Biomedical subjects

J F Bishop

Publications and source records attributed to J F Bishop.

At least 73 records · Page 4Linked to original sources

PubMed1993

Characterization of a corticotropin releasing hormone responsive region in the murine proopiomelanocortin gene.

The most potent, physiologic activator of proopiomelanocortin (POMC) gene transcription is corticotropin releasing hormone (CRH) and increased intracellular cAMP is critical for this effect. The 5'-flanking region of the murine POMC gene has several potential binding sites for regulatory proteins. To characterize the region between nucleotides -141 and -106, which includes a TRE-like site and an adjacent AP-2 consensus sequence, and to study its role in signal-transcription coupling, gel mobility shift assays and transient expression of CAT chimeras were performed. In transient transfections of AtT-20 cells with pCATp-141/-106, CRH treatment led to significant increases in CAT expression compared with CRH treatment of cells transfected with the enhancerless vector. However, no response to direct activation of cAMP dependent protein kinase or protein kinase C was detected. Despite the high homology of the sequence -137/-131 to the consensus AP-1 binding site (TRE), the nuclear factor(s) in AtT-20 cells binding to this region appears to be different than authentic AP-1 since neither a competitor oligonucleotide having the authentic TRE sequence nor antibodies against Jun or Fos affected the gel shift pattern of a probe having the -137/-131 sequence. We conclude that the -141 to -106 region of the murine POMC gene contains a functional CRH responsive element and that second messenger systems that transduce the CRH signal to this element do not exert their actions solely through activation of PKA or PKC.

Animals↗

PubMed1993

Oral methotrexate for superficial transitional cell carcinoma of the bladder.

A total of 22 patients with superficial transitional cell carcinoma of the bladder, uncontrolled cystoscopically and unsuitable for or having failed intravesical therapy, received 50 mg. oral methotrexate per week for 12 months. Of the patients 7 (32%) achieved or remained in complete remission and 5 achieved a partial response, while 4 remained stable, 3 had progression and 3 were not evaluable. Patients who were still alive had a median followup of 2.5 years. Two patients with complete remission had relapse at 16 and 26.4 months, and 5 were disease-free at 34.5, 31.3, 18.6, 17.8 and 16.8 months, respectively. The methotrexate was generally well tolerated but 2 patients discontinued therapy because of dyspnea (1 subsequently died of respiratory failure that was possibly related to the methotrexate) and 1 because of persistent grade 2 mucositis. Grade 3/4 toxicities occurred in 3 patients: 1 each with reversible increases in creatinine and aspartate aminotransferase, and 1 with gastric bloating. There was little hematological toxicity. Reversible skin lesions developed in 4 patients. This oral treatment may provide an effective alternative to intravesical therapy but can be associated with severe toxicity.

Administration, Oral↗

PubMed1993

The effect of danazol on tumour control and weight loss in patients on tamoxifen therapy for advanced breast cancer: a randomised double-blind placebo controlled trial.

To assess the effect of danazol in advanced breast cancer 183 patients were randomised to receive either tamoxifen plus danazol or tamoxifen plus placebo. Patients underwent systemic work-up pretreatment then every 12 weeks or sooner if they clinically progressed. There were no differences in objective response rates with tamoxifen plus danazol vs. tamoxifen plus placebo (27% vs. 24%), time to progression (median 6.4 vs. 6.2 months) or survival (median 22.6 vs. 23.5 months) when the two arms were compared (all P > 0.5). The addition of danazol to tamoxifen had no effect on time to progression when adjusted for significant prognostic factors in a multivariate analysis. However, it was found incidentally that weight was stable on tamoxifen plus danazol (average gain 0.6 kg, S.E. 0.6 kg) compared with a significant loss on tamoxifen plus placebo (average loss 2.0 kg, S.E. 0.6 kg, P = 0.003). The average weight was maintained on tamoxifen plus danazol even in patients who did not respond to treatment.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

A phase I and pharmacokinetic study of 12-h infusion of flavone acetic acid.

This phase I study investigated flavone acetic acid (FAA) given as a 12-h intravenous infusion every 3 weeks in the absence of urinary alkalinisation. Cohorts of three patients were treated at doses of 7, 10 and 13 g/m2. One subject had colon cancer; 5, renal cancer; and 3, lung cancer. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in four patients, 1 in two subjects and 2 in three cases. The maximum tolerated dose was 13 g/m2. The dose-limiting toxicities were WHO grade 3 hypotension and grade 3 diarrhoea. Other toxicities included lethargy and dizziness, nausea, temperature fluctuation, myalgia and dry mouth, but no significant myelosuppression was encountered. One patient receiving 10 g/m2 for renal cancer showed a partial response that lasted for 3 months and included the resolution of pulmonary and cutaneous metastases. The pharmacokinetics showed large interpatient variability. At 12-16 h post-infusion, the plasma elimination profile entered a plateau phase, with frequent increases in concentration suggesting enterohepatic recycling. Neither peak FAA levels nor AUC values were dose-dependent at the doses studied. Peak plasma levels were 101-402 micrograms/ml and AUC (0-48 h) values were 75-470 mg ml-1 min. Plasma protein binding varied with total concentration. Two metabolites were detected in the plasma, and both also underwent apparent enterohepatic recycling. Repeat dosing resulted in decreases of up to 48% in peak levels and AUC values for FAA in three of six patients. Of the total FAA dose, 39%-77% was excreted in the urine as FAA or metabolites within 2 days. The dose recommended for further phase II studies is 10 g/m2.

Adult↗

PubMed1992

A randomised double-blind study of high-dose intravenous prochlorperazine versus high-dose metoclopramide as antiemetics for cancer chemotherapy.

High-dose prochlorperazine 0.8 mg/kg administered intravenously 30 min pre and 7 h 30 min post the initial dose of emetogenic chemotherapy was compared to high-dose metoclopramide 2 mg/kg over 20 min every 2 h for five doses starting 30 min prior to chemotherapy in a randomised, double-blind, parallel subjects design study. On the prochlorperazine arm intravenous dextrose placebos every 2 h maintained blinding. Complete suppression of vomiting occurred in 42% on metoclopramide (53% with non-cisplatin regimens) and 36% on prochlorperazine (52% with non-cisplatin-containing regimens) while major responses (2 or less vomits) occurred in 58% on metoclopramide and 54% on prochlorperazine. In patients who vomited after cisplatin, prochlorperazine achieved a significantly shorter duration of vomiting, a median of 5 h compared to 15 h on metoclopramide (P = 0.03). The response rate to prochlorperazine for cisplatin-induced emesis between 12 and 24 h was significantly better than for metoclopramide (prochlorperazine = 0.02). Toxicities were equivalent except for significantly greater sedation and dry mouth on prochlorperazine. Extrapyramidal reactions were recorded equally on both arms but were only severe enough to stop treatment on metoclopramide. The metoclopramide regimen was five times as expensive as prochlorperazine. High-dose prochlorperazine is an active and cost-effective antiemetic.

Adolescent↗

PubMed1992

A randomised trial of dexamethasone, lorazepam and prochlorperazine for emesis in patients receiving chemotherapy.

To define further the place of dexamethasone in antiemetic combinations, lorazepam, prochlorperazine and placebo (LP) were compared with lorazepam, prochlorperazine and dexamethasone (DLP) in a randomised, double-blind, crossover study. Both patient and observer assessments were documented in 84 patients receiving both cisplatin and non-cisplatin chemotherapy. The addition of dexamethasone significantly reduced the severity of nausea (P = 0.002) and vomiting (P less than 0.0001), duration of nausea (P = 0.01) and vomiting (P = 0.002) and the number of vomiting episodes (P = 0.003). DLP was the superior regimen in subsets of patients receiving cisplatin and the non-cisplatin chemotherapy. The improvements produced by the dexamethasone regimen were large and of major benefit to our patients. Patients documented significantly improved tolerance to chemotherapy with DLP courses (P = 0.0006). Overall, significantly more patients preferred DLP (P less than 0.0001). Patient assessments produced results similar to observer assessments but gave a broader understanding of their experience. The addition of dexamethasone to prochlorperazine and lorazepam significantly improved our patients' experience while receiving chemotherapy.

Adult↗

PubMed1992

The cost of breast cancer recurrences.

Information about the costs of recurrent breast cancer is potentially important for targeting cost containment strategies and analysing the cost-effectiveness of breast cancer control programmes. We estimated these costs by abstracting health service and consumable usage data from the medical histories of 128 patients, and valuing each of the resources used. Resource usage and costs were summarised by regarding the recurrence as a series of episodes which were categorised into five anatomical site-based groups according to the following hierarchy: visceral, central nervous system (CNS), bone, local and other. Hospital visits and investigations comprised 78% of total costs for all episodes combined, and there were significant differences between the site-based groups in the frequency of hospital visits and most investigations. Total costs were most accurately described by separate linear regression models for each group, with the natural logarithm of the cost of the episode as the dependent variable, and predictor variables including the duration of the episode, duration squared, duration cubed and a variable indicating whether the episode was fatal. Visceral and CNS episodes were associated with higher costs than the other groups and were more likely to be shorter and fatal. A fatal recurrence of duration 15.7 months (the median for our sample) was predicted to cost $10,575 (Aus + 1988; or 4,877 pounds). Reduction of the substantial costs of recurrent breast cancer is likely to be a sizable economic benefit of adjuvant systemic therapy and mammographic screening. We did not identify any major opportunities for cost containment during the management of recurrences.

Adult↗

PubMed1992

A phase II study of cisplatinum and continuous infusion 5-fluorouracil for metastatic melanoma.

Advanced or metastatic melanoma responds poorly to chemotherapy, which has no impact on survival. Responses have been recorded using cisplatinum as a single agent. This study tested the established combination of cisplatinum 100 mg/m2 and 5-fluorouracil 1 g/m2/day continuously intravenously for 5 days repeated every 3 weeks in patients with disseminated melanoma. Twenty-nine patients, 13 having received no prior systemic chemotherapy, received 49 cycles of therapy (median 1, range 1-4). Only one previously untreated patient achieved a partial response with a failure-free survival of 6.5 months and an overall survival of 7.7 months from the commencement of therapy. The major toxicities were nausea and vomiting, (grade 3 in eight patients), stomatitis (grade 4 in two patients, grade 3 in two patients), and myelosuppression. The study showed that cisplatin and 5-fluorouracil have a low order of activity in patients with advanced or disseminated melanoma.

Adult↗

PubMed1992

The definition of refractoriness to platelet transfusions.

The relationship between the 1 and 20 h post-transfusion platelet count and three parameters used to define refractory transfusions, namely the corrected increment (CI), platelet increment (PI), and percentage platelet recovery (%REC), was studied in 437 non-HLA matched platelet transfusions given to 102 patients with bone marrow failure. The percentage agreement between common definitions of refractoriness was calculated based on these parameters. As the maintenance of platelet counts above 20 x 10(9)/l is a relevant clinical goal for platelet support, the values of the CI, PI and %REC, which best corresponded to 1- and 20-h post-transfusion counts of 20 x 10(9)/l, were identified. A 1-h post-transfusion CI < 3 (PI < 7 x 10(9)/l or % REC < 8%) corresponded to clinically unsuccessful transfusions with a 1-h platelet count < 20 x 10(9)/l. A 1-h CI > or = 5.5 (PI > or = 12 x 10(9)/l or %REC > or = 14%) corresponded to clinically successful transfusions with a 20-h post-transfusion count of > or = 20 x 10/l. These data tie together the end points reported in the literature for defining refractory transfusions.

Blood Platelets↗

PubMed1992

Symptomatic choroidal metastases in breast cancer.

A series of 21 consecutive patients with carcinoma of the breast and symptomatic choroidal metastases was reviewed. All patients were symptomatic of choroidal metastases at presentation. Most patients had disease progression at other sites at the time of diagnosis. The incidence of cerebral metastases was not increased in this group compared to that in patients with metastatic breast cancer at other sites. Radiotherapy using a direct anterior field proved effective palliation for this disease site. Of the 32 eyes treated, serial visual acuity was documented in 23. Seventeen showed objective improvement and six showed stabilisation. The median duration of improvement was 11.5 months.

Adult↗

PubMed1992

Carboplatin/etoposide in small cell lung cancer.

Carboplatin/etoposide is an active combination in small cell lung cancer. In phase II studies, it produces results that appear equivalent to cisplatin/etoposide, but it has not been compared in a randomized study. It has a better toxicity profile than cisplatin/etoposide when compared in non-small cell lung cancer. The combination of carboplatin/etoposide is very well tolerated by elderly patients. Carboplatin/etoposide lacks important nonhematologic side effects, which has led to its assessment in dose escalation studies with colony-stimulating factors and autologous bone marrow transplantation.

Aged↗

PubMed1992

Carboplatin-containing regimens for small cell lung cancer: implications for management in the elderly.

The efficacy and toxicity of two regimens based on etoposide/carboplatin with or without cyclophosphamide/vincristine in the management of small cell lung cancer (SCLC) were assessed by the Australian Lung Cancer Study Group. Response rates of 77% and 85% were noted for the two- and four-drug regimens, respectively, among patients with limited disease (LD). Response rates among patients with extensive disease (ED) were 58% and 79%, respectively. The profiles of nonhematologic toxicity were modest; myelosuppression was dose-limiting when colony-stimulating factors were not used. Twenty-six patients (14%) were older than 70 years of age. Although hematologic toxicity was more severe in the elderly group, there was no significant difference in nonhematologic toxicity, response rate, or overall survival between the geriatric and younger groups. When LD only was considered, 33% of those younger than 70 were alive at 2 years; no patients aged 70 years or older with LD were alive beyond 2 years. In patients with ED, there was no age-related difference in survival. Cytotoxic regimens based on etoposide/carboplatin constitute useful treatment for SCLC, with high response rates and manageable toxicity, irrespective of patient age.

Adult↗

PubMed1992

Current experience with high-dose carboplatin therapy.

Carboplatin is well suited to dose escalation because its major dose-limiting toxicity is myelosuppression when given in 1,200 mg/m2 doses without marrow support. Repeated 800 mg/m2 doses can be given in an investigational setting. With autologous bone marrow rescue the maximum tolerated single-agent dose is approximately 1.8 to 2 g/m2, with dose-limiting toxicities being hepatitis, renal dysfunction, and ototoxicity. Combinations of carboplatin with other agents plus bone marrow rescue are now being investigated in germ cell tumors, ovarian cancer, breast cancer, and small cell lung cancer. High-dose carboplatin plus etoposide combinations are being evaluated with colony-plus stimulating factors in an effort to ameliorate myelosuppression. Future high-dose carboplatin studies could be designed with more predictable toxicity, using an assessment of carboplatin renal clearance. Carboplatin is an important new drug warranting further investigation at escalated doses.

Animals↗

PubMed1992

Etoposide in the treatment of leukemias.

Etoposide (VP16-213), a topoisomerase II inhibitor, has produced complete responses in 17% of previously treated patients with acute nonlymphocytic leukemia (ANLL) but has little activity in acute lymphoblastic leukemia. As salvage therapy for relapsed ANLL etoposide produces 28% complete responses in combination with amsacrine, 49% with 5-azacytidine, and 51% with anthracycline. It has been successfully combined with high-dose cytarabine as a salvage treatment. In a randomized trial in previously untreated patients with ANLL, etoposide significantly prolonged remission duration. Etoposide has been used to intensify postinduction therapy with or without bone marrow rescue, but its exact role in that setting has not been clarified. Because of its schedule dependency in other tumors, etoposide should be investigated using different schedules in ANLL.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

A phase II trial of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisolone rapidly alternating with doxorubicin and vincristine (CMFP/AV) in advanced breast cancer.

Sixty-seven patients with advanced breast cancer were prospectively entered into a Phase II trial of cyclophosphamide 100 mg/m2 orally on days 1-14, methotrexate 40 mg/m2 intravenously (i.v.) on day 1, 5-fluorouracil 600 mg/m2 i.v. on day 1, and prednisolone 40 mg/m2 orally on days 1-14 (CMFP) rapidly alternating with doxorubicin 25-30 mg/m2 i.v. on day 8 and vincristine 1.4 mg/m2 i.v. on day 8 (AV). Complete responses (CR) were seen in 7 patients, partial responses (PR) in 25 (CR + PR, 48%), stable disease in 24, and progressive disease in 9. The median time to disease progression was 9.8 months, and the median survival 19.4 months. Neutropenia was the major toxicity with WHO grade 3 or 4 neutropenia in 50% of patients. CMFP/AV is a well-tolerated, effective regimen in advanced breast cancer but does not appear to be superior to CMFP alone.

Adult↗

PubMed1991

High-performance liquid chromatographic method for the determination of toremifene and its major human metabolites.

A high-performance liquid chromatographic method has been developed for the measurement of toremifene and its major human metabolites in plasma and urine. We have simplified other published methods, such that our assay uses protein precipitation in place of organic extraction, and ultraviolet detection instead of photochemical activation followed by fluorescence detection. In a stability study toremifene and metabolites remained unchanged for up to seven weeks at -70 degrees C. This simple and specific assay allowed toremifene and three metabolites to be quantitated for pharmacokinetic analyses in a high-dose Phase I trial.

Chromatography, High Pressure Liquid↗

PubMed1991

Etoposide in leukemia.

Etoposide (VP16-213, NSC 141540) induces a complete response (CR) in 15% to 25% of previously treated patients with acute nonlymphocytic leukemia (ANLL) when used as a single agent. Etoposide has been used successfully in combination with cytarabine, daunorubicin, and amsacrine for salvage and consolidation therapies. Previously untreated ANLL patients 15 to 70 years of age were randomly assigned to cytarabine (100 mg/m2) on days 1 to 7 plus daunorubicin (50 mg/m2) on days 1 to 3 (7-3) or to the same drugs plus etoposide (75 mg/m2) on days 1 to 7 (7-3-7). Patients achieving a CR received two consolidation courses (5-2, attenuated 7-3 or 5-2-5). Among 264 eligible patients, there was a 56% CR rate with 7-3 therapy and a 59% CR rate with 7-3-7 therapy. Remission duration was significantly improved with 7-3-7 (median, 12 months with 7-3 and 18 months with 7-3-7; P = 0.01), but survival was not. Subset analysis in patients younger than 55 years of age revealed prolonged remission (median, 12 months with 7-3 and 27 months with 7-3-7; P = 0.01) and survival (median, 9 months with 7-3 and 17 months with 7-3-7; P = 0.04) with the 7-3-7 regimen. Hematologic toxicity was similar for both regimens during induction, but significantly more severe for 7-3-7 during consolidation therapy. Etoposide is active in ANLL and prolongs remission when used in induction therapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Factors influencing 20-hour increments after platelet transfusion.

The 20-hour posttransfusion platelet count determines transfusion policy for patients requiring platelet support, and yet factors influencing the 20-hour count have been poorly defined. The clinical factors influencing both the 1- and 20-hour corrected count increment (CCI), were studied in 623 human leukocyte antigen (HLA)-unmatched platelet transfusions in 108 patients. The 1- and 20-hour CCIs were highly correlated (r = 0.67, p less than 0.001). On average, the 20-hour CCI was 64 percent of the 1-hour CCI. Multiple linear regression analyses identified splenectomy, bone marrow transplantation, disseminated intravascular coagulation, administration of amphotericin B, palpable spleen, and HLA antibody grade as the major factors influencing the 20-hour posttransfusion CCI. Platelet-specific antibodies, number of concurrent antibiotics, clinical bleeding, and temperature did not significantly influence the 20-hour posttransfusion CCI. The 1-hour CCI was the only significant factor influencing the 20-hour CCI in a regression model containing the 1-hour CCI and the above factors. Thus, the same clinical factors exert a major influence on the CCI at both 1 and 20 hours after platelet transfusion, with no evidence that any factor has more influence at 20 hours after transfusion than at 1 hour.

Blood Platelets↗