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Biomedical subjects

M J Kennedy

Publications and source records attributed to M J Kennedy.

At least 73 records · Page 4Linked to original sources
PubMed1995

Phase I and pharmacologic study of the alkylating agent modulator novobiocin in combination with high-dose chemotherapy for the treatment of metastatic breast cancer.

PURPOSE: Resistance to alkylators may potentially be overcome by drugs that inhibits DNA repair, thus improving the efficacy of high-dose chemotherapy. This trial was performed to determine if novobiocin, an agent that inhibits DNA repair, could be given with high-dose alkylators. Study aims were to define the toxicities and maximal-tolerated dose (MTD) of novobiocin and the pharmacokinetics of novobiocin and high-dose cyclophosphamide and thiotepa. PATIENTS AND METHODS: Thirty-eight women with responsive metastatic breast cancer received high-dose cyclophosphamide (3 to 6 g/m2 over 4 days), thiotepa (400 to 800 mg/m2), and novobiocin (0.5 to 5.0 g/d x 7, orally) with autologous marrow support. Toxicity was monitored. The pharmacology of novobiocin, cyclophosphamide, and thiotepa was evaluated. RESULTS: There were no toxic deaths. The MTD of novobiocin was 4 g/d. All seven patients treated at 5 g/d developed grade III/IV mucositis and vomiting. The severity of mucositis correlated with the plasma levels of novobiocin. Other severe toxicities were not observed. Plasma novobiocin levels > or = 100 micrograms/mL, which are associated with reversal of drug resistance in animal models, were consistently seen at dose levels greater than 2 g. The dispositions of cyclophosphamide and thiotepa were not altered by novobiocin. CONCLUSION: Novobiocin may be given with high-dose alkylators in doses that produce plasma levels that augment the activity of these cytotoxics in experimental models. The pharmacology of high-dose cyclophosphamide and thiotepa is unaffected. Novobiocin 4 g/d orally for 7 days is recommended for future study.

Adult↗
PubMed1995

Treatment of metastatic breast cancer with combination paclitaxel/cyclophosphamide.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated substantial single-agent activity against both minimally pretreated and resistant metastatic breast cancer. Evaluation of paclitaxel-based combinations has demonstrated appreciable activity, but also toxicity, for the paclitaxel/doxorubicin combination. The paclitaxel/cyclophosphamide combination is potentially attractive because of the significant single-agent activity of both drugs against metastatic breast cancer and the paucity of shared nonhematologic toxicities. This combination is being evaluated in women with doxorubicin-refractory metastatic breast cancer. Dose escalation to paclitaxel 200 mg/m2 over 24 hours and cyclophosphamide 2,000 mg/m2 administered every 21 days with granulocyte colony-stimulating factor support has been performed. The final dose level was complicated by dose-limiting toxicity. The maximum tolerated dose for this combination is currently being defined. There is preliminary evidence of sequence-dependent toxicity. Grade 4 neutropenia and neutropenic fevers are more frequent in cycles in which paclitaxel is administered first.

Adult↗
PubMed1995

Detection of tumor cells in the bone marrow, peripheral blood, and apheresis products of breast cancer patients using flow cytometry.

One of the possible drawbacks to autologous bone marrow (BM) and peripheral blood progenitor cell (PBPC) transplantation in breast cancer patients is the potential for tumor cell contamination in the transplanted product. To assess the presence of breast cancer cells, we have developed a flow-cytometric method using cytokeratin-FITC and CD45-phycoerythrin (PE) to detect very low levels of cytokeratin-positive (CK+) tumor cells in mononuclear cell (MNC) preparations. In a model system using PBMNC and the breast cancer cell line CAMA, the sensitivity of detection of this flow-cytometric method was one tumor cell in 200,000 MNC. This method was used to evaluate BM, PB, and apheresis products (AP) from 44 patients with metastatic breast cancer. When possible, stained cytologic examination was performed on smears of the unprocessed specimens and on flow cytometry-sorted cells. Results indicated that CK+ tumor cells could be detected by flow cytometry in all three specimen types. When present, however, the tumor content (per MNC) tended to be higher in BM than in PB or AP. Samples from a given patient taken serially over the course of chemotherapy revealed variable results, suggesting that the presence of tumor contamination may be sporadic and requires evaluation of each stem cell product. Of 75 samples tested with both flow cytometry and cytology, the results were concordant in 54 cases (72%). In the remaining samples, flow cytometry only was positive in 15 cases (20%), and cytology only was positive in six cases (8%). This flow-cytometric technique is useful in the evaluation of transplant products for CK+ tumor cell contamination.

Adenocarcinoma↗
PubMed1994

Bone marrow micrometastases in chemotherapy-responsive advanced breast cancer: effect of ex vivo purging with 4-hydroperoxycyclophosphamide.

Tumor contamination of hematopoietic stem cell grafts may influence the outcome of breast cancer patients treated with high-dose chemotherapy. The goals of this study were: (a) to evaluate the prevalence of tumor contamination of bone marrow (BM) harvests in patients responding to systemic chemotherapy; (b) to evaluate reduction of BM tumor contamination by ex vivo purging with 4-hydroperoxycyclophosphamide (4HC); and (c) to compare the tumor contamination of peripheral blood progenitor cell collections and BM in advanced-stage breast cancer patients designated for peripheral blood progenitor cell infusion. We evaluated pre- and post-4HC purge BM specimens from 20 patients for tumor contamination using immunocytochemistry and for in vitro growth potential of tumor cells using a tumor cell clonogenic assay. Pre-4HC purge BM specimens from 15 of 20 (75%) patients were immunocytochemistry and tumor cell clonogenic assay negative. The remaining 5 BM specimens were immunocytochemistry positive, but only 3 of 5 specimens were tumor cell clonogenic assay positive. In vitro tumor colony growth was not observed in any post-4HC purge BM specimens. We also evaluated nine patients with bone or BM metastases from the start of induction chemotherapy. We found less tumor involvement of peripheral blood progenitor cell collections than of simultaneously obtained bone marrow aspirates. We conclude that bone marrow micrometastases occur with low frequency in women with chemotherapy-sensitive breast cancer and that ex vivo purging with 4HC may render tumor cells nonviable.

Adult↗
PubMed1994

Determination of plasma novobiocin levels by a reversed-phase high-performance liquid chromatographic assay.

A simple and specific reversed-phase high-performance liquid chromatographic (HPLC) assay for the determination of novobiocin levels in human plasma has been developed. The sample preparation was performed by deproteinization with methanol. Prednisone was used as an internal standard. Both novobiocin and prednisone were separated on a C8 column with a gradient elution of acidic water (pH 3.0)-methanol. The recovery of novobiocin from plasma was nearly complete. The linear range was 5-1000 microM in 0.5 ml of plasma with a minimum limit of determination of 2.25 fmol of novobiocin at 254 nm. The method has been implemented and validated in an ongoing clinical trial.

Chromatography, High Pressure Liquid↗
PubMed1994

The efficacy of ivermectin (pour-on) against the eyeworms, Thelazia gulosa and Thelazia skrjabini in naturally infected cattle.

Sixteen crossbred beef cattle, 6-8 months of age, were used to determine the efficacy of ivermectin in a pour-on formulation against natural infections of Thelazia spp. Cattle were weighed on Day 0, ranked in descending order by bodyweight and sequentially paired. Within each pair, one animal was randomly assigned to an untreated control group, while the other animal was treated with a pour-on formulation of ivermectin applied topically at 1.0 ml per 10 kg bodyweight to achieve a dosage of 500 mg ivermectin kg-1 body weight. On Day 14 all animals in both treatment groups were slaughtered. The eyes and surrounding tissues were removed and examined for eyeworms. A total of 86 adult worms (74 Thelazia skrjabini and 12 Thelazia gulosa) were recovered from the untreated control animals. T. skrjabini was found in seven, and T. gulosa in three, of the eight untreated control animals. Two T. skrjabini, one from each of two animals, were found on the surface of the eyes of cattle that had received ivermectin treatment. The reduction in the geometric mean number for T. gulosa collected from treated animals was 100% (P > 0.1) relative to controls, and 97.02% (P = 0.0025) for T. skrjabini relative to controls.

Administration, Topical↗
PubMed1994

Breast cancer marker Ca549. A multicenter study.

A multicenter study of CA549, a marker for breast cancer, was conducted using sera from 1721 patients with benign and malignant conditions by an immunoradiometric assay, BRESMARQ. Acceptable assay performance was demonstrated by studies of intra-assay (2.2% to 12% coefficient of variation [CV]), interassay (4.1% to 11.8% CV), and interlaboratory (4.8% to 8.7% CV) precision; sensitivity (.3 kU/L); linearity; recovery; high-dose hook effect (up to 10,000 kU/L); and interferences (human antimouse antibodies; protein, bilirubin, hemoglobin levels; lipid and cancer therapeutic agents). A reference interval of 0-12.5 kU/L (women) and 0-11.9 kU/L (men) was established from 746 healthy persons. The distribution of values exceeding the reference range for benign conditions was as follows: pregnant and lactating women (2%); benign breast disease (5%); and seven other benign diseases, including liver (24%), lung (19%), prostate (14%), colon, endometrial, gastric, and ovarian (< 10%). For nonbreast cancers, the distribution was Hodgkin's (7%), colon (10%), endometrial (15%), gastric (15%), lymphoma (15%), prostate (20%), ovarian (39%), and liver (45%). For breast cancer, the distribution was stage I (5%), stage II (14%), stage III (32%), and stage IV (74%). The receiver-operating characteristic analysis demonstrated the usefulness of CA549 as a marker in stage IV breast cancer.

Antibodies, Monoclonal↗
PubMed1994

Systemic adjuvant therapy for breast cancer.

Systemic adjuvant therapy reduces the mortality due to breast cancer to a modest extent. Current research directions focus on both increasing the efficacy of therapy, predominantly by increasing the intensity of treatment, and attempting to reduce toxicity by treating only those patients at significant risk of relapse. Improved understanding of both the metastatic process and the mechanisms by which cytotoxic treatments exert their effects hold the promise for more effective treatments in the future. Cost-benefit analyses demonstrate the relative cost-effectiveness of adjuvant systemic therapies for patients at significant risk of recurrence, for whom the effectiveness of treatment is substantial.

Breast Neoplasms↗
PubMed1994

Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

PURPOSE: We investigated if interferon gamma (IFN-gamma) could augment cyclosporine (CSA)-induced graft-versus-host disease (GVHD) following autologous bone marrow transplant in women with metastatic breast cancer and defined the toxicities of this therapy. PATIENTS AND METHODS: Thirty-six women with advanced breast cancer were treated with CSA 2.5 mg/kg daily for 28 days and IFN-gamma 0.025 mg/m2 subcutaneously (SC) every other day, days 7 to 28 following autologous bone marrow transplantation and monitored for induction and severity of GVHD and toxicity of therapy. RESULTS: GVHD was induced in 56% of patients. The severity of GVHD was greater than in a historic control population treated with CSA alone. Stage III rash was seen in 36% of patients, compared with 3% in the historic control population. Fourteen of 36 patients required therapy with topical corticosteroids and two of 36 required systemic treatment. Only three of 31 historic controls needed topical corticosteroids and no patient was treated systemically. There was no severe visceral GVHD. Hematopoietic recovery was not delayed. There were three toxic deaths. CONCLUSION: CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.

Adult↗
PubMed1994

Site segregation of Thelazia skrjabini and Thelazia gulosa (Nematoda: Thelazioidea) in the eyes of cattle.

One thousand three hundred and twenty-two eyes obtained from slaughtered cattle throughout Alberta were examined for eyeworms. Each eye was partitioned into 9 sites and all eyeworms were recorded by site. Seven hundred eyeworms were recovered from 121 infected eyes. The distribution of Thelazia skrjabini across the 9 sites differed significantly (P < 0.001) from that of Thelazia gulosa. The 2 major lacrimal ducts associated with the Harderian gland contained 58% (354/613) of the T. skrjabini present, whereas the large ventral lateral duct of the orbital gland contained 58% (50/87) of the T. gulosa recovered. Eyeworms occurred more often (90%, 631/700) in a duct as a single species than as a mixed species infection (10%, 69/700). The data suggest that T. skrjabini and T. gulosa are more site specific than previously believed.

Animals↗
PubMed1994

The effect of treating beef cattle on pasture with ivermectin on the prevalence and intensity of Thelazia spp. (Nematoda: Thelazioidea) in the vector, Musca autumnalis (Diptera: Muscidae).

Trihedron sticky traps were used to monitor the prevalence and intensity of Thelazia spp. in face flies associated with 2 groups of cattle. Traps were set for 24 hr once a week beginning 2 wk before cattle were turned out to pasture following winter housing and continued until flies reached diapause in October. The 50 heifers in group 1 received 1 treatment with ivermectin (Ivomec Pour-On for cattle, 500 micrograms/kg body weight) on the day of turnout onto pasture. The 50 cows and their calves in group 2 were not treated. Treating cattle with ivermectin delayed the onset of infection in Musca autumnalis by 20 days and reduced the prevalence to 2.2% compared to 26.9% in flies from the control pasture. Although residues of ivermectin eradicate many fly larvae developing in cattle feces, there was no significant difference in the number of flies counted on the faces of cattle or in the number of flies caught on sticky traps on the 2 pastures (P > 0.05).

Alberta↗
PubMed1993

Administration of human recombinant granulocyte colony-stimulating factor (filgrastim) accelerates granulocyte recovery following high-dose chemotherapy and autologous marrow transplantation with 4-hydroperoxycyclophosphamide-purged marrow in women with metastatic breast cancer.

Stem cell contamination by tumor is common in many diseases for which autologous bone marrow transplantation is used. In in vitro models chemotherapeutic purging reduces contamination and may have an impact on clinical outcome. Purging, however, delays engraftment. Little is known about the ability of granulocyte colony-stimulating factor (G-CSF) to accelerate myelopoiesis after purged autologous bone marrow transplantation. We treated 22 women with metastatic breast cancer with high-dose cyclophosphamide and thiotepa and, following the infusion of 4-hydroperoxycyclophosphamide-purged marrow, administered G-CSF, 16 micrograms/kg daily, from day 0 to engraftment. Results were compared with a control population of 24 women with breast cancer who received identical chemotherapy and purged marrow but not growth factor. Neutrophil recovery was accelerated in the G-CSF-treated population. An absolute neutrophil count of 500 was reached in 19 days compared with 29 for the historic controls. The median number of days febrile was reduced (8 versus 5.5) as were the number of days of hospitalization from marrow infusion (33 versus 25). There was no difference in the number of days on antibiotics or time to last platelet transfusion. G-CSF was administered without any notable toxicity. G-CSF accelerates myelopoiesis following the infusion of 4-hydroperoxycyclophosphamide-purged autologous marrow and shortens hospitalization.

Adult↗
PubMed1993

Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques.

Although peripheral blood stem cell collections (PBSC) are thought to have less tumor involvement than bone marrow (BM), the incidence of circulating tumor cells in patients with breast cancer has not been widely investigated. We prospectively investigated the incidence and viability of tumor cell involvement in PBSC and BM collections from breast cancer patients undergoing high-dose chemotherapy/hematopoietic stem cell transplantation. Paired samples of PBSC and BM from 48 patients were analyzed using an immunocytochemical technique that detects one epithelial-derived tumor cell per 5 x 10(5) mononuclear cells. Immunostained tumor cells were detected in 9.8% (13/133) PBSC specimens from 9/48 (18.7%) patients and in 62.3% (38/61) BM specimens from 32/48 (66.7%) patients, a significantly higher rate than in PBSC (P < .005). The geometric mean concentration of tumor cells in contaminated PBSC specimens was 0.8/10(5) mononuclear cells (range 0.33 to 2.0/10(5)) compared with 22.9/10(5) mononuclear cells in BM (range 1 to 3,000/10(5), P < .0001). In culture experiments, clonogenic tumor colonies grew in 21/26 immunocytochemically positive specimens. No tumor colony growth was detected in 30/32 immunocytochemically negative specimens. Immunocytochemical detection of tumor involvement in BM and PBSC correlated significantly with in vitro clonogenic growth (P < .0001). We conclude that PBSC contain fewer tumor cells than paired BM specimens from patients with advanced breast cancer and that these tumor cells appear to be capable of clonogenic growth in vitro.

Adult↗