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Biomedical subjects

M E Gore

Publications and source records attributed to M E Gore.

At least 109 records · Page 6Linked to original sources
PubMed1992

Future directions with carboplatin: can therapeutic monitoring, high-dose administration, and hematologic support with growth factors expand the spectrum compared with cisplatin?

This paper reviews the role of pharmacokinetic methods in the clinical use of carboplatin. Published data establish that pretreatment renal function is the most significant determinant of carboplatin pharmacokinetics. Evidence suggests that the area under the plasma concentration versus time curve (AUC) correlates well with hematologic toxicity. Published data also suggest that a relationship exists between the AUC and therapeutic outcome in testicular teratoma and in ovarian cancer, although in the latter case the data are not conclusive. It is suggested that pharmacokinetically based dosing schemes may be advantageous and that randomized trials should be performed to test this hypothesis. In some clinical situations where dose prediction is not feasible, a simple therapeutic drug-monitoring strategy may prove useful. Since the toxicities of carboplatin are mainly hematologic, it has been possible to study the use of high-dose carboplatin with various forms of hematologic support. Carboplatin doses have been increased fourfold to sixfold and high response rates have been reported in ovarian cancer. An overall therapeutic advantage for this strategy has not yet been demonstrated in a randomized setting. Published data on ovarian cancer cell lines suggest that the range of sensitivities encountered is very large (30- to 100-fold). If the range of sensitivities found in vivo is equally large, then a clinical dose escalation of 10- to 100-fold may be necessary to produce a curative therapy for this disease. The investigation of the use of hematopoietic growth factors in association with carboplatin has just begun. Early data suggest that some support of the WBC count may be achieved, but the toxicities of granulocyte-macrophage colony-stimulating factor have themselves been a problem. Our own studies will attempt to achieve a substantial escalation in the administered AUC of carboplatin by increasing the frequency of carboplatin dosing, while administering granulocyte colony-stimulating factor and platelet support.

Blood Transfusion↗
PubMed1991

Phase II trial of trimelamol in refractory ovarian cancer.

Trimelamol is an analogue of hexamethymelamine which exhibited activity against refractory ovarian cancer in phase I clinical trial. The dose limiting toxicity was leukopenia. In a phase II study, 42 patients with recurrent, or platinum-complex resistant, advanced ovarian cancer were treated using the dose schedule 800 mg m-2 i.v. daily for 3 days. There were one complete, three partial and five minor responses, objective response rate: 9.5%. The main toxicity observed was nausea and vomiting, myelosuppression was minor. The role of Trimelamol in the treatment of ovarian cancer remains to be defined, but its activity is limited in refractory disease.

Adult↗
PubMed1990

Ondansetron--a new safe and effective antiemetic in patients receiving high-dose melphalan.

A total of 33 patients with myeloma receiving treatment with high-dose melphalan (140-200 mg/m2 i.v.) were given the 5HT3 antagonist Ondansetron (Glaxo) as an antiemetic. In 42% of patients, emetic episodes were either abolished (15%) or reduced to two or less (27%). Efficacy was not related to scheduling (two regimens) or total dose. No sedative or other significant side effects were seen. Ondansetron is a highly effective non-sedative antiemetic that justifies further assessment in combination with other antiemetics in patients receiving cytotoxic drugs associated with the production of severe nausea and vomiting.

Administration, Oral↗
PubMed1990

Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds.

Fifty-four patients with ovarian cancer who achieved a complete or partial remission with cisplatin or carboplatin were rechallenged with the same drug or crossed over to the other platinum compound at relapse. Fifteen of 43 (35%) crossover patients and 1/11 (9%) rechallenged patients responded; the difference was not significant and there was no difference in survival between the two groups. Responders survived significantly longer than nonresponders (P = 0.001) but there was no survival difference between those who responded to a rechallenge and those who responded to crossing over to the other platinum compound. The progression-free interval between the end of initial treatment and relapse was a significant prognostic factor for response to treatment and survival; 17% (6/35) of patients who relapsed before 18 months responded as compared to 53% (10/19) who relapsed after 18 months (P = 0.006) and median survival was 221 and 486 days, respectively, for these two groups (P = 0.026).

Antineoplastic Agents↗
PubMed1990

Enhanced anti-tumour activity of carmustine (BCNU) with tumour necrosis factor in vitro and in vivo.

The effects on experimental melanoma of a combination of recombinant human tumour necrosis factor alpha (rhTNF alpha) and carmustine (BCNU) were studied in vitro and in vivo. In vitro, BCNU alone was cytotoxic to murine B16 melanoma cells, and at all concentrations of BCNU this toxicity was increased by the addition of TNF. In vivo, BCNU and TNF, when given separately, caused tumour growth delay of B16 melanoma and of human melanoma xenografts in immune-deprived mice. The combination of TNF at low dose 2.5 x 10(5) U kg-1 = 122 ng kg-1) with BCNU (35 mg kg-1) resulted in significant growth delay (compared with either drug alone) in B16 melanoma (P = 0.005). There was no significant increase in toxicity as assessed by weight loss and peripheral blood counts. Experiments with human melanoma xenografts yielded similar results (P = 0.001) but only at higher doses of TNF (1 x 10(6) U kg-1 = 489 ng kg-1). The enhancement of BCNU cytotoxicity by TNF may be important if it can be translated into patients with melanoma. A randomised study is now underway to investigate the clinical potential of this observation.

Animals↗
PubMed1990

Chemotherapy for malignant melanoma: combinations and high doses produce more responses without survival benefit.

In a consecutive series of studies, 164 patients with symptomatic and/or visceral metastatic malignant melanoma were treated with single agent vindesine, high dose melphalan with autologous bone marrow transplantation (AMBT), high dose BCNU with ABMT or the BOLD (bleomycin, vincristine, CCNU and DTIC) combination. The high dose treatments and the combination chemotherapy resulted in significantly higher response rates but no prolongation of survival. Factors associated with longer survival included the absence of visceral metastases, the absence of bulky disease and good performance status. For all treatments, life table estimates of survival at 1 and 2 years were only 10% and 4% respectively.

Adolescent↗
PubMed1990

Evidence that multiple myeloma may be regulated by homeostatic control mechanisms: correlation of changes in the number of clonogenic myeloma cells in vitro with clinical response.

Myeloma colonies (MY-CFUc) could be grown in vitro for 6 months (median time) after a group of 12 myeloma patients had reached complete remission (CR). In a second group of 25 patients MY-CFUc increased in 17/25 and GM-CFUc in 20/25 patients after cyclophosphamide even though 24/25 patients had a partial response to VAMP and one was in CR. These data suggest that cell killing by cyclophosphamide stimulates residual tumour cells into proliferation and adds further support to the idea that myeloma is under some degree of homeostatic control which may be analogous to that in normal bone marrow. Although lymphoplasmacytoid myeloma cells may be more drug resistant than plasmacytoid myeloma cells in vitro, it was not possible to conclude that the emergence of lymphoplasmacytoid cells at relapse was indicative of resistance to further treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Characterization of monoclonal antibodies reactive with normal resting, lactating and neoplastic human breast.

Mouse monoclonal antibodies reacting with human mammary gland constituents have been generated and characterized in an attempt to raise breast- or breast-cancer-specific antisera. The immunogens used in these studies included fractionated human milk fat globule membrane, the human breast cancer cell line MCF7 and a crude membrane preparation derived from an axillary nodal metastasis from a patient with breast cancer. Of the antibodies obtained, 8 were characterized and found to bind to different structures in the normal breast. The antibody LICR-LON-LC28 recognizes secretory component and binds strongly to normal resting and lactating breast, but only focally to a minority of breast carcinomas. The antibodies LICR-LON-14.1 and 32.2 react strongly with the lactating breast and recognize kappa- and beta-casein, respectively. Caseins are not produced by breast tumors. The antibodies LICR-LON-TW19.5, H10A and 39.8 all react with carbohydrate epitopes and bind heterogeneously to normal resting breast luminal epithelium and cellular subsets of breast carcinomas. LICR-LON-59.2 and 19.2 react with normal breast myoepithelial cells and the basement membrane, respectively. LICR-LON-59.2 is unusual as a myoepithelial marker in that it stains cells in the majority of breast carcinomas. LICR-LON-19.2 shows extensive reactivity to tumor cell lines in culture but has no reactivity with carcinoma cells from breast biopsies.

Animals↗
PubMed1989

Intensive treatment of multiple myeloma and criteria for complete remission.

50 previously untreated patients with multiple myeloma received two-phase treatment: repeated cycles of 4 day infusion with vincristine, doxorubicin, and methylprednisolone (VAMP) followed by high-dose melphalan (HDM), with autologous bone marrow transplantation where possible. The overall response rate was 74% (37/50), with 25 patients (50%) achieving complete haematological and biochemical remission. These remissions were associated with a good quality of life as measured by performance status, pain grade, and the reversal of humoral immunosuppression. 6 patients died during the VAMP phase and there was 1 death related to HDM. The achievement of complete remission, as defined here, in such a high proportion of patients is exceptional and may represent a useful advance in the management of myeloma.

Adult↗
PubMed1989

The impact of computed tomography and ultrasonography on the management of patients with carcinoma of the ovary.

We have carried out a prospective study on the impact of computed tomography (CT) and ultrasonography (US) on the management of patients with carcinoma of the ovary. Seventy-eight CT and 88 US scans were performed on 94 patients. Clinicians decided patient management prospectively at the time the CT and/or US was ordered. Clinical assessment differed from the result obtained by CT or US in 45% of cases (35/78 and 40/88, respectively). CT and US altered patient management in only a minority of cases (14/78, 18% and 9/88, 10% respectively). Even when the scan and clinical assessments differed, management was only altered on 14/35 (40%) occasions after CT and on 9/40 (23%) occasions after US, a difference which was not significant. In patients with clinically undetectable disease, management was altered by CT on 17% of occasions and by US on 10%. We conclude that in patients with carcinoma of the ovary CT and US alters patient management in a minority of cases. In view of current financial restrictions in health care, clinicians should be more selective in the use of these imaging techniques. Furthermore, we recommend that similar prospective studies are performed for other clinical situations.

Carcinoma↗
PubMed1989

Cisplatin/carboplatin cross-resistance in ovarian cancer.

Forty-six patients who were treated with cisplatin or carboplatin for ovarian cancer developed resistant disease (no change in measurable disease or progressive disease) and 'crossed over' to the other platinum compound. Three patients (6.5%) responded to this second treatment but these patients had no survival advantage compared to the non-responders. One responder had progressive disease on cisplatin before crossing over to carboplatin.

Adult↗