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Biomedical subjects

S B Kaye

Publications and source records attributed to S B Kaye.

At least 163 records · Page 9Linked to original sources
PubMed1994

Pattern electroretinogram and automated perimetry in patients with glaucoma and ocular hypertension.

To determine whether the pattern electroretinogram can improve the objectivity of visual field assessment, 39 patients with glaucoma and ocular hypertension were studied. This was to establish whether there is a correlation between the pattern electroretinogram and the global indices (mean deviation and corrected pattern standard deviation) provided by automated perimetry using the Humphrey visual field analyser. A significant correlation was found between the amplitude of the P50 + N95 wave of the pattern electroretinogram and the mean deviation and corrected pattern standard deviation components of the visual field. The larger the deviation from normal of these indices, particularly the corrected pattern standard deviation, the smaller the amplitude of the pattern electroretinogram. This correlation between the pattern electroretinogram and visual field indices provides an additional measure of confidence when interpreting equivocal results of automated perimetry.

Adult↗
PubMed1994

New drugs in clinical development in Europe.

This article deals with new antitumor agents currently in Phase I or II evaluation in various European centers. Drugs reviewed in this article include Taxotere, Camptothecin analogues, CPT-11, and Topotecan. Rhizoxin, D1694, and Bryostatin are among other agents reviewed in this article.

Antineoplastic Agents↗
PubMed1993

Increased accumulation of p53 protein in cisplatin-resistant ovarian cell lines.

We have examined p53 protein levels in cell lines selected for resistance to the chemotherapeutic drug cis-diamminedichloroplatinum (II), cisplatin. The majority of the independent cisplatin-resistant clones isolated by a single selection with cisplatin from the ovarian tumour cell line A2780 showed increased levels of p53 protein compared to the parental cell line. Elevated p53 protein levels were also observed in cisplatin-resistant ovarian human tumour lines isolated after multiple exposures to cisplatin (A2780/cp70 and OVIP/DDP). Direct PCR sequencing of p53 cDNAs showed that both the A2780/cp70 and the parental A2780 cell lines had a wild-type p53 gene sequence. The OVIP and OVIP/DDP lines both had a heterozygous mutation at codon 126. Cell-cycle analysis after gamma-irradiation or cisplatin treatment showed evidence of a G1/S and G2/M cell-cycle checkpoint in both A2780/cp70 and the sensitive parental cell lines. However, the resistant cell line A2780/cp70 showed less inhibition of DNA synthesis after gamma-irradiation than the sensitive cell line. Transfection of a mutant p53 gene construct (containing a mutation at codon 143, val to ala) into the A2780/cp70 resistant cells conferred a significantly increased sensitivity to cisplatin, suggesting that p53 is a direct determinant of cisplatin resistance in these cells. However, expression of this mutant p53 in the A2780 cells did not affect sensitivity.

Cell Cycle↗
PubMed1993

Management of malignant teratoma: does referral to a specialist unit matter?

The causes of geographical differences in cancer survival among regions of the UK are unclear. Population-based audit of management of patients with non-seminomatous germ-cell tumours (NSGCT) in the west of Scotland enabled us to assess the relative contributions to outcome of recognised prognostic factors, treatment centre, and protocol treatment. Data on treatment and outcome were analysed for 440 (97%) of 454 men with NSGCT diagnosed between 1975 and 1989. All but 11 patients were treated at tertiary referral centres; 235 were treated at a single unit (unit 1) and 194 at four other units (2-5). 99 men have died, 89 (20%) from NSGCT. Independent prognostic factors for NSGCT survival were extent of tumour at diagnosis (p < 0.001), 5-year period of diagnosis (from 1975-79 to 1985-89, p < 0.001), and treatment unit (unit 1 vs units 2-5, p < 0.001). Unit 1, which had the best survival rates, treated most patients overall (53%), including the majority (70%) in the worst prognostic category (poor-prognosis metastatic disease). The proportion of men receiving nationally agreed protocol treatment was higher at unit 1 than elsewhere (97 vs 61%, p < 0.0001). However, analysis restricted to men who received protocol treatment, adjusted for other important prognostic variables, still showed a survival advantage for this unit (relative death rate units 2-5 vs unit 1, 2.82 [95% CI 1.53-5.19], p < 0.001). These findings suggest that centralisation of treatment for NSGCT improves outcome; the benefit seems to be additional to any advantage resulting from protocol treatment.

Adult↗
PubMed1993

Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion.

N-Debenzoyl-N-tert-butoxycarbonyl-10-deacytyl taxol (Taxotere, RP 56976) is a semisynthetic analogue of taxol, prepared from a noncytotoxic precursor extracted from the needles of the European yew tree (Taxus baccata L.). It has a broad spectrum of antitumor activity against a variety of transplantable tumors in mice. In vitro cytotoxicity assays suggest that it is 2-5-fold more potent than taxol. In this phase I study Taxotere was administered by 24 h i.v. infusion at 3-week intervals. Thirty patients with solid tumors refractory to conventional therapy were treated; 70 courses of Taxotere were administered at doses ranging from 10 to 90 mg/m2. Grade 4 neutropenia and grade 3 mucositis were dose limiting but reversible at 90 mg/m2. The pattern and grade of toxicity at this dose were similar in 3 heavily pretreated patients compared with 7 patients who had received a maximum of one previous chemotherapy regimen. Alopecia occurred at 55 mg/m2 and above. Other mild toxicities included phlebitis, diarrhea, emesis, and sensory peripheral neuropathy, but these were neither dose-limiting nor clearly dose-related. One patient treated at 70 mg/m2 had an anaphylactoid reaction following the second dose of Taxotere. No cardiovascular toxicity was observed. No partial or complete responses were documented. Plasma concentrations of Taxotere were determined by high-performance liquid chromatography, and end-of-fusion levels at the maximum tolerated dose exceeded drug concentrations which are cytotoxic in vitro. The maximum tolerated dose for Taxotere administered as a 24-h infusion is 90 mg/m2.

Adult↗
PubMed1993

Phase I clinical study of LL-D49194 alpha 1 with retrospective pharmacokinetic investigations in mice and humans. The EORTC ECTG.

LL-D49194 alpha 1 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D49194 alpha 1 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.

Aged↗
PubMed1993

Co-amplification of erbB2, topoisomerase II alpha and retinoic acid receptor alpha genes in breast cancer and allelic loss at topoisomerase I on chromosome 20.

The DNA topoisomerase enzymes are targets for the cytotoxic effects of a number of anticancer agents termed topoisomerase inhibitors. We have analysed breast cancer biopsy specimens for genetic alterations at and around topoisomerase loci in order to obtain molecular insight into factors which may determine how tumours respond to chemotherapy. We show that of 50 tumours examined, the topoisomerase II alpha locus is co-amplified in 3 cases out of 6 with erbB2 amplification and that amplification can be accompanied by high expression of topoisomerase II alpha. In our attempts to distinguish amplification from aneuploidy and define the limits of amplification, we also observed co-amplification of the retinoic acid-alpha receptor with erbB2 and topoisomerase II alpha in the same three samples. At the topoisomerase I locus on chromosome 20, we observed allelic loss in two out of 17 samples. Genetics abberations at topoisomerase loci, therefore, appear to be relatively common in breast cancer.

Aged↗
PubMed1993

Oral piritrexim, an effective treatment for metastatic urothelial cancer.

Piritrexim is a lipid-soluble inhibitor of dihydrofolate reductase (DHFR) that enters tumour cells rapidly by passive diffusion, cannot be polyglutamated, and is as effective as methotrexate in inhibiting DHFR. Bioavailability after oral dosing is approximately 75%. We performed a phase II study with oral piritrexim in non-chemotherapy pretreated patients with metastatic urothelial cancer. Thirty-three patients were treated with 25 mg three times daily for 5 consecutive days, repeated weekly, with provision for dose escalation or reduction according to the toxicity observed. Of 29 evaluable patients, one patient achieved a complete response of 19+ weeks duration, and ten patients achieved a partial response with a median duration of 22 weeks (range 16-48), for a total response rate of 38%. Piritrexim was generally well tolerated, with myelosuppression as the major toxicity, that frequently required dose modification. We conclude that piritrexim appears to be an active agent in patients with metastatic urothelial cancer when administered as a 5-day, low-dose oral schedule. It would be attractive to investigate the combination of piritrexim and cisplatin.

Administration, Oral↗
PubMed1993

What have we learnt from meta-analyses in ovarian cancer?

BACKGROUND: Meta-analyses aim to provide an overview of certain key questions such as optimal chemotherapy, dose-response relationships, and factors predicting long-term survival. MATERIALS AND METHODS: A review was done of recently published meta-analyses trying to answer the above questions. RESULTS: Two studies suggest that platinum containing combination chemotherapy is superior with regard to survival. Both show the limitation of all meta-analyses with variations in terms of follow-up and in trial details, and the conclusions must be regarded as tentative. Prospective studies which have attempted to confirm the importance of cisplatin dose-intensity (as opposed to total dose) have actually failed to do so. Two meta-analyses found a strong correlation between surgical complete response and survival. In a Dutch long-term follow-up study of about 400 cases cisplatin combination, pathologically documented complete remission, optimal debulking, and grade all were associated with a significant survival benefit. The results of other analyses, suggesting that the treatment centre involved, and adherence to study protocols, are independent prognostic factors are particularly provocative. CONCLUSIONS: Recognizing their limitations, meta-analyses are intended to stimulate ideas for future trials and as such have a positive impact.

Clinical Trials as Topic↗
PubMed1993

Randomized phase II trial of iproplatin and carboplatin in advanced breast cancer. The EORTC Early Clinical Trials Group and the EORTC Data Center.

BACKGROUND: The observed activity of cisplatin in breast cancer and its unattractive toxicity profile in palliative treatment warranted further study of platinum analogues in this disease. PATIENTS AND METHODS: Sixty-two patients with recurrent or metastatic breast cancer, 61 of whom had been previously treated with chemotherapy, were randomly assigned to therapy with either iproplatin (n = 32) or carboplatin (n = 30). Both platinum analogues were administered intravenously, iproplatin at a dose of 240 mg/m2 every 4 weeks and carboplatin at a dose of 450 mg/m2 every 5 weeks. RESULTS: Only two patients responded to iproplatin (7%) for durations of 21 and 61 weeks, and one patient responded to carboplatin (3%) for a duration of 64 weeks. All responses were complete. At the given dose schedules carboplatin was more myelosuppressive than iproplatin. Non-hematologic toxicities included nausea and vomiting (93% vs. 90%), diarrhea (20% vs. 10%) and hemorrhage (16% vs. 10%) for iproplatin and carboplatin, respectively. Two patients developed alopecia with carboplatin. No renal toxicity was observed. CONCLUSIONS: Both iproplatin and carboplatin have limited activity in previously treated women with advanced breast cancer when given in conventional dosages.

Adult↗