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Biomedical subjects

R C Leonard

Publications and source records attributed to R C Leonard.

At least 73 records · Page 4Linked to original sources
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

p53 mutation is a common genetic event in ovarian carcinoma.

Using the single-strand conformational polymorphism technique, we have screened 66 malignant ovarian tumors for p53 mutation in exons 5 to 8. Thirty-four of the tumors demonstrated a single-strand conformational polymorphism band shift in this region of the gene, including 6 in exon 5, 7 in exon 6, 12 in exon 7, and 10 in exon 8 (one of the tumors showed a shift for exons 7 and 8). All of the single-strand conformational polymorphism shifts have been further characterized by DNA sequencing, and 31 of 35 have been shown to represent genuine DNA alterations. These include 27 point mutations (23 missense, 2 nonsense, and 2 silent mutations), 3 deletions (a 2-base pair deletion introducing, by frameshift, a stop codon further downstream; a 3-base pair deletion; and an unusual 6-base pair deletion made up of separate 2-base pair and 4-base pair deletions), and a 4-base pair insertion (introducing a stop codon downstream). In total, 29 of the 66 (44%) carcinomas analyzed had mutations affecting the primary sequence of the p53 protein. p53 mutation was found in tumors of all International Federation of Gynecologists and Obstetricians stages, suggesting that it might be an earlier genetic event in the progression of epithelial ovarian tumors than previously thought. A significantly greater number of p53 mutations were seen in high-grade serous carcinomas than in those of endometrioid and mucinous types (0.02 > P > 0.01). Analysis of the distribution of point mutations showed no preference for any particular mutation type.

Base Sequence↗
PubMed1993

The value of the human milk fat globule membrane antigen HMFG2 in epithelial ovarian cancer monitoring: comparison with CA125.

We assayed serum HMFG2 in serial samples from 215 primary epithelial ovarian cancer patients using an 'in-house' single determinant ELISA, 45% of patients with stage I, 54% with stage II, 61% with stage III and 75% with stage IV disease had elevated serum HMFG2. Post-operative levels were significantly related with residual tumour volume (P < 0.005), and fell in the majority of responders, although the association with response to first-line chemotherapy was not significant. HMFG2 had a sensitivity of 50% specificity of 83%, accuracy of 61%, PVP of 86% and PVN of 45% for disease at second-look laparotomy. Serial levels gave a lead time to clinical relapse in 47% of patients who responded to therapy, including one patient with negative CA125 levels. HMFG, paralleled CA125 in many respects, although it was elevated in fewer patients. In a stepwise discriminant analysis, HMFG2 added to the discrimination of CA125 (r = 0.183, P < 0.005), although additional accurate information was only given in patients with advanced poorly differentiated serous cystadenocarcinoma. Given that HMFG2 is expressed in few patients who are CA125 negative it is unlikely that it will have a significant clinical impact upon patient management.

Antibodies, Monoclonal↗
PubMed1993

The prognostic value of early CA125 serum assay in epithelial ovarian carcinoma.

We examined the prognostic value of early serum CA125 assay in 58 patients with advanced epithelial ovarian cancer together with residual disease, age, tumour grade, performance status, and the presence of ascites or adhesions at primary surgery. CA125 was a highly significant predictor of both progression free and overall survival after the first cycle and throughout primary chemotherapy. After the first cycle, CA125 was by far the most significant predictor of progression free survival (P < 0.0005). At this time, CA125 was a highly significant predictor of survival (P < 0.005), but did not add to performance status (P < 0.001) in multivariate analysis. We were able to identify three statistically-distinct prognostic groups. Patients in the upper quartile, with CA125 levels greater than 450 U ml-1, had a very poor median survival of 7 months. Patients in the lower quartile, with CA125 levels less than 55 U ml-1 had a good median survival of 23 months. Those in the two interquartile groups, who had CA125 levels ranging from 58-221 U ml-1 and 228-434 U ml-1, had relatively intermediate median survival times of 16 months and 15 months respectively. Although CA125 levels provided significant prognostic information, in the majority of patients CA125 merely confirmed overall clinical impression.

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

An assessment of the clinical usefulness of two serum markers, CA15 3 and HMFG 2 in localized and metastatic breast cancer.

CA 15 3 is a circulating glycoprotein defined by two monoclonal antibodies (115 D 8 and DF 3) with good specificity for breast cancer. Tumour-associated antigens have been detected by the monoclonal antibody HMFG 2 using a low pH ELISA method. We compare the values obtained using these two assays in patients with localized and metastatic breast cancer. CA 15 3 and HMFG 2 levels were measured in 61 patients, 24 localized and 37 metastatic, evaluated by standard biochemical and radiological testing. Of the patients with metastatic disease 78.4 per cent had an elevated CA 15 3 level whereas only 8.3 per cent of patients with localized disease had an elevated level (chi 2 = 28.2 p = 0.001); 29.8 per cent of patients with metastatic disease had elevated HMFG 2 levels while among those with localized disease 16.7 per cent had elevated levels (chi 2 = 0.57 p = NS). We conclude that only CA 15 3 is a useful marker in advanced disease.

Adult↗
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↗
PubMed1993

Identification of prognostic groups in follicular lymphoma. The Scotland and Newcastle Lymphoma Group Therapy Working Party.

Follicular lymphoma is often seen as an indolent disease with a reasonable medium-term survival. We have used the information in the Scotland and Newcastle Lymphoma Group database to devise an index which is easily calculated and differentiates patients into poor, intermediate and good prognostic groups with 5 years survivals of 24%, 61% and 86% respectively. The key factors at presentation are age, ECOG performance status, stage and the presence or absence of B symptoms or gastro-intestinal tract involvement. The use of such an index permits early identification of patients with a poor prognosis for whom more intensive treatment could be offered.

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↗