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Biomedical subjects

R A Figlin

Publications and source records attributed to R A Figlin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Amplification and overexpression of the cyclin D1 and epidermal growth factor receptor genes in non-small-cell lung cancer. Lung Cancer Study Group.

PURPOSE: To study the structure and expression of the cyclin D1 and the epidermal growth factor receptor (EGFR) genes in a cohort of 298 non-small-cell lung cancer (NSCLC) specimens. METHODS: Gene structure was studied by Southern analysis, and gene expression was studied by Northern analysis and immunohistochemical analysis. RESULTS: Amplification of the cyclin D1 locus was found in 14/298 (5%) specimens. All 12/12 specimens with amplification of the cyclin D1 gene for which RNA was available were found to express the cyclin D1 transcript, and 11/12 overexpressed the transcript to levels higher than that of uninvolved lung. The EGFR gene was amplified in 17/286 samples of NSCLC tested, and was overexpressed in 22/169 (13%) cases tested, including 12/13 cases with amplification of the gene for which RNA was available. Cyclin D1 gene amplification was associated with advanced lymph node involvement (P = 0.043), but not with larger tumor size or adverse outcome. Cyclin D1 gene amplification and overexpression occurred independently of retinoblastoma tumor-suppressor gene (RB) inactivation, but tumors with amplification of the cyclin D1 gene were more likely to have EGFR gene amplification (P < 0.005). No correlation of EGFR gene amplification or overexpression with tumor size, lymph node involvement, patient demographic data, or survival was identified. CONCLUSIONS: These data indicate that the cyclin D1 and EGFR genes are amplified and overexpressed in NSCLC, and amplification of the cyclin D1 gene occurs frequently in conjunction with amplification of the EGFR gene.

Adenocarcinoma↗
PubMed1999

Renal cell carcinoma: management of advanced disease.

PURPOSE: We provide a current review of the management of advanced renal cell carcinoma. MATERIALS AND METHODS: A comprehensive literature review of peer reviewed articles which address the current management of metastatic renal cell carcinoma was performed. RESULTS: Renal cell carcinoma is the seventh leading cause of cancer, accounting for 3% of malignancies in men. The incidence of renal cell carcinoma has increased significantly by 38% from 1974 through 1990 at least in part related to earlier diagnosis with the common use of new radiological techniques. Cytotoxic chemotherapy remains poor as a treatment alternative. Interferon-alpha produces responses in 15 to 20% of patients but clinical usefulness as monotherapy has been surpassed by interleukin-2 (IL-2). IL-2 is the first immunotherapy to produce durable remissions resulting in approval by the Food and Drug Administration. Although high dose bolus IL-2 schedules have the longest followup, IL-2 administered on other schedules may have enhanced efficacy. Randomized trials are attempting to delineate the appropriate role for various doses and schedules. CONCLUSIONS: Advanced renal cell carcinoma, once a disease relegated to the incurable, during the last decade has evolved into a malignancy that may be associated with cure. The first evidence of this potential is the clear and unequivocal demonstration that IL-2 produces durable complete remissions. Building upon this immunotherapeutic approach the future treatment of renal cell carcinoma will incorporate new immunological technology, including gene, dendritic cell, vaccine and antibody therapy.

Carcinoma, Renal Cell↗
PubMed1999

Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma.

PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs. RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board. CONCLUSION: Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.

Adolescent↗
PubMed1999

Technology evaluation: interleukin-2 gene therapy for the treatment of renal cell carcinoma.

Leuvectin is a plasmid DNA/lipid complex comprised of a plasmid DNA expression vector (VCL-1102, 30) encoding human interleukin (IL)-2 complexed in a 5:1 mass ratio with DMRIE/DOPE lipid that has been developed for the treatment of cancer. DMRIE/DOPE is a cationic lipid, which facilitates in vitro and in vivo transfection of plasmid DNA. In vitro transfection with the IL-2 plasmid DNA/DMRIE/DOPE complex results in the expression of sustained levels of biologically active IL-2. Human tumor cell lines and primary human tumor cells established from biopsies were readily transfected in vitro resulting in the expression of IL-2. Following in vitro transfection, IL-2 expression continued up to several weeks post-transfection in primary tumor cells. In preclinical efficacy studies in a murine model of renal cell carcinoma (RCC), the direct intratumoral administration of an IL-2 plasmid DNA/DMRIE/DOPE complex resulted in the generation of tumor specific lymphocytes and complete tumor regression in the majority of the mice. In preclinical animal safety studies, repeated administration of Leuvectin was safe and well-tolerated. Following these promising preclinical results, Leuvectin has entered clinical trials and two pilot phase I/II trials are described.

Animals↗
PubMed1998

Phase II study of intravenous adenosine 5'-triphosphate in patients with previously untreated stage IIIB and stage IV non-small cell lung cancer.

Fifteen patients with Stage IIIB or IV non-small cell lung cancer gave informed consent to receive three or more 96-hour infusions of ATP at a dose of 50 mcg/kg/min or higher to determine whether ATP has antineoplastic activity against this tumor type and to better define the spectrum of toxicity for ATP given as a single agent. There were no objective complete or partial responses observed. The median survival of the overall group was 187 days and the median time to tumor progression was 113 days. The major toxic side effects were chest pain and dyspnea, leading to the cessation of treatment in 5 patients. We conclude that ATP at this dose and schedule of administration is an inactive agent in patients with advanced non-small cell lung cancer.

Adenosine Triphosphate↗
PubMed1997

Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2 and cytokine-primed or CD8(+) selected tumor infiltrating lymphocytes from primary tumor.

PURPOSE: Metastatic renal cell carcinoma is a disease with a mean survival of 6 to 10 months. Interleukin-2 (IL-2), the only approved therapy for metastatic renal cell carcinoma, is associated with a 14% response rate and durable remissions in some patients with high performance status. We performed a series of trials of IL-2 plus tumor infiltrating lymphocyte cell therapy and report the clinical results from 62 patients enrolled in these trials. MATERIALS AND METHODS: Patients were eligible if they had metastatic renal cell carcinoma with the primary tumor in place and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were treated with cytokines before nephrectomy and preparation of cytokine primed tumor infiltrating lymphocytes or CD8(+) tumor infiltrating lymphocytes were isolated for infusion into patients. Of 62 patients enrolled 55 were treated with tumor infiltrating lymphocytes and IL-2, and were evaluable for toxicity, response and survival. RESULTS: There were no postoperative mortalities. Of the patients 7 (11%) could not undergo systemic therapy. No unexpected IL-2 related toxicities or significant toxicities related to cell infusion were noted. Overall 5 patients (9.1%) achieved a complete response and 14 (25.5%) achieved a partial response. The responses were durable with a median duration of 14 months (range 0.8+ to 64+). The actuarial survival was 65% at 1 year and 43% at 2 years from the time of nephrectomy, with an overall median survival for all patients of 22 months (range 2 to 70+). The median survival for the responding patients has not yet been reached (range 2 to 63+). CONCLUSIONS: These results demonstrate that immunotherapy with radical nephrectomy, tumor infiltrating lymphocytes, and IL-2 provides substantial clinical benefit in the majority of patients. Component cellular therapy with enriched cell fractions allows the administration of a more standardized cell product. The present results with nephrectomy, tumor infiltrating lymphocytes and IL-2 are encouraging, and a randomized clinical trial of nephrectomy, CD8(+) tumor infiltrating lymphocytes, plus IL-2 versus nephrectomy and IL-2 alone is currently in progress.

Adult↗
PubMed1997

Health related quality of life outcomes in patients treated for metastatic kidney cancer: a pilot study.

PURPOSE: We assessed health related quality of life in patients with advanced renal cell carcinoma treated with nephrectomy and tumor infiltrating lymphocyte therapy in combination with interleukin-2. MATERIALS AND METHODS: A total of 20 patients with advanced renal cell carcinoma who underwent nephrectomy and combination immunotherapy with tumor infiltrating lymphocytes and interleukin-2 completed a retrospective, cross-sectional health related quality of life instrument. Established reference populations with other chronic medical conditions, or breast, prostate or other cancers were used for comparison of health related quality of life scores. General health related quality of life was measured with a RAND 36-Item Health Survey 1.0. Cancer targeted quality of life was measured with the Cancer Rehabilitation Evaluation System-Short Form. Sociodemographic and co-morbidity variables were also collected. RESULTS: General health related quality of life in patients treated with tumor infiltrating lymphocytes and interleukin-2 was significantly better than that in heart failure patients on 1 of 8 scales but significantly worse than in the general population on 6 of 8 scales. General health related quality of life in the former patients was also significantly worse than in those with hypertension on 5 of 8 scales and significantly worse than in diabetics on 2 scales. Cancer targeted health related quality of life in patients given immunotherapy was significantly better than in men with prostate cancer on 1 of 5 scales, significantly better than in women with breast cancer on 2 of 5 scales and significantly better than patients with other cancers (nonbreast and nonprostate) on 3 of 5 scales. CONCLUSIONS: Patients undergoing nephrectomy and adjuvant tumor infiltrating lymphocytes plus interleukin-2 therapy for advanced renal cell carcinoma report better health related quality of life than those with other malignancies and better physical function than patients with congestive heart failure. However, health related quality of life is worse than in the general population and similar or worse than in patients with hypertension or type II diabetes. This surveyed population is selective and may represent the best responders among survivors of a highly toxic therapy. Nevertheless, quality and quantity of life should be addressed with patients when considering immunotherapy for metastatic kidney cancer.

Carcinoma, Renal Cell↗
PubMed1996

Evaluation of cisplatin, carboplatin, and etoposide in metastatic nonsmall cell lung carcinoma. A phase II study of the Southwest Oncology Group.

BACKGROUND: The combined use of cisplatin and carboplatin chemotherapy offers a unique means of platinum dose intensification. Response rates using either of these agents in combination with etoposide are comparable. In a Phase II trial, the authors investigated the combination of cisplatin and carboplatin with etoposide for the treatment of patients with advanced nonsmall cell lung carcinoma. METHODS: Eligible patients were chemotherapy naive and had histologically confirmed, evaluable, or measurable selected Stage IIIB and Stage IV nonsmall cell lung carcinoma. Based upon the results of an earlier Phase I and II pilot study, patients received carboplatin, 225 mg/m2, on Day 1; cisplatin, 50 mg/m2, on Days 2 and 3; and etoposide, 75 mg/m2, on Days 1, 2, and 3 every-4-weeks. RESULTS: Eighty-three patients (75 eligible patients) received chemotherapy with cisplatin, carboplatin, and etoposide. Two patients refused therapy after registration and were not analyzable. Thirty-six of the remaining 75 patients had Grade 4 toxicities, mostly hematologic, and 6 patients died of toxicity. The confirmed response rate was 24% (95% confidence interval, 15-35%). Median progression-free survival was 4 months and the median survival was 8 months. CONCLUSIONS: Combination cisplatin, carboplatin, and etoposide chemotherapy appears to be no better than cisplatin/etoposide or carboplatin/etoposide for the treatment of patients with nonsmall cell lung carcinoma. The toxicity of this regimen may be higher, and therefore it cannot be recommended for general use.

Adult↗
PubMed1996

Integrated multimedia timeline of medical images and data for thoracic oncology patients.

A prototype multimedia medical database has been developed to provide image and textual data for thoracic oncology patients undergoing treatment of advanced malignancies. The database integrates image data from the hospital picture archiving and communication system with textual reports from the radiology information system, alphanumeric data contained in the hospital information system, and other electronic medical data. The database presents information in a timeline format and also contains visualization programs that permit the user to view and annotate radiographic measurements in tabular or graphic form. The database provides an efficient and intuitive display of the changing status of oncology patients. The ability to integrate, manage, and access relevant multimedia information may substantially enhance communication among distributed multidisciplinary health care providers and may ensure greater consistency and completeness of patient-related data.

Databases, Factual↗
PubMed1996

The biology of the cytokine sequence cascade.

Pretransplant and posttransplant use of hematopoietic growth factors in bone marrow transplantation (BMT) has shortened the time to engraftment. Severe neutropenia and thrombocytopenia have been the major clinical problems associated with autologous BMT. Efforts to maintain posttransplant levels of circulating neutrophils have focused on exploiting the synergistic action between various hematopoietic growth factor families. Ex vivo generation of distinct populations of expanded cells through simultaneous and sequential addition of hematopoietic growth factors was attempted. Cultures of CD34-selected cells with combinations of growth factors consisting of either recombinant human stem cell factor (rhSCF), recombinant human interleukin-6 (rhIL-6), and recombinant human interleukin-3 (rhIL-3) or rhSCF, rhIL-3, and recombinant human granulocyte-colony stimulating factor (rhG-CSF) generated two distinct but overlapping populations of cells. Delayed addition (on day 7) of rhIL-3 and rhIL-6 to cells cultured with rhSCF generated a population of cells significantly less mature than those cultured with continuous rhSCF, rhIL-3, and rhIL-6 alone. It appears that optimal generation of immediate and delayed cell populations can be achieved by simultaneous culture with rhSCF, rhIL-3, and rhG-CSF; and with rhSCF, rhIL-6, and rhIL-3. Questions remain regarding the cell populations most effective for generating and sustaining the required neutrophil numbers.

Animals↗
PubMed1996

Quantitative polymerase chain reaction does not improve preoperative prostate cancer staging: a clinicopathological molecular analysis of 121 patients.

PURPOSE: To improve on current staging and monitoring methods for prostate cancer, we applied the technique of quantitative polymerase chain reaction to measure the degree of tumor burden in the circulation and correlate this with pathological tumor stage. A reproducible, highly sensitive and specific, reverse transcriptase-polymerase chain reaction amplification technique to quantify prostate specific antigen (PSA) and prostate specific membrane antigen gene expression in the peripheral circulation was developed. Using a 32phosphorus-gamma-adenosine triphosphate-5'PSA and prostate specific membrane antigen primer incorporation assay, the ribonucleic acid signal extracted from a single neoplastic cell (LNCaP) premixed in 10 cc normal whole blood could be amplified. PSA and prostate specific membrane antigen polymerase chain reaction indexes have been created for clinical application. MATERIALS AND METHODS: From September 1994 through July 1995 specimens from 121 patients were prospectively analyzed for PSA and prostate specific membrane antigen signals. RESULTS: Circulating PSA producing cells were present in 29 of 33 patients (88%) with metastatic prostate cancer. Two of 19 patients (11%) with no known prostate cancer exhibited positive signals (1 later had prostate cancer), establishing a sensitivity of 88% and specificity of 94% for our assay. Positive PSA polymerase chain reaction signals were detected in 30 of 51 patients (59%) with stages pT1 and pT2 disease and in 13 of 18 (72%) with stage pT3 cancer. No statistically significant relationship of a positive PSA polymerase chain reaction signal to pathological stage, tumor grade, apical involvement or positive surgical margins was found, and no benefit was derived by measuring the quantity of circulating PSA polymerase chain reaction signals. Circulating prostate specific membrane antigen polymerase chain reaction signals were identified mostly in patients with advanced prostate cancer and offered no benefit to preoperative staging. CONCLUSIONS: Given the high incidence of false positive signals in patients with pathologically determined localized disease, in our experience polymerase chain reaction based assays offer no immediate benefit for preoperative prostate cancer staging. The prognostic significance of detecting circulating prostate specific signals awaits longer followup in this cohort of patients, which is currently under study.

Antigens, Neoplasm↗
PubMed1996

Immunotherapy and gene therapy.

Currently, there are many options for the treatment of metastatic renal cell carcinoma (RCC). Being a mostly chemoresistant malignancy, renal cell carcinoma is usually treated with immunotherapy. These therapies are generally based on interleukin-2 (IL-2) or interferon alfa (IFN-alpha), or involve more novel techniques such as gene therapy. IL-2 is a biological agent that has been approved by the U.S. Food and Drug Administration and leads to durable remissions in a subset of patients with metastatic RCC. Patients presenting with a good performance status and without serious concomitant cardiac or pulmonary disorders should be considered for IL-2-based therapy as first-line treatment.

Carcinoma, Renal Cell↗
PubMed1995

Expression patterns of immediate early transcription factors in human non-small cell lung cancer. The Lung Cancer Study Group.

In 1995, there will be 172,000 new cases of lung cancer diagnosed and 153,000 deaths from this disease in the United States. While the pathogenesis of the disease process is poorly understood, a growing body of evidence suggests that abnormalities in cellular regulatory genes may play an important role in the induction, maintenance and/or progression of some tumor types. These genes include both growth promoting oncogenes as well as growth inhibitory or suppressor genes. Included among these genetic sequences are several cellular transcription factors. A group of these factors including c-jun, c-fos and EGR1 are members of a class of genes known as immediate early genes whose expression are inducible by a variety of stimuli including mitogenic and differentiation inducing growth factors, indicating a potential important role for these genes in normal growth processes. Since these genes are involved in early regulation of cellular growth properties and at least two (c-jun and c-fos) can act as oncogenes, we wished to determine whether their expression levels were altered in human non-small cell lung cancers (NSCLC) compared to normal lung tissue. To address this, Northern blot analyses were performed using c-fos, c-jun and EGR1 probes on RNA extracted from 101 NSCLC tumor specimens and adjacent uninvolved lung tissue. Analysis of this cohort revealed that 72% of the normal tissues demonstrate significantly greater expression of these transcription factors as compared to adjacent malignant tissue. Moreover, this expression pattern appeared to be coordinate for all three genes in the majority of cases. This differential expression pattern was confirmed at the protein level using an immunohistochemical approach with antibodies directed against the c-jun, c-fos and EGR1 gene products. Southern blot analyses demonstrated no gross alterations of these sequences at the DNA level, indicating that the observed differential expression pattern was not due to gross structural changes in the genes. These data suggest that down-regulation of these genes may be involved in the pathogenesis of lung cancer.

Base Sequence↗
PubMed1995

Intrapleural chemotherapy for patients with incompletely resected malignant mesothelioma: the UCLA experience.

From 1986 to 1993, 15 patients with malignant pleural mesothelioma were treated by pleurectomy/decortication and intrapleural cisplatin (100 mg/m2) and cytosine arabinoside (1,200 mg). All patients were without known extrathoracic disease and had a mean age of 63 +/- 7.9 years (range 51-78); 13 were male. Histologic subtype of disease were epithelial (47%), sarcomatoid (27%), and mixed-biphasic (27%). The major morbidity and mortality rates were 13% and 0%, respectively. The mean length of hospital stay was 6.5 +/- 2.1 days. Postoperatively, adjuvant chemotherapy and radiation therapy were given to 46% and 73% of the patients respectively. Median survival from date of treatment was 11.5 months. Those patients with an epithelial histologic subtype experienced significantly improved survival compared to those of sarcomatoid subtype (P = 0.024). Whether adjuvant chemotherapy or radiation therapy were given had no significant effect on survival. These data suggest that although this treatment regimen can be administered with very limited morbidity and no mortality, the role of this approach in the treatment of malignant pleural mesothelioma appears limited and cannot currently be recommended.

Aged↗
PubMed1994

A phase 3 randomized trial of immediate combination chemotherapy vs delayed combination chemotherapy in patients with completely resected stage II and III non-small cell carcinoma of the lung.

The purpose of this trial (Lung Cancer Study Group [LCSG] 853) was to perform a comparative study of immediate combination chemotherapy (cyclophosphamide, doxorubicin, cisplatin [CAP]) vs delayed combination chemotherapy (CAP) administered at the time of first systemic relapse in patients with completely resected stage II and stage III non-small cell cancer of the lung. We randomly assigned 188 patients with resected stage II or stage III non-small cell lung cancer of the lung (squamous, 53%; nonsquamous, 47%) to receive either immediate or delayed combination chemotherapy. Careful intraoperative staging was performed in all patients. Before randomization, patients were stratified according to stage--II (hilar nodes positive) vs III (mediastinal nodes positive or T3)--and histologic features (squamous vs nonsquamous). Ninety-four patients were randomized to receive immediate CAP vs 94 patients randomized to receive delayed CAP. Prognostic variables such as extent of disease, histologic features, sex, race, TN status, and Karnofsky performance status were equally distributed between randomized groups. The treatment groups differed with respect to greater than 10% weight loss. Forty-one percent of patients had stage II disease and 59% of patients had stage III disease. Median time to recurrence (19.5 months) and survival (32.7 months) did not differ between treatment groups. Immediate combination chemotherapy was associated with a 12% reduction in risk of recurrence and an 18% reduction in risk of death, although these rates were not statistically significant. Histologic features, sex, race, Karnofsky performance status, nodal status, and weight change were associated with higher risks of recurrence.

Antineoplastic Combined Chemotherapy Protocols↗