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Biomedical subjects

R C Leonard

Publications and source records attributed to R C Leonard.

At least 19 recordsLinked to original sources
PubMed1995

Prospective randomized study of surgical morbidity following primary systemic therapy for breast cancer.

The influence of primary systemic therapy in treating operable breast cancer on postmastectomy morbidity rates was investigated. The contribution of other risk factors was assessed by multiple logistic regression. Seventy-nine eligible patients were randomly allocated, 39 to undergo immediate modified radical mastectomy, and 40 to receive initial cytotoxic or endocrine treatment followed by mastectomy. Postoperative wound seroma, infection and necrosis were recorded prospectively. Fourteen minor and six major complications occurred in 17 patients treated conventionally, while 14 patients developed 11 minor and six major complications after systemic therapy (P > 0.4). Median hospital stay was 8 days for both groups. Age, smoking, immediate breast reconstruction and the type of primary systemic treatment given were not independent predictors of complication risk. Obesity emerged as a significant risk factor for postmastectomy complications (P = 0.015). Primary systemic therapy does not increase the rate of morbidity after mastectomy.

Adult↗
PubMed1995

Chromosome 11 allele imbalance and clinicopathological correlates in ovarian tumours.

Allele imbalance on chromosome 11 loci in ovarian cancer is a frequent event, suggesting the presence of tumour-suppressor genes for ovarian carcinogenesis on this chromosome. Ten highly polymorphic (CA) repeat microsatellites were used to determine allele imbalance in 60 primary ovarian tumours, including 47 epithelial ovarian cancers (EOCs). Forty EOCs (85%) showed allele imbalance at one or more loci, and in 39 of these (83%) the data suggested subchromosomal deletions: eight of 11p only; six of 11q only; and 25 of both 11p and 11q. Three consensus regions of deletion were indicated at 11p15.5-p15.3, 11q12-q22 and 11q23.3-q24.1. Allele imbalance at the 11q subtelomeric region (D11S912) correlated significantly with adverse survival, while imbalance at 11q14.3 and retention of heterozygosity at 11q22 (close to the site of the progesterone receptor gene) were associated with favourable clinicopathological features. The findings allow development of a preliminary model for the molecular evolution of epithelial ovarian cancer.

Adenocarcinoma↗
PubMed1994

Sensitive determination of 8-chloroadenosine 3',5'-monophosphate and 8-chloroadenosine in plasma by high-performance liquid chromatography.

8-Chloroadenosine 3',5'-monophosphate (8-Cl-cAMP) is progressing through clinical evaluation as an anticancer drug. There is debate as to whether 8-Cl-cAMP is the active principal or its cytotoxic metabolite 8-Cl-adenosine. Separate high-performance liquid chromatographic methods are described for (i) 8-Cl-cAMP and its nucleotide metabolites (with 8-Br-cAMP as internal standard), and (ii) 8-Cl-adenosine. Both methods use a reversed-phase (Spherisorb ODS-2) stationary phase and a mobile phase consisting of sodium phosphate buffer (10 mM, pH 3.5) and methanol but with gradient elution for the nucleotides and isocratic elution for 8-Cl-adenosine. 8-Cl-cAMP and related nucleotides are extracted from plasma using strong anion-exchange solid-phase extraction (SPE) and 8-Cl-adenosine is extracted using reversed-phase (C8) SPE. Both techniques enabled analyses to be performed at high detector sensitivity with minimal interference. Limit of detection in plasma was 10 ng/ml for both 8-Cl-cAMP and 8-Cl-adenosine. When applied to the analysis of plasma samples from a patient treated with a low dose continuous infusion of 25 micrograms/kg/h, steady-state concentrations centred around 60 ng/ml 8-Cl-cAMP were determined. In the same patient 8-Cl-adenosine was not detected. Application of this methodology will aid in the further development of 8-Cl-cAMP as a potential new form of anticancer treatment.

2-Chloroadenosine↗
PubMed1994

Chemotherapy prolongs survival in inoperable pancreatic carcinoma.

Forty-three patients with irresectable advanced pancreatic cancer were randomized to receive chemotherapy using a combination of 5-fluorouracil, Adriamycin and mitomycin or no chemotherapy. Groups were well matched with regard to age, extent of disease and performance status on entry. Chemotherapy was well tolerated and, although common, side-effects were usually mild. Psychological measurements based on the Hospital Anxiety and Depression score were made in 31 patients. These showed significantly less depression but not anxiety in the treated group immediately after randomization and following 2 months of chemotherapy. Median survival in the treated group was 33 (range 9-80) weeks compared with 15 (range 1-62) weeks in the untreated group (P < 0.002). Chemotherapy should be considered in all patients presenting with advanced inoperable pancreatic cancer.

Adult↗
PubMed1994

Continuous 5-fluorouracil in the treatment of breast cancer.

Prolonged infusions of 5-fluorouracil (5-FU) have been used since the early 1960s, but recently there has been a major resurgence of interest, partly because of the advent of electronically controlled portable infusion pumps. This paper looks at the published data on continuously infused 5-FU in breast cancer. As a single agent, bolus 5-FU has a response rate of around 25%; this includes many patients in older series who were chemotherapy naive. The overall response rate across all the studies with continuously infused 5-FU is 29%. However, the majority of these patients were heavily pretreated, and response rates of up to 54% have been reported. What is more encouraging is the response rate in combination chemotherapy--even for pretreated patients with metastatic disease, response rates up to 89% have been found. However, this level of benefit brings a new toxicity--palmar--plantar erythrodysaesthesia; and of course myelotoxicity still remains a problem in the combination regimens. Randomised trials to assess the role of infusional 5-FU are now indicated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Can long-term survival be improved in patients with small-cell lung cancer (SCLC) and good performance status? Medical Research Council Lung Cancer Working Party.

Results from a long-term follow-up suggest that in patients with limited small-cell lung cancer (SCLC) and normal performance status intensive alternating chemotherapy and radiotherapy improve long-term survival rates. In a non-randomised study, 22 patients with SCLC of limited extent and good performance status were prescribed six cycles of etoposide, doxorubicin, cisplatin and cyclophosphamide at 4 week intervals with doses of thoracic radiotherapy following the second, third and fourth cycles. Although only six patients received all their prescribed treatment, nine (41%) were alive at 1 year, seven (32%) at 2 years, six (27%) at 3 years, and four are still alive at, respectively, 42, 47, 50, and 61 months, all four being in the subgroup of eight patients with WHO performance status grade 0 at the start of treatment. In a comparison with similar patients receiving conventionally scheduled chemotherapy and radiotherapy in a concurrent trial, no difference in survival was seen in the patients with performance status grade 1 or 2, but a large difference in favour of the alternating schedule in those with grade 0 status was seen. We encourage other investigators to report the results achieved with intensive treatment in patients with WHO grade 0 performance status at the start of treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo-controlled randomized trial.

PURPOSE: To evaluate the effect of quinidine, a putative modulator of P-glycoprotein-mediated drug resistance, on the response rate and toxicity profile of epirubicin in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1989 and 1992, 223 eligible patients were randomized in double-blind fashion to receive epirubicin 100 mg/m2 by intravenous (i.v.) bolus and prednisolone 25 mg orally twice daily, along with either placebo or quinidine (250 mg) capsules, taken for 4 days before and 2 days after chemotherapy. Treatment was continued for a maximum of eight courses. RESULTS: Ten eligible patients did not complete the first cycle of treatment. Of the remaining patients, 106 in the placebo arm received 619 courses of treatment, and 107 in the quinidine arm received 612 courses. The median cumulative dose of epirubicin in both arms was 600 mg/m2. The median quinidine level (measured before epirubicin administration in 288 courses) was 5.5 mumol/L; at this concentration, the drug partially reverses anthracycline resistance in multidrug-resistant (MDR) breast carcinoma cells in vitro. There were no statistically significant differences in hematologic or gastrointestinal toxicity between the two arms. The response rate in the placebo arm was 44% (6% complete remission [CR], 38% partial remission [PR]), and in the quinidine arm was 43% (4% CR, 39% PR). Surviving patients have been monitored for a median time of 74 weeks, and there is no significant difference in the overall or progression-free survival between the two arms. The median survival times were 59 weeks for placebo and 47 weeks for quinidine patients. The estimated relative death rate (quinidine/placebo) was 1.2 (P = .247; 95% confidence interval [CI], 0.88 to 1.63). CONCLUSION: Quinidine at this dose does not significantly alter the toxicity profile, response rate, or survival after epirubicin chemotherapy in patients with advanced breast cancer. This may be due to ineffective modulation of P-glycoprotein by quinidine or the lack of expression of mdr-1 in a sufficient proportion of cells in these tumors, or alternative mechanisms underlying resistance to epirubicin.

Adult↗
PubMed1993

Successful application of a previously derived prognostic index in the analysis of a randomised trial of 281 patients with high grade non-Hodgkin's lymphoma (HIGNHL).

BACKGROUND: The selection of patients for experimental therapies for high grade non-Hodgkin's lymphoma (NHL) is now recognised to be very influential in affecting results. We showed previously that simple clinical indices could be used to create an index of risk of death in a series of 972 patients. We wished to test this prognostic index in a subsequent randomised treatment trial of CHOP-based chemotherapy. PATIENTS AND METHODS: 281 patients with high grade NHL randomised between two chemotherapy designs were followed up from 1-6 years and survival analysed to develop a Cox model which was then compared against the previously described prognostic index. RESULTS: The previous index based on age, sex, performance status, stage and symptoms was similar to the data-derived model. Three year survivals for the best (109), intermediate (93) and worst (79) cohorts were 69%, 50% and 24% respectively, similar to the survivals in the previous series. CONCLUSIONS: CHOP-based chemotherapy is probably adequate for around 40% of cases of high grade NHL. The prospective test of a prognostic index shows that we can be confident about selecting poor-risk patients for trials of novel therapies, including dose intensification.

Aged↗
PubMed1993

Serological markers for metastatic breast cancer.

Three serum markers, TPS, CA 15.3 and CEA, were used to monitor the response to treatment of 20 patients with metastatic breast cancer. At the time of the first evidence of metastases or at the time of progression of known metastatic disease, 84% of TPS values were above the reference limit, as compared to 74% for CA 15.3 and 84% for CEA. If the treatment instituted was effective, 60% of TPS values showed an early (within 2 or 3 weeks after commencement or change of therapy) reduction in level against only 27% of CA 15.3 and 27% of CEA levels. This suggests that TPS provides a more sensitive and earlier predictor of therapeutic response. In patients with clinical evidence of further progression of disease while on therapy, 86% of TPS values showed persistent elevation or increase, as compared to 71% of CA 15.3 levels and only 36% of CEA levels. It was also noted in these patients that TPS values rose earlier than either CA 15.3 or CEA. This indicates that TPS is a more reliable predictor of response to treatment than the other two markers. In addition, we found that, at the time of presentation, in women who had visceral metastases (liver, lung, or brain alone or in combination), 87% of TPS values were raised, as compared to 80% of CA 15.3 and 73% of CEA values. In women who had bone and soft tissue metastases at presentation, 75% of TPS values were elevated, against 50% of CA 15.3 and 75% of CEA values.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1993

Pilot study and randomised trial of mitozantrone and ifosfamide for relapsed non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma group (SNLG) Working Party on Therapy.

This report compares a pilot study followed by a trial of the combination of mitozantrone and ifosfamide for relapsed lymphoma. In the pilot study (15 patients) toxicity and activity of the combination was tested on a variety of relapsed non-Hodgkin's lymphoma. In the trial (19 patients) the therapy was confined to patients with high and intermediate grade non-Hodgkin's lymphoma in which the combination was compared against single agent mitozantrone. The median survival of patients on the pilot and trial was very poor at around six months, but some individuals survived for several years from both groups. The main toxicities of treatment were, predictably, nausea and vomiting and bone marrow suppression on the combination, and bone marrow suppression alone on the single agent mitozantrone. There was no obvious disadvantage of the single agent treatment when compared with the combination, but this statement has to be interpreted with caution given the high death rate amongst all patients and the very small numbers who entered the randomised trial.

Adult↗
PubMed1992

A phase I and pharmacology study of GR63178A, a water-soluble analogue of mitoquidone.

GR63178A is a water-soluble analogue of mitoquidone, a pentacyclic pyrroloquinone. This group of drugs exhibit a novel structure and activity against several murine solid tumours and xenografts. In the present phase I study the toxicity and pharmacokinetics of GR63178A given on 5 consecutive days of a 21-day cycle were examined. A total of 24 patients presenting with a wide range of tumours were treated at 5 doses escalated to reach the maximal tolerated dose (MTD). Linear pharmacokinetics was documented over the dose range studied, and there was no difference in parent drug handling between day 1 and day 4 of dosing. A number of metabolites were detected. The toxicity profile was unusual in that pain occurred in 20/24 patients, most often at the site of known disease. This was the dose-limiting toxicity. Other side effects included nausea and vomiting (23/24), phlebitis at the infusion site (6/24) and headache (7/24). No treatment response was seen in this study. The MTD was demonstrated to be 160 mg/m2 daily (total, 800 mg/m2 per treatment cycle). The drug has now entered phase II trials at 120 mg/m2 daily x 5, repeated every 21 days.

Adult↗