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Biomedical subjects

R A Figlin

Publications and source records attributed to R A Figlin.

At least 19 recordsLinked to original sources
PubMed1992

Different lymphoid cell populations produce varied levels of neopterin, beta 2-microglobulin and soluble IL-2 receptor when stimulated with IL-2, interferon-gamma or tumour necrosis factor-alpha.

Immune activation is central to many immune disorders. Clinical investigations have shown that immune activation can be quantified by measurements of soluble immune activation products in serum. Most in vitro studies of these immune activation products have focused on single products. In this study the specific cell sources and the major lymphokines inducing multiple activation products were investigated. In vitro addition of interferon-gamma (IFN-gamma) or IL-2 stimulated peripheral blood mononuclear cells to produce neopterin, beta 2-microglobulin (beta 2-M) and soluble IL-2 receptor (sIL-2R). These two lymphokines can act independently, because neutralizing antibodies to one of the lymphokines did not block the inducing activity of the other. Tumour necrosis factor-alpha (TNF-alpha) was also investigated and shown to be a less powerful inducer than IL-2 or INF-gamma. Separated lymphoid subpopulations responded differently to specific lymphokines. Monocytes produced only neopterin and only in response to INF-gamma. T cells released beta 2-M and sIL-2R in response to IL-2. B cells, however, were capable of producing all three immune activation products. Neopterin production in B cells was induced by either INF-gamma of IL-2, indicating that B cells have additional mechanisms for responding to lymphokines. To investigate whether these in vitro findings also occur in vivo, sera from patients who had received either rIL-2 or INF-gamma treatment were tested. INF-gamma administration led to substantial increases in serum neopterin but only a moderate beta 2-M increase and no increase in the serum sIL-2R levels. rIL-2 administration caused a substantial increase of all three serum immune activation products, consistent with our in vitro findings. The results confirm that increased serum levels of soluble immune activation products are indicators of increased cytokine production by lymphocytes and monocytes and also that B cells can be a prominent source of immune activation products.

B-Lymphocytes↗
PubMed1992

Concomitant administration of recombinant human interleukin-2 and recombinant interferon alfa-2A: an active outpatient regimen in metastatic renal cell carcinoma.

PURPOSE: A phase II trial of interleukin-2 (IL-2) and interferon alfa (IFN-alpha) in metastatic renal cell carcinoma (RCCa) was conducted. A lower dosage of IL-2 was given via continuous intravenous (IV) infusion, a route with documented tumor activity associated with less toxicity, with the purpose of improving the therapeutic index of this treatment in an outpatient setting. PATIENTS AND METHODS: Thirty patients with metastatic RCCa were treated with the combination of IL-2 and IFN-alpha-2A. IL-2 was administered on days 1 through 4 of each treatment week, as a continuous IV infusion at a dose of 2 x 10(6) U/m2/d. IFN-alpha-2A was administered intramuscularly or subcutaneously on days 1 and 4 of each treatment week, at a dose of 6 x 10(6) U/m2/d. One treatment course included 4 weeks of treatment followed by a 2-week rest. Patients received therapy as outpatients except for the first 4 days of treatment, cycle 1 only. All patients were assessable for toxicity and response assessment. A total of 105 courses of therapy were administered, 51% at full dose. RESULTS: Sixteen patients experienced toxicities resulting in dosage modification. The major treatment-limiting toxicities were gastrointestinal, neurologic, and fatigue. Nine patients (30%) had partial remissions (PRs) with a median duration of responses of 12+ months. The median time to response was 11 weeks. Two partial responders whose sites of metastatic disease were renal fossa and mediastinal lymph nodes (LN), respectively, were found to have achieved a pathologic complete remission (pCR) after surgery. A third patient with a pCR of axillary LN was rendered into a surgical complete remission (sCR) with salvage nephrectomy. Median survival of patients obtaining a PR has not been reached with a median follow-up time of 19+ months. CONCLUSION: IL-2 and IFN-alpha-2A is well tolerated in the outpatient treatment setting and demonstrates significant clinical activity against RCCa.

Adult↗
PubMed1991

Bullous pyoderma gangrenosum after granulocyte colony-stimulating factor treatment.

The hematopoietic growth factors are under investigation for the treatment of patients with chemotherapy-induced bone marrow suppression. One such trial at the University of California, Los Angeles involves chemotherapy with or without granulocyte colony-stimulating factor (G-CSF) in patients with small cell lung cancer. The authors report a case of a patient who had bullous pyoderma gangrenosum at the site of previous eczema during treatment with G-CSF. The lesions resolved promptly when the drug was discontinued. Other investigators have recently reported inflammatory complications of G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) but this is the first case report of biopsy-proven neutrophilic dermatosis associated with administration of a hematopoietic growth factor. Patients should be monitored for development of inflammatory processes during G-CSF therapy and this therapy should be given with caution to those patients with existing inflammatory conditions.

Carcinoma, Small Cell↗
PubMed1991

Thyroid function abnormalities associated with the chronic outpatient administration of recombinant interleukin-2 and recombinant interferon-alpha.

We prospectively examined thyroid function during and following chronic, outpatient therapy with recombinant interleukin-2 (rIL-2) and Roferon-A (rIFN-alpha 2a). Twenty-two of 30 patients with advanced renal cell carcinoma treated on a phase II open pilot study of concomitant rIL-2 and rIFN-alpha 2a were included. Serum levels of thyroxine, triiodothyronine, free thyroxine index, thyrotropin, antithyroid antibodies, and thyrotropin (TSH) receptor binding antibodies were measured before therapy and after every other cycle. Selected patients underwent studies after every cycle and following completion of therapy. Twenty patients (91%) developed laboratory evidence of thyroid dysfunction, 11 (50%) developed hypothyroidism, five (23%) had a biphasic pattern, and four (18%) had hyperthyroidism. The incidence of thyroid dysfunction increased with increased number of treatment cycles. Transient hyperthyroidism was noted in six of the 11 patients studied after the first cycle and persisted after cycle three in only two patients. Hypothyroidism was not observed after cycle 1, but became increasingly frequent between cycles 2 (56%) and 6 (90%). Thyroid function normalized following therapy in nine of 12 patients tested. Antithyroid antibodies were identified pretherapy in five patients (23%) and de novo in none; TSH receptor binding antibodies were not detected. This study demonstrates a remarkably high frequency of reversible thyroid dysfunction in patients with advanced renal cell carcinoma treated with repeated cycles of rIL-2 plus rIFN-alpha 2a. We conclude that chronic therapy with rIL-2 and rIFN-alpha 2a produces thyroid dysfunction in virtually all patients most likely secondary to a nonspecific, nonautoimmune, toxic manifestation of prolonged treatment. IL-2 therapy may, therefore, produce thyroid dysfunction by more than one mechanism.

Adult↗
PubMed1991

The role of interferon and interleukin-2 in the immunotherapeutic approach to renal cell carcinoma.

Approximately 24,000 cases of renal cell carcinoma are expected in the United States in 1990. Although approximately 50% of patients with local disease are cured by surgery, in patients with metastatic disease the median survival is only approximately 10 months. Neither chemotherapy nor radiation therapy has been shown to be effective against metastatic renal cell carcinoma. Immunotherapy has come to the forefront of clinical research for the treatment of metastatic renal cell carcinoma. In the past decade, the development of recombinant DNA techniques has enabled the production of large quantities of biologic response modifiers such as the interferons and interleukins. Following initial reports in 1983 by the University of California-Los Angeles (UCLA) group and the investigators at M. D. Anderson Hospital, in Houston, TX, numerous trials have demonstrated a reproducible objective response rate to interferon of 15% to 20%. These responses are independent of the interferon preparation used, and optimal dosage/schedule has not been determined. In general, responses have been correlated with the following patient factors: previous nephrectomy, good performance status, a long disease-free interval, and lung-predominant disease. Median response durations of from 8 to 10 months can be expected. The addition of vinblastine, gamma-interferon, or aspirin has not improved the therapeutic index. Interleukin-2 therapy has produced encouraging results in 10% to 15% of patients. Although high-dose therapy is associated with substantive side effects, a small cohort of patients have been in continuous remission for extended periods of time, raising the possibility of "true" complete remissions of clinical significance. Recent trials, including our trials at UCLA, have combined the interleukins and interferons in this patient population. This combination has a sound scientific basis and the results are encouraging, especially when the toxicity profile is considered. Most patients receive these combinations as outpatients and have not required hospitalization nor suffered the toxicities of the high-dosage regimens. Complete pathologic remissions have been observed using this lower dosage, outpatient schedule. Clinical trials suggest that interferon and interleukin-2 may have an expanding role in metastatic kidney cancer both as single agents and in combination outpatient biologic therapy. The future clinical trials of kidney cancer will continue to incorporate these biologic response modifiers into the therapeutic strategies of the 1990s.

Carcinoma, Renal Cell↗
PubMed1991

Metastatic renal cell cancer: interleukin-2 toxicity induced by contrast agent injection.

We describe a clinical syndrome occurring after contrast medium injection in patients who previously received recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha 2A treatment for metastatic renal cancer. The clinical picture mimics many aspects of rIL-2-related systemic side effects. The patients were managed conservatively but the potential for severe manifestations can occur, requiring more intensive treatment.

Carcinoma, Renal Cell↗
PubMed1991

Renal cell carcinoma: basic biology and current approaches to therapy.

Renal cell carcinoma (RCC) represents an unusual solid tumor for which no treatment other than surgical therapy has been effective. The remarkable heterogenous behavior of this tumor and the documented rare spontaneous regressions suggest an unusual sensitivity to host immunologic control. In recent years, exciting developments in molecular genetics, growth factors, modulators of invasion of metastases, and cytokine-lymphocyte interactions have produced new hypotheses and a wealth of information regarding the origin, behavior, and control of RCC. Interest in the immunotherapy of metastatic RCC has recently increased with the demonstrated reproducible tumor responses obtained with recombinant human interferon-alpha or interleukin-2. Durable clinical remissions in some patients with advanced RCC can now be achieved by using cytokine therapy alone or in combination with activated killer cells. This article reviews the current understanding of the basic biology of RCC, surgical approaches to localized RCC, and biologic therapy for advanced disease.

Carcinoma, Renal Cell↗
PubMed1989

Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer. Does chemotherapy make a difference?

Current chemotherapy treatment of metastatic non-small cell lung cancer has demonstrated some objective responses, but is still largely palliative. This report reviews the results of a randomized trial in patients with advanced metastatic non-small cell lung cancer which compared treatment with supportive care (treatment with palliative radiation, psychosocial support, analgesics, nutritional support) to supportive care plus combination chemotherapy with cisplatin and vinblastine. Although the patients receiving combination chemotherapy had a slightly longer median survival (20.43 weeks versus 13.57 weeks), it was not statistically significant (P = 0.09). In addition, the patients receiving chemotherapy experienced serious toxicity, and showed no significant benefit in terms of quality of life as measured by Karnofsky performance status score. The authors conclude that contemporary combination chemotherapy provides only modest survival benefit to patients with advanced metastatic non-small cell lung cancer and should not be considered standard therapy. Future investigations of chemotherapy in patients with unresectable non-small cell lung cancer should continue to utilize control arms which provide high-quality supportive care.

Aged↗
PubMed1989

Pulmonary toxicity of recombinant human tumor necrosis factor.

Tumor necrosis factor is a cytokine produced by activated macrophages that causes hemorrhagic necrosis in various tumours. In preliminary clinical trials, patients have developed various degrees of respiratory insufficiency following administration of rTNF. Twenty-seven patients were studied prospectively to evaluate the effect of administration of rTNF on pulmonary function. Sixteen of the 27 patients completed the eight-week course of daily IM injection of rTNF. Spirometric data and Dsb were measured at baseline and on days 8, 15, and 56 of treatment. Both patients with and without progressive pulmonary metastases demonstrated a comparable mean decline in Dsb (-10.7 +/- 9.6 percent [+/- SD] and 14.7 +/- 10.0 percent, respectively; p less than 0.01) not accounted for by either a decline in the hemoglobin content of the blood or a reduction in alveolar volume. Marked interindividual variability in the response of Dsb to rTNF therapy was noted. The reduction in Dsb reached a plateau by day 15. In contrast, alveolar volume and FVC remained essentially unchanged throughout the course of treatment. Measurements of Dsb performed two weeks after cessation of rTNF therapy in seven of the 27 patients showed only a modest trend toward recovery, which was not statistically significant. We conclude that the administration of rTNF for the treatment of malignant neoplasms in this dosage and schedule can cause significant pulmonary injury reflected by a reduction in Dsb which reaches a plateau by two weeks after initiation of therapy.

Adult↗
PubMed1989

Biotherapy in clinical practice.

The interferons are the first of a new class of biologic response modifiers that include, among others, the interleukins, colony-stimulating factors, erythropoietin, additional growth factors, and monoclonal antibodies. Interferons have exhibited important clinical activity in hematologic malignancies, lymphomas, and solid tumors. Specific diseases responding to interferons include hairy-cell leukemia (HCL), chronic myelogenous leukemia (CML), low-grade non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, multiple myeloma, superficial bladder carcinoma, malignant carcinoid, acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma, ovarian carcinoma, renal cell carcinoma, and malignant melanoma. The potentially antigenic nature of the recombinant interferons can result in the formation of antibodies. These antibodies have been associated with the abrogation of some of the clinical responsiveness of some patients treated with interferons. It is hoped that the controversy existing over the role of antibody formation in treatment efficacy can be resolved by prospective trials using standardized methodology in such areas as assay type, sampling time, route of drug administration, treatment schedule, cumulative dose, and duration of treatment.

Antibody Formation↗
PubMed1989

Systemic administration of recombinant methionyl human interleukin-2 (Ala 125) to cancer patients: clinical results.

Nineteen evaluable patients with advanced malignancy were treated with recombinant methionyl human interleukin-2 (Ala 125), 5 days per week by intravenous bolus. Patients were entered in five groups at starting doses ranging from 0.05 to 2.56 x 10(6) U/m2. Doses were escalated weekly as tolerated toward a potential maximal dose of 11.6 x 10(6) U/m2. Maximal tolerated dose was 3.84 x 10(6) U/m2. Dose-limiting toxicity included fatigue, rigors, nausea/vomiting, fever, and diarrhea. Other toxicities included hyperesthesias, arthralgias/myalgias, rash, fluid retention, balanitis, and mild confusion. Leukocytosis, including granulocytosis, eosinophilia, and mild lymphocytosis, was observed, as was rare mild thrombocytopenia. No partial or complete response occurred. T1/2 alpha averaged 13.4 min, with interleukin-2 detectable 2 h after doses of greater than or equal to 2.56 x 10(6) U/m2. Three patients developed anti-IL-2 antibodies without demonstrable clinical significance.

Body Weight↗
PubMed1988

Intracranial recurrence of carcinoma after complete surgical resection of stage I, II, and III non-small-cell lung cancer.

We retrospectively analyzed the risk of intracranial recurrence of cancer in 1532 patients who were surgically treated between 1977 and 1986 for Stage I, II, or III non-small-cell lung cancer, after rigorous surgical and pathological staging. This analysis was undertaken as a background for a possible randomized clinical trial of prophylactic cranial irradiation in such patients. One hundred four patients (6.8 percent) had documented first recurrences involving the brain, including 98 patients (6.4 percent) in whom the brain was the sole site of first recurrence. Sixty patients (3.9 percent) had only intracranial involvement at the time of death. Prognostic variables that had a significant effect on the time to recurrence in the brain were histologic features of the carcinoma (patients with nonsquamous-cell cancers were more at risk than those with squamous-cell cancer), the T1N1/T2N0 and T2N1 staging subsets (T1, tumor less than or equal to 3 cm in diameter; T2, tumor greater than 3 cm; N0, no regional lymph-node metastasis; N1, ipsilateral hilar-lymph-node metastasis), and initial weight loss of more than 10 percent. We conclude that prophylactic cranial irradiation would at best benefit only a very small subset of these patients. We believe, therefore, that neither prophylactic cranial irradiation nor a randomized trial is indicated in patients with non-small-cell lung cancer who have undergone complete resection.

Brain Neoplasms↗
PubMed1988

Estimating the quality of life in a clinical trial of patients with metastatic lung cancer using the Karnofsky performance status and the Functional Living Index--Cancer.

Serial assessments of Karnofsky performance status (KPS) and of the Functional Living Index--Cancer (FLIC) have been used to estimate the quality of life (QOL) of patients in a prospective, randomized trial of supportive care versus supportive care given with combination chemotherapy to patients with metastatic non-small cell lung cancer. There was a good correlation between KPS and FLIC scores at study entry, thus confirming results originally reported using the FLIC. However, a number of unexpected problems were encountered in data collection and quality control with this QOL assessment instrument. This made it impossible to look for differences in treatment effect on QOL in this clinical trial. It is believed that QOL assessment should be an integral part of cancer clinical trials; however, investigators must acknowledge the difficulties in collecting this type of data. The development of new instruments and the refinement of old ones will facilitate the collection of data for this important aspect of clinical trials research.

Aged↗
PubMed1988

Selective decrease in Leu8-negative T cell subpopulations following treatment with recombinant interferon-alpha 2a (rIFN-alpha 2a).

The effects of in vivo treatment with recombinant human IFN-alpha 2a (rIFN-alpha 2a) on the distribution of T cell subpopulations were examined in 21 patients with renal cell adenocarcinoma, using two-color flow cytometry with anti-Leu8 in combination with anti-Leu2 and anti-Leu3. Other parameters indicative of immune status, such as the number and percentage of total (CD3) T cells, in vitro proliferation to mitogen, and spontaneous immunoglobulin secretion, were also measured, prior to the initiation of treatment with rIFN-alpha 2a, and during treatment. Total T cell number decreased after treatment with rIFN-alpha 2a, to a low of 54% of mean pretreatment values after 4 weeks. The CD4/CD8 ratio did not change appreciably following treatment with rIFN-alpha 2a. However, the number of Leu8-negative T cells, within both the CD4 and the CD8 T cell populations, decreased more than the number of Leu8-positive T cells. An increase in spontaneous immunoglobulin-secreting cells followed treatment with rIFN-alpha 2a.

Antibodies, Monoclonal↗