastatic disease evident at the time of initial diagnosis treatment involved removal of the primary tumor followed by transfer factor therapy. Of these patients 3 had a temporary stabilization of metastatic disease. Three patients with recurrent metastatic disease after previous nephrectomy were treated, 2 of whom showed a temporary stabilization of metastatic disease. There were 2 additional patients without clinically evident metastases but at a high risk for recurrent disease who were treated and remain free of disease. We used 5 immunologic parameters to evaluate the clinical effects of transfer factor. No objective clinical regression was noted in any patient treated with measurable disease.

Fifteen patients with germ cell neoplasms (9 testicular primary, 4 extragonadal, 2 adult teratoma syndrome) with features indicative of a poor prognosis were treated with chemotherapy followed by surgery. In patients with testicular primary sites, 2 patients have relapsed and all 9 remain alive (median follow-up 36 months). In patients with extragonadal tumors 2/4 are alive without disease, and both patients with the adult teratoma syndrome have died. Combination chemotherapy and surgery can be employed successfully in this subset of patients with germ cell neoplasms.

The long-term results of regional chemotherapy plus intra-arterial cisplatin with or without doxorubicin as an adjuvant before cystectomy and urinary diversion in patients with invasive transitional cell carcinoma of the bladder were evaluated. A total of 27 patients with T3aNxMo (8), T3bNxMo (14) and T4NxMo (5) disease participated in a phase II trial completed in 1985. Of the patients 19 received cisplatin and doxorubicin intra-arterially, and cyclophosphamide intravenously, and the remaining 8 received 70 to 100 mg. per m.2 cisplatin intra-arterially. A total of 19 patients underwent cystectomy after chemotherapy. Patients in this group had a pathological complete response (no evidence of disease after surgical restaging) or the presence of residual disease at operation that could (surgical complete response) or could not (pathological partial response) be completely resected. Of the 19 patients undergoing cystectomy surgical complete response was observed in 47.4%, pathological complete response in 26.3% and pathological partial response in 26.3%. At a median followup of 27 months for the group 66% of the patients with a surgical complete response, 100% with a pathological complete response and 40% with a pathological partial response were alive with no evidence of disease. The over-all survival for patients with a pathological or surgical complete response is 76.9%. In the patients not operated upon because of persistent or advanced disease after chemotherapy survival was brief (less than 4 months). Prolonged survival in patients achieving a pathological or surgical complete response with neoadjuvant chemotherapy occurs, and this modality may have a role in patients with invasive tumors.

T- and B-cell markers of lymphocytes in peripheral blood, involved node and spleen, PHA response of peripheral blood lymphocytes, serum immunoglobulin levels, and skin test reactivity to six common antigens were studied in 16 cases of untreated non-Hodgkin's lymphoma. Impaired response of peripheral lymphocytes to PHA was observed in 13 of 16 cases, regardless of the proportion of T lymphocytes. Of 12 cases in which skin tests were done, two were positive and had a normal PHA response, seven cases were positive in spite of low PHA response, and three were negative with low PHA response. In the lymph nodes from involved areas two cases showed monoclonal increase of B-cells, five showed "null" cell increase, and the remaining nine showed no increase or decrease of subpopulation of lymphocytes. No correlation with surface marker of lymphocytes to histologic classification was seen. From the above observations it was concluded: 1) a low PHA response in non-Hodgkin's lymphoma was not due to the decreased population of T-cells; 2) a low PHA response may not necessarily indicate impaired delayed hypersensitivity; and 3) non-Hodgkin's lymphoma can be classified in the following ways--B-cell proliferative type, "null" cell increase type, and normal T/B proportion type.

Lymphocyte subpopulations were studied in the peripheral blood, lymph nodes, and spleens in a group of 17 patients with untreated Hodgkin's disease. In 12 of 15 cases, diminished absolute levels of T-lymphocytes in the peripheral blood were found; however, this was correlated with total lymphopenia. No direct relationship between "T-lymphopenia" and diminished cellular immunity, as measured by phytohemagglutinin and pokeweed mitogen blast transformation, and delayed cutaneous hypersensitivity was demonstrated. In eight lymph nodes involved histologically by Hodgkin's disease, a preponderance of T-lymphocytes was found when compared with a group of seven hyperplastic nodes (78.2 +/- 8.9% versus 54.5 +/- 11.0%, P is less than 0.01). These latter data appear to be consistent with the hypothesis that the pathogenesis of Hodgkin's disease involves a cell-mediated immune response to a neoplastic (antigenic) element.

Eleven patients with recurrent and/or resistant nonseminomatous germinal cell neoplasms refractory to conventional chemotherapy were treated with the combination. VP16-213, cis-diamminedichloroplatinum, and adriamycin. One complete response, four partial responses which at surgery were benign teratomas, and six partial responses have been observed. Four patients are prolonged survivors (greater than 18 months). The possibility that this regimen may offer true salvage for refractory patients exists. Incorporation of VP16-213 into initial treatment regimens for germinal cell neoplasms is warranted.

Drug resistance to chemotherapy agents such as doxorubicin appears to be an important cause of therapeutic failure in cancer treatment. Based on preclinical information demonstrating that the phenothiazine calmodulin-inhibitor trifluoperazine can enhance retention and cytotoxicity of doxorubicin in resistant cells, a phase I/II trial of the combination was performed to determine the maximally tolerated dose (MTD) of trifluoperazine that could be administered with doxorubicin. Patients with intrinsic (no previous response) and acquired (previous response with relapse) doxorubicin resistance were eligible. Doxorubicin was administered as a 96-hour continuous infusion (60 mg/m2) on days 2 through 5. Trifluoperazine was administered in divided doses orally on days 1 through 6, with dose escalation from 20 to 100 mg/d. Thirty-six patients were evaluable. The MTD of trifluoperazine was 60 mg/d, with dose-limiting toxicity being extrapyramidal side effects. No alteration of doxorubicin toxicity was observed. Seven of the 36 patients responded (one complete response [CR], six partial responses [PR]), with seven of 21 patients having acquired resistance, and zero of 15 with intrinsic resistance demonstrating responses. Doxorubicin plasma levels were not affected by trifluoperazine, and the maximal trifluoperazine plasma levels achieved were 129.83 ng/mL. This trial demonstrates the combination of trifluoperazine and doxorubicin is well tolerated, and the schedule recommended for phase II trials is doxorubicin, 60 mg/m2 (continuous infusion) days 2 through 5, and trifluoperazine, 15 mg four times per day orally days 1 through 6. Continued investigation of this combination is indicated for patients with acquired doxorubicin resistance.

Twenty-seven patients with measurable liver metastases from colorectal carcinoma were entered on a protocol of intermittent hepatic artery infusion (HAI) of 5-fluorouracil (5-FU) followed by consolidation with hepatic irradiation. Five partial responses were observed in 23 evaluable patients. Median duration of response was 3.5 months. A response was evident after chemotherapy alone in four of five responders. Hepatic irradiation converted one patient with stable disease after chemotherapy to a partial responder. Median survival for all patients was 9.0 months (range 1.5-34.0). Combined modality treatment with HAI of 5-FU followed hepatic irradiation was well tolerated but did not appear to be synergistic.

Heterogeneity in daunorubicin uptake by leukemic blast cells obtained from the bone marrow of 16 patients with acute leukemia (10 acute nonlymphocytic leukemia and 6 acute lymphocytic leukemia) was determined by laser flow cytometry following drug treatment in vitro for 1 hr. Fluorescence profiles of cellular anthracycline levels in the various samples indicated a marked heterogeneity in daunorubicin uptake and the range of detectable drug fluorescent cells was 34%-99%. A retrospective analysis of disease outcome in these patients who were treated with a daunorubicin or doxorubicin containing induction regimen indicated the following: (a) 8 of 11 patients who entered complete remission had greater than 80% of leukemic blast cells accumulating detectable amounts of daunorubicin; and (b) 3 of 4 patients who did not respond to chemotherapy had less than 40% of the leukemic blast cells accumulating detectable amounts of daunorubicin. These results suggest that laser flow cytometry may be useful in determining qualitative and quantitative differences in daunorubicin levels in heterogeneous tumor cell populations.

Mononuclear cell-mediated tumor cell destruction was studied in 114 patients with malignant melanoma, renal cell carcinoma, or sarcomas, and in 122 non-tumor-bearing control subjects, with the use of the microcytoxicity assay. Cytotoxic reactions were found in all patients and control groups against melanoma, renal carcinoma, sarcoma, and fibroblast-derived cell cultures; mean levels of cytotoxicity against allogeneic combinations of tumor cells and fibroblasts were similar in tumor-bearing and control patients. These results support the concept that the reactions found represent nonspecific cytotoxicity.

The Southwest Oncology Group conducted a phase II study of anguidine in 134 patients with gastrointestinal malignancies. Anguidine was administered as a 4-hour infusion at doses of 3.0 and 4.5 mg/m2 daily x 5. Response rates for patients with colon carcinoma were 22% (four of 18 patients without previous chemotherapy) and 6% (four of 63 patients with previous chemotherapy). There were no responses in patients with pancreatic cancer (four patients) or gastric cancer (six). Toxic effects included thrombocytopenia (19.8%), leukopenia (18.8%), nausea and vomiting (49%), hypotension (37%), and confusion (12%). Antitumor activity of anguidine in patients with colon cancer may be similar to that of 5-FU, but nonhematologic toxicity is substantial.

Fifty-seven patients with renal cancer were treated with AZQ, utilizing one of three IV push schedules. Only one partial response was seen in 55 evaluable patients, and considerable myelosuppression was encountered. Gastrointestinal toxicity was more severe in those patients who had received prior treatment. At these higher doses AZQ is deemed an inactive agent in patients with renal cell carcinoma, at least when the drug is administered as a push schedule.

The medical records of 94 consecutive patients with acute nonlymphocytic leukemia (ANLL) were reviewed to identify significant prognostic factors. The data were analyzed using 1) Cox's linear hazard and linear logistic models, 2) chi-square comparison of the groups living longer than 2 years and those living less than 2 years, and 3) the Gehan-Breslow test of equal survival curves. The only statistically significant finding was that the presence of promyelocytic cell type and complete remission correlated with increased survival (p less than .05), but this was negated by the small number of patients with this cell type. There was a suggestive association between higher initial hemoglobin and survival (p = .09). The Gehan-Breslow test revealed a possible difference in survival between those patients more than 51 years of age and those less than 51 (p = .10). Thus none of the commonly accepted prognostic factors in acute nonlymphocytic leukemia was definitely shown to be useful. The findings of this study support an aggressive approach toward all patients with this disease.

A case of IgD myeloma in a 48-year-old Caucasian man is reported. The unusual features of this case included the absence of osteolytic lesions by x-ray, absence of anemia, absence of monoclonal spike on serum electrophoresis, association of kappa light chains, absence of Bence Jones proteinemia and Bence Jones proteinuria, and a remarkable, temporary clinical response to therapy. Immunoelectrophoresis of whole serum yielded a pattern consistent with IgD kappa monoclonal gammopathy. Immunoelectrophoresis of a pure serum IgD preparation, previously separated by gel chromatography (Sephadex G-200), revealed definitive information about an IgD kappa monoclonal gammopathy. Immunomicroscopic examination of bonemarrow smears showed the presence of delta and kappa chains only in the cytoplasm of plasma cells.

A prospective Phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors was conducted by the Southwest Oncology Group. The therapy included 5-fluorouracil, Adriamycin, cyclophosphamide, and streptozotocin (FAC-S) or the same combination without Adriamycin (FC-S) in patients with heart disease. Seventy-four patients were entered and two were ineligible. Sixty-nine of the 72 were histologically reviewed. Six patients were declared ineligible after this review. Fifty-six patients received FAC-S, and nine received FC-S (one patient was inevaluable). The response rates were 31% and 22%, respectively. The median survival of all patients was 10.8 months. The analyses of various clinical and histologic parameters indicated that responses were more common in patients with gastrintestinal carcinoids; there was also a tendency toward shorter survival in patients with tumors that had a higher mitotic rate or the atypical and/or undifferentiated histologic pattern. The FAC-S combination can produce objective responses in patients with metastatic carcinoid tumors, but these are generally partial and brief. It was also concluded that currently available chemotherapy is inadequate.