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Biomedical subjects

E M Rankin

Publications and source records attributed to E M Rankin.

At least 19 recordsLinked to original sources
PubMed2005

Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group.

PURPOSE: This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. PATIENTS AND METHODS: Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC). RESULTS: Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life. CONCLUSION: In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.

Adult↗
PubMed1998

The luminescence immunoassay S-100: a sensitive test to measure circulating S-100B: its prognostic value in malignant melanoma.

In this study we measured S-100B using a recently developed luminometric immunoassay with a detection limit of 0.02 microg l(-1). By measuring serum S-100B concentrations in 58 apparently healthy individuals a reference value of 0.16 microg l(-1) was found. To assess the sensitivity of the assay we measured levels of S-100B protein in the serum of 251 patients with cutaneous malignant melanoma before the start of treatment. Only one of 179 patients with limited disease had a serum concentration higher than the reference value, whereas elevated levels were seen in 79% of patients with metastasized disease. In the latter group the NSE serum concentration was elevated in 42%. Using a receiver operating characteristic (ROC) curve it is shown that S-100B is a significantly better parameter than neuron-specific enolase (NSE) for distinguishing patients with limited disease from those with extensive melanoma. Pretreatment S-100B values were highly predictive for the period of survival. Patients with limited disease have increased risk for early death with increasing levels of S-100B protein. Within the group of patients with positive lymph nodes and/or with distant metastases, elevated S-100B levels strongly identified high-risk patients. Our study indicates that the measurement of S-100B as a tumour marker in the management of patients with cutaneous malignant melanoma has clinical significance.

Adolescent↗
PubMed1996

IL-1 beta does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer.

The use of IL-1 in humans is associated with dose-limiting toxicity which resembles that of TNF-alpha or IL-2. Activation of neutrophils is thought to contribute to the toxicity caused by these two cytokines. We studied the effect of IL-1 in vivo on changes in neutrophil numbers and neutrophil degranulation as well as on the formation of neutrophil agonists, such as complement activation products, and on levels of TNF, IL-6, IL-8, and nitrite/nitrate (as a measure of nitric oxide production). Six patients with metastatic melanoma were treated with 3 ng/kg recombinant human IL-1 beta daily. One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L. IL-1 did not induce significant changes in plasma levels of TNF or of the complement activation products C3a and C4b/c. Although IL-1 induced neutrophilia, levels of elastase and lactoferrin did not change. The failure of IL-1 to degranulate neutrophils was confirmed in an ex vivo model with whole blood culture in which doses of up to 100 microgram/L IL-1 beta or IL-1 alpha failed to induce significant elastase or lactoferrin release, whereas TNF, tested as a positive control, was able to do so. These results demonstrate that, unlike TNF, IL-1 does not cause neutrophil degranulation in man, despite its ability to cause neutrophilia and the rapid release of IL-6, IL-8, and nitrite/nitrate.

Adult↗
PubMed1996

Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.

PURPOSE: In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS: After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS: The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION: Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Treatment of low-grade non-Hodgkin's lymphoma with continuous infusion of low-dose recombinant interleukin-2 in combination with the B-cell-specific monoclonal antibody CLB-CD19.

Seven patients with low-grade non-Hodgkin's lymphoma were treated with a combination of a murine monoclonal antibody directed against the B-cell-specific antigen CD19 (CLB-CD19), given twice weekly, and continuous infusion of low-dose recombinant interleukin-2 (rIL-2). We demonstrated stable serum CLB-CD19 levels throughout the 12 weeks of treatment, and homing of the antibody into the tumour sites. A variable degree of antigenic modulation was noted. Prolonged treatment resulted in a sustained increase in the number of natural killer cells in the circulation with enhanced cytotoxic capacity, including antibody-dependent cellular cytotoxicity. During the first weeks of treatment, T cell activation occurred in the majority of patients. Toxicity was related to the rIL-2 treatment and consisted of transient constitutional symptoms and a flu-like syndrome without organ dysfunction. A partial remission occurred in one patient, and in another patient who was primarily leukaemic a greater than 50% reduction of circulating B cells was noted. An antitumour effect occurred early during treatment and could not be related to rIL-2-induced modulation of natural killer cell or T lymphocyte activation.

Adult↗
PubMed1995

Scientific aspects of gene therapy in melanoma.

Melanoma is one of the first tumors in which gene therapy protocols are being tested. The promising results of in vitro and animal studies are now being translated into phase I studies in patients with metastatic disease. Attention is being paid to the safety of the various techniques for gene transfer. As yet, almost all protocols involve ex vivo delivery of genetic material because we lack techniques to ensure 100% transduction of target cells in vivo. The majority of studies in animal models and most current clinical trials involve cytokine gene-modified cells. For melanoma, a number of the target epitopes for cytotoxic lymphocytes have been discovered so that rational testing of the immunomodulatory effects of such therapy is now possible.

Animals↗
PubMed1994

Phase II study of intermittent continuous infusion of low-dose recombinant interleukin-2 in advanced melanoma and renal cell cancer.

BACKGROUND: Previously we described the immunological and clinical effects of prolonged continuous infusion of low dose rIL-2. In this phase II study we explored the therapeutic efficacy of intermittent continuous infusion of low dose rIL-2. PATIENTS AND METHODS: We selected 15 patients with advanced melanoma and 8 patients with renal cell cancer in good clinical condition, with low tumour burden and no previous systemic treatment. A treatment cycle consisted of infusion of 1.8 x 10(6) IU/m2/24 hrs rIL-2 for 3 weeks on an out-patient basis followed by a 3-week rest. A maximum of four cycles were given. RESULTS: A total of 35 cycles were given. Treatment was well tolerated. Transient hyperthyroidism occurred in 8 patients. No objective responses were noted. We noted a high incidence of central nervous system involvement occurring shortly after treatment. CONCLUSIONS: Intermittent continuous infusion of low dose rIL-2 in advanced melanoma and renal cell cancer is well tolerated but the initial therapeutic results are not promising.

Adult↗
PubMed1994

Report of a symposium on: diagnosis and treatment of cutaneous head and neck melanoma.

A series of presentations and discussions was held during a symposium on the diagnosis and treatment of cutaneous head and neck melanoma. The purpose of this meeting was to define certain guidelines on diagnosis and treatment of head and neck melanoma. The results of this symposium are summarized and condensed in this report. Recommendations are made for diagnostic strategies and for treatment. It is indicated that research efforts in immunology need to be expanded to develop rational immunotherapy.

Head and Neck Neoplasms↗
PubMed1994

Catheter-related complications in 52 patients treated with continuous infusion of low dose recombinant interleukin-2 via an implanted central venous catheter.

In this study we evaluated the catheter-related complications in 52 patients with advanced melanoma, renal cell cancer or non-Hodgkin's lymphoma treated with continuous infusion of low-dose recombinant interleukin-2 by central venous access (CVA) of the port-a-cath type. We noted a high incidence (55.5%) of catheter infection, defined as positive blood cultures drawn from the CVA in symptomatic or asymptomatic patients. Six infections were noted before rIL-2 treatment was started. Twelve of the 30 documented infections were symptomatic (fever and/or chills), with only four documented bacteraemias. The most frequently cultured microorganism was Staphylococcus epidermidis (73%). Treatment initially consisted of systemic antibiotics via the CVA, but as experience increased, the mostly asymptomatic CVA infections were not treated. In 30% of the documented CVA infections a thrombus at the tip of the catheter was found by radiological contrast examination. Local thrombosis can be effectively treated with constant infusion of low dose streptokinase via the CVA.

Adult↗
PubMed1993

Phase I clinical study of LL-D49194 alpha 1 with retrospective pharmacokinetic investigations in mice and humans. The EORTC ECTG.

LL-D49194 alpha 1 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D49194 alpha 1 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.

Aged↗
PubMed1993

Possible role for cytotoxic lymphocytes in the pathogenesis of acute interstitial nephritis after recombinant interleukin-2 treatment for renal cell cancer.

A patient with renal cell cancer developed acute renal failure due to biopsy-proven acute tubulo-interstitial nephritis (AIN) in the 6th week of continuous infusion of 9 x 10(6) IU m-2 day-1 recombinant interleukin-2 (rIL-2). We investigated whether the AIN was the result of a cellular cytotoxic reaction induced by the rIL-2 treatment. The cytolytic activity of cryopreserved peripheral blood lymphocytes (PBL), isolated before and at the end of the rIL-2 treatment (at the time of AIN), was studied after 5 days of culture with or without rIL-2 or anti-CD28 and immobilized anti-CD3 antibodies. The PBL isolated before and at the end of the rIL-2 treatment showed cytolytic activity towards a number of allogeneic targets. However, only the PBL isolated at the end of the rIL-2 treatment showed, when stimulated with rIL-2 in vitro, significant cytolytic activity against an autologous renal cell line cultured from the AIN biopsy specimen and against an allogeneic renal cell cancer cell line. These PBL displayed no enhanced killing capacity towards autologous PBL and the melanoma cell line M14. These observations suggest that the AIN may be the result of a cytotoxic lymphocyte-mediated reaction induced by the rIL-2 treatment.

Acute Kidney Injury↗
PubMed1993

Reconstitution of recombinant interleukin-2 (rIL-2): a comparative study of various rIL-2 muteins.

In a previous clinical study using a continuous infusion schedule of recombinant interleukin-2 (rIL-2) we noted a nearly complete loss of activity of EuroCetus rIL-2 when dissolved in 10 ml saline and infused at a very low rate through a plastic infusion device. In the present study, we demonstrated that the loss resulted from a concentration-dependent precipitation of rIL-2 in saline and adherence of the protein to the tubing material. These phenomena were not noted for four other rIL-2 muteins tested [Glaxo, Hoffmann-LaRoche, Amgen (2 muteins)]. EuroCetus rIL-2 was found to be completely soluble in water and 5% glucose.

Albumins↗
PubMed1993

A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part II: Immunological aspects.

Previously we described the clinical aspects of a phase I study of prolonged continuous infusion of low-dose recombinant interleukin-2 (rIL-2). In the present paper we report several immunological effects in 13 patients with melanoma and renal cell cancer treated on an out-patient basis with rIL-2 for uninterrupted periods ranging from 5 to 18 weeks. Groups of three patients were treated at following dose levels 0.18, 0.6, 1.8 or 6 x 10(6) IU m-2 24 h-1 and one patient was treated with 3 x 10(6) IU m-2 24 h-1. Prolonged rIL-2 treatment resulted in a dose-dependent and sustained increase in the percentage and absolute number of (CD56+, CD8dim) natural killer cells. Within this population a preferential increase in the CD56bright cells with low expression of CD16 was observed. The CD27 antigen was also upregulated in the CD56bright CD16dim population. This increase of NK cells was accompanied by an enhancement of the cytotoxic capacity of the peripheral lymphocytes. No consistent signs of T cell activation or expansion were noted.

Adult↗