The use of polyethylene glycol-modified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG-IL-2.

Background: Conjugation of polyethylene glycol to recombinant human interleukin-2 (IL-2) results in a compound, polyethylene glycol-modified IL-2 (PEG-IL-2) that retains the in vitro and in vivo activity of IL-2, but exhibits a markedly prolonged circulating half-life. In mice, one dose of PEG-IL-2 results in tumor regression comparable to that achieved with multiple bolus doses of IL-2. Based on these preclinical studies, a Phase I study with PEG-IL-2 was undertaken in patients with metastatic renal cell carcinoma (RCC) and melanoma.

Early history of neurosurgery in Manitoba: threads in the tapestry of world neurosurgery.

The author describes the history of neurosurgery in Manitoba, with particular emphasis on events that occurred after his arrival there in 1950. Highlights of global neurosurgery are spliced into the author's reminiscences to anchor the local history with that of neurosurgery as a whole.

Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy.

Purpose: To determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma.

Patients And Methods: Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.

Acute, oral ethanol administration suppresses episodic growth hormone secretion in the male rat.

The effect of single dose ethanol administration on GH secretion was studied in young adult male rats bearing indwelling gastric and right-atrial cannulas. Rats (nonfasted) received saline or ethanol (1, 2, 3, or 4 g/kg) via gastric cannula 2h before the onset of the daily dark period; blood was sampled every 15 min for 5 h. Each rat served as its own control, receiving saline and one ethanol dose separated by 2-3 days.

Lateral sellar compartment: history and anatomy.

The pertinent history leading to our current knowledge of the anatomy in the lateral sellar compartment is presented along with the known and unknown anatomic details of this region. The reasons why "cavernous sinus" is a misleading term for this compartment are presented.

Renal dysfunction associated with the administration of high-dose interleukin-2 in 199 consecutive patients with metastatic melanoma or renal carcinoma.

Purpose: To describe the incidence and management of renal dysfunction associated with the use of high-dose interleukin-2 (IL-2) (as is currently approved) in the treatment of cancer patients.

Patients And Methods: One hundred ninety-nine consecutive patients with metastatic renal carcinoma or melanoma were treated with intravenous bolus infusions of IL-2 alone (720,000 IU/kg) every 8 hours.

Results: Patients received 310 courses (589 cycles) of therapy and most experienced oliguria, hypotension, and weight gain; 13% of cycles were discontinued due to increased serum creatinine levels.

Overcoming sleep problems in babies and toddlers.

In infants, sleep patterns are not so well developed as in adults. More of the infant's sleep is active (REM sleep) than the adult's. There is a wide range of normal sleeping behaviour in infancy, from almost continuous sleeping to less than nine hours out of 24.

Evidence that increases in lymphocyte tyrosine phosphorylation precede cardiac allograft rejection. Effects of cyclosporine and potential use in clinical management.

Tyrosine phosphorylation is an early, critical event in lymphocyte signal transduction. We measured tyrosine phosphorylation in a porcine experimental transplant model to evaluate its utility in monitoring the allograft immune response. Using flow cytometry, we demonstrate a biphasic increase in phosphotyrosine (ptyr) levels in peripheral blood mononuclear cells (PBMC), and that increases are detectable as early as 1 day posttransplantation in untreated transplanted animals (n = 4).

Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2.

Background: Studies of human tumor-infiltrating lymphocytes (TILs) derived from patients with a variety of histologic types of cancer have demonstrated that cellular immune reactions against established malignancy exist in humans.

Purpose: We report the results of using autologous TILs plus high-dose bolus interleukin 2 (IL-2), with or without the concomitant administration of cyclophosphamide, in the treatment of 86 consecutive patients with metastatic melanoma.

Methods: From May 1987 through December 1992, 86 patients (38 female and 48 male) with metastatic melanoma were treated (145 courses) with autologous TILs plus high-dose intravenous bolus IL-2 (720,000 IU/kg every 8 hours).

Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report.

Purpose: A randomized prospective study was performed to compare the efficacy and toxicity of high-dose intravenous bolus interleukin-2 (IL-2) and a lower-dose intravenous bolus regimen for the treatment of metastatic renal cell carcinoma (RCC).

Patients And Methods: Between March 1991 and April 1993, 125 patients with metastatic RCC were randomized to receive IL-2 by intravenous bolus every 8 hours at either 720,000 IU/kg (high-dose) or 72,000 IU/kg (low-dose) to the maximum-tolerated number of doses (or a maximum of 15 doses). After approximately 7 to 10 days, both treatment groups were re-treated with a second identical cycle of therapy.

Clinical applications of IL-2.

Several years of clinical trials with IL-2, including modifications of dose and schedule and combinations with other biologic agents or chemotherapy, have shown much more limited anticancer activity for this agent than was anticipated from the preclinical studies. Even for its FDA-approved indication (metastatic renal cell carcinoma patients with good performance status), IL-2 probably benefits only a small subset of patients, and no prognostic factors have yet been identified to pinpoint these patients. In addition, clinical activity in patients with renal cell carcinoma treated with high-dose IL-2 is achieved at the expense of substantial acute toxicity.

A phase I trial of intravenous interleukin-6 in patients with advanced cancer.

Eighteen patients were treated with escalating doses of recombinant, Escherichia coli-derived human interleukin-6 (IL-6) intravenously every 8 h. Therapy was given for two cycles of 7 days each separated by a week off therapy. Fevers and chills were observed in most patients.

Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2.

Objective: To determine the efficacy of treatment using high-dose bolus interleukin 2 (IL-2) in patients with metastatic melanoma or renal cell cancer.

Design And Setting: Consecutive series of all patients treated with high-dose IL-2 in the Surgery Branch of the National Cancer Institute from September 1985 through December 1992.

Patients: Two hundred eighty-three patients with metastatic melanoma or metastatic renal cell cancer who had failed standard treatment for their cancers.

Potential autoantigens in IDDM. Expression of carboxypeptidase-H and insulin but not glutamate decarboxylase on the beta-cell surface.

Insulin, carboxypeptidase-H (CP-H), and glutamate decarboxylase (GAD) have been identified as potential autoantigens in insulin-dependent diabetes mellitus (IDDM). Previous studies have described immunoreactive insulin as a surface molecule on the plasma membrane of rat islet cells and suggested that cell-surface insulin was derived during exocytosis by the fusion of insulin secretory granules with the beta-cell plasma membrane. These findings predict that insulin and other secretory granule-derived proteins such as the putative autoantigen CP-H may be colocalized with insulin at specific sites of exocytosis on the beta-cell surface.

Cell kinetic analysis in pediatric brain and spinal tumors: a study of 117 cases with Ki-67 quantitation and flow cytometry.

We present cell kinetic data including Ki-67 quantitation and flow cytometry on 117 pediatric brain/spinal cord tumors and review the literature. Although, in general, these proliferation indices are in agreement with the histologic grade, they are useful in prognostication in some instances when the histological features of malignancy are equivocal. Specific examples in which flow cytometry may prove particularly useful in this context are childhood ependymomas, which do not show frank anaplasia but have cellular foci with focal increase in mitoses, and choroid plexus neoplasms, where elevated S phase fractions have been associated with an adverse outcome.

A phase II clinical trial of interleukin-2 and lymphokine-activated killer cells in advanced colorectal carcinoma.

Patients (n = 22) with metastatic or unresectable colorectal carcinoma were treated with interleukin (IL)-2 and lymphokine-activated killer (LAK) cells in a phase II study conducted by the IL-2/LAK Working Group (ILWG). Eligibility criteria for the study included bi-dimensionally measurable disease, performance status 0 or 1, and normal function of all vital organs. The median age of patients was 49 (range, 28-61) years.

Clinical development of anticancer agents from natural products.

Recent years have seen the introduction into clinical trials of new classes of chemotherapeutic agents which are derived from natural sources and have novel mechanisms of action. Examples of some of these newer classes of agents are presented here to illustrate both the opportunities they represent with respect to cancer treatment applications and the challenges which they represent from the clinical development perspective. Cumulatively the problems encountered with the development of the agents described are representative of the spectrum of issues encountered in the development of natural products, ranging from initial characterization and purification through the difficulties encountered in obtaining sufficient quantities of material for preclinical studies and then ultimately for clinical trials.