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Biomedical subjects

G W Sledge

Publications and source records attributed to G W Sledge.

At least 91 records · Page 5Linked to original sources
PubMed1993

High-dose carboplatin and mitoxantrone with autologous bone marrow support in the treatment of advanced breast cancer.

Ten patients with Stage II (four) and Stage IV (six) breast cancer were enrolled in a trial of conventional-dose induction therapy followed by high-dose therapy with autologous bone marrow support. Cyclophosphamide, methotrexate, and 5-fluorouracil were given to best response or five courses (Stage II). Those patients without progression were eligible for the high-dose portion of the protocol, which consisted of carboplatin 1,500 mg/m2 and mitoxantrone at either 40 mg/m2 (first five patients) or 50 mg/m2. Two patients did not receive the high-dose portion of the treatment due to progression on induction therapy (one) and insurance refusal (one). Of the remaining eight patients who completed the high-dose portion of the protocol, three were Stage II, of whom one died of transplant-related complications, one progressed, and one is alive and free of disease 24 months after therapy. Of the five Stage IV patients, two achieved a partial remission, one of whom died of progressive disease 1 year after therapy and the other died of BMT-related complications; of the other three Stage IV patients, one had stable disease and died at +9 months, one with progression died at +3 months, and one died of BMT-related causes. Overall, three patients died of infectious complications, with two having alpha streptococcal septic shock syndrome.

Adult↗
PubMed1992

Phase III double-blind comparison of intravenous ondansetron and metoclopramide as antiemetic therapy for patients receiving multiple-day cisplatin-based chemotherapy.

BACKGROUND: Ondansetron hydrochloride is a selective serotonin subtype 3 (5HT3) receptor antagonist that has been shown to be an effective antiemetic in patients receiving cisplatin chemotherapy. METHODS: This double-blind study compared the safety and efficacy of intravenous ondansetron with metoclopramide in patients receiving a 4- or 5-day regimen of cisplatin (20-40 mg/m2/day) combination chemotherapy. Forty-five patients were enrolled, and efficacy of the drug therapy could be studied for all 45. Patients were randomly assigned (1:1) to receive three daily intravenous doses of either 0.15 mg/kg ondansetron or 1 mg/kg metoclopramide. All patients were monitored daily for the number of emetic episodes (vomiting or retching), severity of nausea, adverse events, and laboratory safety parameters. RESULTS: Seven (30%) patients who received ondansetron had no emetic episodes throughout the entire study period compared with two (9%) who received metoclopramide (P = 0.077). The greatest difference in antiemetic efficacy was seen on day 1, when 18 (78%) patients who received ondansetron had no emetic episodes compared with 3 (14%) patients who received metoclopramide (P < 0.001). Significantly fewer antiemetic treatment failures (more than five emetic episodes or withdrawal from the study) occurred with patients given ondansetron (9%) than with those given metoclopramide (50%) during the entire study period (P = 0.002). The most commonly reported adverse event associated with ondansetron therapy was headache (controlled with acetaminophen), whereas diarrhea and restlessness were the most commonly reported adverse events associated with metoclopramide therapy. Extrapyramidal symptoms were judged to have occurred in 13 patients who received metoclopramide and 1 patient who received ondansetron. However, the patient who received ondansetron subsequently was judged to have had an anxiety attack. In patients with low or normal baseline transaminase values, a greater percentage who received ondansetron had transient increases as great as twice the upper limit of normal in aspartate transaminase (5% versus 0%) and alanine transaminase (17% versus 6%) than those who received metoclopramide. CONCLUSIONS: Ondansetron is superior to metoclopramide as antiemetic therapy for multiple-day cisplatin-based chemotherapy.

Adolescent↗
PubMed1992

Cisplatin and platinum analogues in breast cancer.

Therapy for metastatic breast cancer can palliate disease and prolong life, but cannot cure. New drugs will be required if this is to change. Cisplatin and its analogue carboplatin offer new approaches to the treatment of metastatic breast cancer. Cisplatin has significant single-agent, front-line activity in metastatic breast cancer. In combination with other agents (eg, etoposide or 5-fluorouracil), it provides response rates equivalent to other front-line combinations. The activity of carboplatin as a single agent is reportedly less than that of cisplatin in single-agent trials, and few combination trials have been reported. Both cisplatin and carboplatin, when used in high doses in the setting of autologous bone marrow transplantation, appear to be useful agents for the treatment of metastatic disease. Further research is needed to define the role of these compounds in the treatment of breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Binding of insulin-like growth factors to Tera-2 human embryonal carcinoma cells during differentiation.

Differentiation of Tera-2 human embryonal carcinoma cells by exposure to 2.1 mM alpha-difluoromethylornithine resulted in changes in morphology, a decrease in growth rate, and changes in the expression of SSEA-1 differentiation antigen. While the binding of 125I-insulin-like growth factor I (IGF-I) remained relatively constant during differentiation, binding of 125I-IGF-II increased 2-3-fold. Further, the binding of IGF-II was 87 times greater than IGF-I in both undifferentiated and differentiated cells. Undifferentiated Tera-2 cells exhibited a single class of binding sites for both IGF-I (KD = 1.2 nM, 7.0 x 10(3) sites/cell) and IGF-II (KD = 8.3 nM, 3.4 x 10(5) sites/cell). Following differentiation, IGF-I continued to bind to a single class of binding sites (KD 1.0 nM, 6.7 x 10(3) sites/cell) whereas IGF-II bound to both high-affinity sites (KDH 0.3 nM, 2.2 x 10(5) sites/cell) and low-affinity sites (KDL 15.1 nM, 1.6 x 10(7) sites/cell). The binding of iodinated IGF-II was blocked by unlabeled IGF-II but not IGF-I. In contrast, 125I-IGF-I binding was prevented by either IGF-I or IGF-II. Affinity cross-linking experiments demonstrated the presence of both type I and type II IGF receptors along with a number of IGF binding proteins. IGF-I failed to stimulate the incorporation of [3H]thymidine in both undifferentiated and differentiated cells. Although IGF-II caused a significant increase in [3H]thymidine incorporation in both undifferentiated and differentiated Tera-2 cells, the magnitude of the response and the sensitivity of the cells to IGF-II stimulation was diminished following differentiation. The observed changes in IGF-II binding, which occur in conjunction with cellular differentiation, may be an important feature of the expression of the differentiated phenotype by human germ cell tumors.

Binding Sites↗
PubMed1991

Methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic breast cancer. A phase II trial of the Hoosier Oncology Group.

Forty-six eligible patients with metastatic breast cancer (MBC) were treated with a combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) as first-line chemotherapy. Of 44 patients evaluable for response, 28 (64%) had an objective response, including seven (16%) who had a complete response. The median duration of response was 4 months (range, 0 to 38 months), and the median survival from the time of entry was 14 months (range, less than 1 to greater than 45 months). Myelosuppression was the most common dose-limiting toxicity, with 54% of patients experiencing Grade 3 or 4 leukopenia (including 28% with granulocytopenic fever and one septic death), and cumulative Grade 3 anemia occurred in 28% of patients. Grades 3 to 4 stomatitis was observed in 18% of patients. An active, although highly toxic regimen when used as first-line therapy in MBC, M-VAC has a response rate and survival duration similar to existing, less toxic combination regimens. As such, M-VAC cannot be recommended in preference to other combination chemotherapy regimens in this clinical setting.

Adenocarcinoma↗
PubMed1991

Etoposide in the management of metastatic breast cancer.

Etoposide, despite extensive use in other malignancies, has played a minor role in the treatment of patients with breast cancer. Single-agent trials in which etoposide is administered to heavily pretreated patients with metastatic breast cancer have demonstrated a low overall response rate (6.6% of 383 patients), with no convincing evidence for either schedule dependence or a relationship between dose intensity and response. The sole single-agent trial in previously untreated patients suggested that the drug has an approximately 15% response rate in untreated patients. Combination therapy trials in which etoposide has been combined with either cyclophosphamide, doxorubicin, or cisplatin have not yet convincingly demonstrated superiority over any of these drugs as single agents, although cisplatin plus etoposide appears to be superior to either agent alone. In vitro studies suggest that pretreating hormone-sensitive breast cancer cells with estradiol may increase their sensitivity to etoposide-induced DNA cleavage. This may represent a future direction in the use of etoposide in breast cancer. Currently, however, the use of etoposide in breast cancer should be considered investigational.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

DNA content as a prognostic index in gestational trophoblastic neoplasia.

Hydatidiform mole will progress to malignant gestational trophoblastic neoplasia (GTN) in some cases. Aneuploidy and high proliferative activity are associated with malignant tumors. Molar pregnancy tissue was considered a precursor to malignant GTN, and was studied retrospectively using paraffin-embedded tissue to determine whether aneuploidy or proliferative rates measured on molar tissue could predict a malignant course. Tissues from 51 complete hydatidiform moles were analyzed for nuclear DNA content by flow cytometric techniques. A chart review identified the clinical course after evacuation of the mole. A satisfactory DNA histogram was generated in 40 cases. Of the 40 patients, 22 (55%) had spontaneous resolution, and 18 patients (45%) required treatment for persistent GTN. The molar tissue was found to be euploid in 27 cases and aneuploid in 13 cases. Eight of the twenty-seven euploid cases (30%) required treatment after evacuation, whereas 10 of the 13 aneuploid cases (77%) required treatment after molar evacuation. Proliferative index (PI) was compared with treatment requirements. Average PI was 0.11 +/- 0.10 for the treatment group and 0.08 +/- 0.06 for the spontaneous resolution group. The correlation of clinical course with ploidy was significant (P less than 0.01). The association with proliferative index was not (P greater than 0.05). Aneuploidy, therefore, identifies a high-risk group of molar pregnancies, and may represent those that have undergone one stage of malignant transformation.

DNA, Neoplasm↗
PubMed1989

Ifosfamide plus doxorubicin in metastatic adult sarcomas: a multi-institutional phase II trial.

Between April 1986 and March 1987, 42 patients with advanced sarcoma were entered in this multi-institutional trial evaluating ifosfamide plus doxorubicin. The majority of patients had leiomyosarcoma and malignant fibrous histiocytoma although two patients with sarcomas of osseous origin were included. Doxorubicin was administered at a dosage of 60 mg/m2 by continuous push and ifosfamide 5.0 g/m2 by continuous infusion over 24 hours with mesna (7.5 g2 over 36 hours) with courses repeated every 3 weeks until progression, toxicity cumulative doxorubicin dosage of 450 mg/m2. Overall, 15 (36%) patients demonstrated objective remissions including three complete and 12 partial remissions (95% confidence limits, 21.5% to 52.0%). The median duration of remission was 7.0 months and the median survival time for all eligible patients was 8.0 months. Toxicity was predominantly hematologic with the median leukocyte nadir being 1,300 per microliter of blood and documented sepsis in six patients. These data support activity for ifosfamide plus doxorubicin in patients with advanced sarcoma, but the actual contribution of ifosfamide needs to be evaluated through prospective randomized trials which are currently underway.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Cisplatin in the management of breast cancer.

Cisplatin's role in metastatic breast cancer was initially confined to heavily pretreated patients. It had relatively little activity in these patients, except when administered with high-dose intensity (greater than 33.3 mg/m2/week). More recent trials in previously untreated patients have suggested that cisplatin is an active single agent, with response rates approaching 50% when administered at a dose of 30 mg/m2/d for four days every 3 weeks. Cisplatin has been safely incorporated into combination chemotherapy regimens, and has been used in high-dose regimens in conjunction with autologous bone marrow transplantation. Future trials should examine the use of cisplatin or platinum analogues as first-line therapy in alternating non-cross-resistant regimens, and should attempt to circumvent the dose-limiting toxicities of cisplatin when used in a dose-intensive fashion.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Relation of proliferative activity to survival in patients with advanced germ cell cancer.

Patients with advanced disseminated germ cell tumors of the testis, retroperitoneum, and mediastinum have impaired survival compared to other patients with disseminated germ cell tumors having less bulky metastatic disease. Among patients with advanced disseminated germ cell tumors, we currently lack adequate predictors of long-term survival. Flow cytometric analysis of the paraffin-embedded, formalin-fixed tumor blocks of 50 of these patients suggests that proliferative activity is significantly correlated with survival (p less than 0.001) in multivariate analysis. Log (beta-human chorionic gonadotropin) is the only other useful predictor of long-term survival in multivariate analysis of prognostic factors in this group of patients. Flow cytometric DNA analysis may be useful in predicting survival in patients with advanced disseminated germ cell tumors.

Cell Cycle↗
PubMed1988

Cisplatin as first-line therapy for metastatic breast cancer.

Cisplatin has had only minimal activity when used as second- and third-line chemotherapy for metastatic breast cancer (MBC). There have been no phase II studies in the United States evaluating cisplatin in patients with MBC with no prior chemotherapy. We therefore treated 20 consecutive patients with cisplatin 30 mg/m2/d for four days every 3 weeks for a maximum of six courses. We obtained partial responses in nine of 19 evaluable patients (47%), with responses in liver, lung, and soft tissue indicator lesions. Our data suggest that cisplatin has substantial single-agent activity as front-line therapy in MBC, and should be considered for inclusion in first-line combination chemotherapy regimens.

Adenocarcinoma↗
PubMed1988

Analysis of phorbol ester stimulated human megakaryocyte development.

Megakaryocytes are relatively rare components of human bone marrow, making the study of their maturation difficult. Phorbol esters can act as differentiating agents in a number of cell systems including murine megakaryocytes. We report the effects of phorbol esters on the previously described long-term human megakaryocytic leukemia cell culture, EST-IU. While two nontransforming phorbols fail to affect these cells, the transforming phorbol 12-O-tetradecanoylphorbol-13-acetate (TPA) induces a phenotype with characteristics of more mature megakaryocytes in a dose-related manner. This phenotype includes an increased adherence to untreated plastic or glass, polyploidization, an increase in cell size, and increased expression of both platelet glycoproteins and factor VIII-related antigen. Two-color flow cytometric analysis allowed simultaneous determinations of DNA content and the expression of surface membrane antigens or alpha-granule constituents, providing evidence that nuclear, membrane, and cytoplasmic maturation occur in parallel in this cellular system. TPA-induced maturation of EST-IU cells provides an important new cellular model for the further study of human megakaryocyte development.

Antigens↗
PubMed1987

Flow cytometry derived DNA content of the primary lesions of advanced germ cell tumours.

We currently lack good prognostic indicators for patients with advanced disseminated germ cell tumours (GCT). An analysis of archival tumour samples of forty-nine patients with advanced GCT for flow cytometry derived DNA content suggests an inverse relationship between tumour proliferative activity and patient survival. The great majority of patients with advanced GCT have aneuploid tumour subpopulations. This analysis suggests that the survival of patients with advanced GCT may depend in part on kinetic variables present in the primary tumour.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients.

Univariate and multivariate analyses of potential prognostic factors for 1,015 women with recurrent breast cancer confirmed that the site of initial recurrence is an important determinant for predicting survival from the time of initial recurrence. However, both estrogen receptor (ER) status and axillary lymph node status at diagnosis, as well as the length of the disease-free interval, provide additional independent information for predicting patient survival after disease recurrence. Involved axillary lymph nodes at the time of initial diagnosis and/or lack of ERs may indicate a highly malignant tumor or a weak host defense, either of which might be related to short survival after relapse. Patients with ER-negative tumors recurred more often in visceral and soft-tissue sites, while patients with ER-positive tumors were more likely to recur in bony sites. However, for each metastatic site, receptor-positive patients had longer survival

Adult↗
PubMed1986

An estrogen-regulated protein in normal and malignant endometrium.

The presence and distribution of a protein with a mol. wt of 24,000 (24K) was determined in endometrial biopsies from regularly cycling women and in women with endometrial carcinoma. This protein, of as yet unknown function and originally found in a breast cancer cell line, was detected by immunohistochemistry using a monoclonal antibody. In regularly cycling women, the 24K protein began to appear in the glandular epithelium during the late proliferative phase and decreased after ovulation. In contrast, in the superficial epithelium, the strongest immunostaining was observed during the secretory phase. Superficial epithelial cells expressed maximal 24K immunoreactivity around day 21 of the cycle and it was clearly seen in the bulbous projections of the apical cytoplasm. These results suggest that the 24K protein may be a marker for hormonal events in the endometrium during the menstrual cycle. In endometrial carcinoma, 24K was correlated with low tumor histologic grade, few mitotic figures, few nucleoli and a low degree of nuclear pleomorphism. These data suggest that 24K may be a potential marker of tumor differentiation.

Antibodies, Monoclonal↗