Biomedical subjects

E Gafney

Publications and source records attributed to E Gafney.

7 recordsLinked to original sources

PubMed1992

A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion.

Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokine in vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40 micrograms/m2 and was ultimately escalated to 200 micrograms/m2. A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160 micrograms/m2 was defined as the MTD. At 160 micrograms/m2 peak serum levels occurred within 5-20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80 micrograms/m2. This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule.

Adenocarcinoma↗

PubMed1990

A phase I study of recombinant human interleukin-2 and alpha-interferon-2a in patients with renal cell cancer, colorectal cancer, and malignant melanoma.

Preclinical data suggest synergy of interleukin-2 (IL-2) combined with alpha-interferon (IFN). In addition, toxicities of IL-2 may be decreased by intermittent continuous infusion. The purpose of this trial was to determine the maximum tolerated dose (MTD) of recombinant IL-2 combined with alpha-IFN in patients with renal cancer, colon cancer, melanoma, and malignant B-cell disease. IL-2 was given by continuous i.v. infusion at an initial dose of 5 X 10(5) units (U)/m2/d for 4 days plus IFN at 6 X 10(6) U/m2/d intramuscularly days 1 and 4 weekly for 4 weeks. Patients who achieved a response or stable disease received an additional 4 weeks of therapy. IL-2 doses were increased to 1, 2, 3, 5, and 7 X 10(6) U/m2/d with three to eight patients at each dose level, at each of the two participating institutions. The dose of IFN was 6 X 10(6) U/m2 days 1 and 4 for all but five patients whose IFN dose was doubled to 12 X 10(6) U/m2/d. Forty-three patients were entered on this study with 34 completing at least 4 weeks of therapy. Six patients were taken off study because of Grades III or IV pulmonary, neurologic, or cardiac toxicity; one for progressive disease; one for CNS metastases, and one for personal reasons. All of the toxicities were reversible. Chills and fever were universal, especially on days 1 and 4. Mild and moderate nausea, vomiting, diarrhea, anorexia, malaise, and cutaneous erythema were present in most patients. Fluid retention and occasional pleural effusions were observed at the higher IL-2 doses but were not dose-limiting. Significant hypotension associated with oliguria was seen, and these patients were treated with vasopressors and colloids. None of the patients required ICU admission. Thirty-four patients were evaluable for response. There were 4/18 (22%) renal cell patients who experienced a partial response. No responses were seen in patients with melanoma, lymphoma, or colorectal cancer. The combined debilitating symptoms of fatigue, diarrhea, hypotension, fluid retention, and anorexia defined the MTD as 5 X 10(6) U/m2/d of IL-2 and 6 X 10(6) U/m2 of alpha-IFN.

Adult↗

PubMed1989

Severe intrahepatic cholestasis in patients treated with recombinant interleukin-2 and lymphokine-activated killer cells.

Immunotherapy with recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells (LAK) has become a new form of therapy that has been shown to induce remissions in patients with renal cell carcinoma and melanoma. Despite encouraging results, this form of therapy has been associated with increasing toxicity, often requiring therapy in an intensive-care unit. In this report severe intrahepatic cholestasis occurred in two patients receiving rIL-2 and LAK cells. This form of cholestasis appeared to be directly related to rIL-2 administration at a doses of 2 x 10(6) U/m2 and 3 x 10(6) U/m2 t.i.d. A liver biopsy showed moderate hepatocellular bile stasis, with lobular and portal inflammation. All other studies for potential cause of this cholestasis were negative, including studies for metastatic disease. When therapy was discontinued, evidence for cholestasis and bile stasis resolved. We conclude that rIL-2 is a drug with a potential to induce severe hepatic injury that is reversible upon cessation of therapy with rIL-2. Further care should be exercised when rIL-2 is administered to patients with abnormal liver function.

Adult↗

PubMed1989

Lack of protection against bacterial infections in patients with advanced cancer treated by biologic response modifiers.

A survey of patients with advanced cancer treated by biologic response modifiers (BRMs), including (i) recombinant interleukin-2 and lymphokine-activated killer cells, (ii) recombinant interleukin-2 and alpha interferon, and (iii) tumor necrosis factor, was done. A total of 52 patients were reviewed. A total of 73 courses of BRMs were administered. Prior to the initiation of therapy, all patients were infection free and not receiving antibiotics. Twelve patients developed bacteremia during treatment with these BRMs. Five of these 12 patients had catheter-related bacteremia. Six patients had bacteremic infections without an obvious source, and one patient had a urinary tract infection with bacteremia. Staphylococcus epidermidis accounted for six of the isolates. Other organisms were Staphylococcus aureus, group B streptococci, viridans group streptococci, and gram-negative bacilli. This was an unexpectedly high incidence of bacterial infections in patients treated with BRMs. These BRMs have been previously shown to be efficacious against infections (by bacteria and other intracellular organisms) in experimental animals. In this study BRMs did not influence host defense mechanisms or offer protection against bacterial infections.

Bacterial Infections↗

PubMed1989

Treatment of patients with advanced cancer using multiple long-term cultured lymphokine-activated killer (LAK) cell infusions and recombinant human interleukin-2.

Escalating doses of recombinant human interleukin-2 (rIL-2) were combined with long-term cultured rIL-2 activated killer cells to treat patients with disseminated melanoma, renal cell cancer, and colon cancer. Twenty-four patients were entered, 12 with renal cell cancer, 8 with colon cancer, and 4 with melanoma; 23 were evaluable for efficacy and toxicity. The (dose-related) toxicities were moderate to severe and consisted of fever, chills, rigors, weight gain, hypotension, mild confusion, elevation of liver enzymes and serum creatinine, thrombocytopenia, and eosinophilia. No cardiac events (arrhythmias or myocardial infarction) were recorded. None of the patients were admitted to the intensive care unit, and no deaths occurred. Two partial responses were observed, one at relatively low doses of rIL-2 in a patient with renal cell carcinoma and one at the highest dose level in a patient with malignant melanoma. The maximally tolerated dose level of rIL-2 for this study was 6 X 10(6) U/m2 i.v./day. The recommended dose for further studies is 3 X 10(6) U/m2 i.v./day in three divided doses.

Adult↗

PubMed1987

Cellular interactions in hemopoiesis.

The role of immunocompetent cells in hemopoiesis remains controversial. We used an autologous system in which activated peripheral blood mononuclear cells (LAK) and interleukin-2 (IL-2) are administered to patients with cancer. We found little change in the numbers of circulating erythroid progenitors. Cocultures of these progenitors with LAK or supernatants lead to a decrease in the numbers of detectable burst forming units-erythroid (BFU-E) in culture. However, using an assay for burst promoting activity (BPA) we noted production of this hemopoietin by these LAK cells. We could not detect circulating levels of gamma interferon (IF). Variable levels were found in the LAK supernatants. We could not detect circulating eosinophil progenitors (CFU-Eo), but we did find evidence of production of a colony stimulating factor (CSF), which gave rise to a high number of eosinophil colonies in cultures of bone marrow. These results suggest that administration of LAK/IL-2 has potent effects on hemopoiesis and that these effects may emphasize the anemia and eosinophilia seen in patients receiving this therapy.

Anemia↗

PubMed1982

Long-distance transportation of specimens for human tumor cloning.

52 malignant effusions and 22 solid tumors were shipped from hospitals farther than 1,500 mi away to a central laboratory for culture in a human tumor-cloning system. Overall, 56% of the malignant effusions and 50% of the solid tumor specimens formed greater than or equal to 30 colonies in control plates (per 500,000 nucleated cells plated). This experience compares favorably to the percent of evaluable specimens which are cultured in the same institution which they are harvested. We conclude that with appropriate preparation, both malignant effusions and solid human tumors can be shipped to a central cloning laboratory with reasonable percentages of growth.

Cell Division↗