PubMed Health⌕ Search

Biomedical subjects

G F Fleming

Publications and source records attributed to G F Fleming.

At least 19 recordsLinked to original sources
PubMed2004

Invariant p53 immunostaining in primary and recurrent breast cancer.

In animal models, acquired mutations of the p53 gene that result in increased p53 protein expression are associated with tumour recurrence following chemotherapy. The aim of this study was to test the hypothesis that breast cancer recurrences following adjuvant therapy exhibit aberrant p53 expression. We therefore evaluated p53 expression in paired primary and recurrent breast tumours: 48% of primary and 32% of recurrent tumours had abnormally increased p53 expression. Of the paired samples, 84% showed no change in p53 expression between the primary tumour and the metastasis. In fact, in no case was low (normal) p53 expression in the primary tumour followed by the development of high (aberrant) p53 expression in the recurrence. These results show that increased p53 expression is not selected for in the malignant cells emerging following adjuvant therapy, suggesting that p53 expression is unlikely to play a central role in breast cancer recurrences.

Adult↗
PubMed2004

Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study.

BACKGROUND: This study was performed to determine whether 24-h paclitaxel plus doxorubicin and filgrastim was superior to cisplatin plus doxorubicin in patients with endometrial cancer with respect to response, progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Eligible chemotherapy-naïve patients were randomly assigned to doxorubicin 60 mg/m2 intravenously (i.v.) followed by cisplatin 50 mg/m2 i.v. (arm 1, n=157) or doxorubicin 50 mg/m2 i.v. followed 4 h later by paclitaxel 150 mg/m2 i.v. over 24 h plus filgrastim 5 microg/kg on days 3-12 (arm 2, n=160). Starting doses were reduced for prior pelvic radiotherapy and age > 65 years. Both regimens were to be repeated every 3 weeks for a maximum of seven cycles. RESULTS: There was no significant difference in response rate (40% versus 43%), PFS (median 7.2 versus 6 months) or OS (median 12.6 versus 13.6 months) for arm 1 and arm 2, respectively. Toxicities were primarily hematological, with 54% (arm 1) and 50% (arm 2) of patients experiencing grade 4 granulocytopenia. Gastrointestinal toxicities were similar in both arms. CONCLUSIONS: Doxorubicin and 24-h paclitaxel plus filgrastim was not superior to doxorubicin and cisplatin in terms of response, PFS or survival in advanced endometrial cancer.

Aged↗
PubMed2003

The separation of codeine from nonprescription combination analgesic products.

In the United Kingdom number of products containing codeine in combination with nonopioid analgesics are available from pharmacies for purchase without a prescription. These products may be abused and it has been reported that in order to avoid nonopioid toxicity, some users may attempt to separate the components of combination analgesics, by mixing the dosage form in water and passing it through a coffee filtration apparatus (coffee filters). The present research sought to test the ease of separation of products available in the United Kingdom. The results obtained indicated that separation was possible; however, the extent of separation was influenced by the volume of water used and the product chosen. Healthcare professionals must be aware that separation may be attempted by those wishing to abuse codeine; however, significant nonopioid toxicity could still arise in the abuser.

Analgesics↗
PubMed2003

Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction.

BACKGROUND: Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice. PATIENTS AND METHODS: Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but < or =3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin > or =5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m(2). 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m(2), and plasma concentrations were measured every 3 h during the first two infusions for each patient. RESULTS: Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m(2) produced dose-limiting toxicity (DLT) in six of 20 evaluable patients. These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance. CONCLUSIONS: Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m(2) with leucovorin 500 mg/m(2) as a 24-h continuous infusion.

Adult↗
PubMed2002

UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity.

The metabolism of irinotecan (CPT-11) involves sequential activation to SN-38 and detoxification to the pharmacologically inactive SN-38 glucuronide (SN-38G). We have previously demonstrated the role of UGT1A1 enzyme in the glucuronidation of SN-38 and a significant correlation between in vitro glucuronidation of SN-38 and UGT1A1 gene promoter polymorphism. This polymorphism (UGT1A1*28) is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Here we report the results from a prospective clinical pharmacogenetic study to determine the significance of UGT1A1*28 polymorphism on irinotecan disposition and toxicity in patients with cancer. Twenty patients with solid tumors were treated with a 90 min i.v. infusion of irinotecan (300 mg m(-2)) once every 3 weeks. The frequency of UGT1A1 genotypes was as follows: 6/6--45%, 6/7--35% and 7/7--20%, with allele frequencies of 0.375 and 0.625 for (TA)7TAA and (TA)6TAA, respectively. Patients with the (TA)7TAA polymorphism had significantly lower SN-38 glucuronidation rates than those with the normal allele (6/6>6/7>7/7, P = 0.001). More severe grades of diarrhea and neutropenia were observed only in patients heterozygous (grade 4 diarrhea, n = 1) or homozygous (grade 3 diarrhea/grade 4 neutropenia, n = 1 and grade 3 neutropenia, n = 1) for the (TA)7TAA sequence. The results suggest that screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity.

Adult↗
PubMed2001

Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology.

OBJECTIVE: To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axillary lymph nodes or locally advanced disease who receive systemic therapy. These guidelines are intended for use in the care of patients outside of clinical trials. POTENTIAL INTERVENTION: The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated. OUTCOMES: The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity. EVIDENCE: An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed. VALUES: Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A "recommendation" was made when level I or II evidence was available and there was consensus as to its meaning. A "suggestion" was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus. RECOMMENDATIONS: The recommendations, suggestions, and expert opinions of the Panel are described in this article. VALIDATION: Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.

Axilla↗
PubMed2001

Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gynecologic malignancies: a Gynecologic Oncology Group study.

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.

Adult↗
PubMed2001

Phase I trial of concomitant vinorelbine, paclitaxel, and pelvic irradiation in cervical carcinoma and other advanced pelvic malignancies.

OBJECTIVE: The aim of this study was to determine the feasibility and toxicity of concomitant vinorelbine, paclitaxel, and pelvic radiation therapy (RT) in patients with advanced cervical cancer and other pelvic malignancies. METHODS: Eligible patients included those with large or locally advanced cervical cancer. In addition, patients with other advanced gynecologic malignancies were eligible. In part I, vinorelbine was administered as a single agent during pelvic RT at a starting dose of 10 mg/m(2)/week with subsequent cohorts being escalated in 5 mg/m(2)/week increments. In part II, paclitaxel was added to vinorelbine (20 mg/m(2)/week) and pelvic RT at a starting dose of 20 mg/m(2)/week. RESULTS: Thirty-three women with pelvic malignancies (22 cervix, 6 vagina, 3 endometrium, 2 vulva) were enrolled. Twenty-seven received vinorelbine and 6 received both paclitaxel and vinorelbine in combination with pelvic RT. Escalating vinorelbine doses to 25 mg/m(2)/week were well tolerated, with the primary toxicity being hematologic. RT was delayed in only 1 patient due to acute hematologic toxicity. In contrast, the combination of paclitaxel, vinorelbine, and pelvic RT was not well tolerated. Five of 6 patients (83%) experienced grade > or = 2 leukopenia, with 2 patients missing > 1 cycle of chemotherapy. Moreover, RT was delayed for 1 week in 2 of 6 patients (33%). CONCLUSIONS: Concomitant pelvic RT and vinorelbine with doses to 25 mg/m(2)/week is well tolerated. The addition of paclitaxel to this combination is associated with significant hematologic toxicity and is thus not a feasible approach.

Adult↗
PubMed2001

The role of the community pharmacist in drug abuse: a comparison of service provision between Northern Ireland and England/Wales.

AIM: The aim of the present research was to establish the current extent of pharmacists' contact with illicit drug users in Northern Ireland, their willingness to provide services for this group and to compare the findings with data from a 1995 national survey of community pharmacies in England and Wales. METHOD: The questionnaire developed by the National Addiction Centre for research in England/Wales was used to collect data. It was mailed on two occasions (March and April 1999) together with a covering letter and a prepaid return envelope to all community pharmacies in Northern Ireland (n = 507). A final reminder letter was included in the local wholesalers' medical delivery for the attention of the pharmacist in May 1999. MAIN OUTCOME MEASURE: The extent to which Northern Ireland pharmacists had contact with and provided services to illicit drug users compared to pharmacists in England/Wales. RESULTS: A response rate of 67.5% was achieved. Respondents in Northern Ireland were providing fewer services to drug users than those in England/Wales. Respondents reported dispensing methadone for the treatment of addiction/misuse to only 9 patients, while only 17 pharmacists had been asked to sell injecting equipment in the previous week and no pharmacist was participating in a needle exchange scheme. However, most respondents indicated their willingness to provide such services. Barriers towards the provision of services were, however, highlighted e.g. the need for training and the establishment of support systems. CONCLUSION: Pharmacists in Northern Ireland are in a position to contribute to the policy agenda in Northern Ireland for drug misuse, prevention, treatment and harm minimisation--roles which the survey indicates they are willing to embrace. However, training programmes, support systems and adequate remuneration packages must be established before they will be in a position to participate fully.

England↗
PubMed2001

Phase I study of pegylated liposomal doxorubicin, paclitaxel, and cisplatin in patients with advanced solid tumors.

BACKGROUND: The combination of doxorubicin, paclitaxel, and cisplatin has activity in gynecologic malignancies but requires colony stimulating factor (G-CSF) support. Moreover, there is concern about cardiotoxicity with doxorubicin/paclitaxel combinations. Pegylated liposomal doxorubicin may result in less myelosuppression and cardiac toxicity than free doxorubicin. The purpose of this study was to determine the maximal tolerated dose of pegylated liposomal doxorubicin with fixed doses of paclitaxel and cisplatin without using G-CSF support in advanced solid malignancies. PATIENTS AND METHODS: Twenty-three patients were enrolled; none of the patients had received prior doxorubicin. Patients received paclitaxel (90 mg/m2 for dose level one, escalating to 135 mg/m2 for all subsequent dose levels), with a fixed dose of cisplatin (60 mg/m2), followed by escalating doses of pegylated liposomal doxorubicin every 21 days. RESULTS: A total of 73 cycles was administered. Grade 4 neutropenia was seen after cycle one in two of eight patients receiving 30 mg/m2 of pegylated liposomal doxorubicin and three of seven patients receiving 40 mg/m2 of pegylated liposomal doxorubicin when combined with 135 mg/m2 of paclitaxel and 60 mg/m2 of cisplatin. Two additional patients at the 40 mg/m2 dose level developed grade 4 neutropenia following cycles 2 and 5. The mean decline in left ventricular ejection fraction (LVEF) after 2 cycles was 5 percentage points (P = 0.012). CONCLUSION: The combination of pegylated liposomal doxorubicin, paclitaxel and cisplatin is feasible without G-CSF support.

Adult↗
PubMed2001

A phase II trial of docetaxel for peripheral blood stem cell mobilization for patients with breast cancer and ovarian cancer.

As docetaxel is known to have significant antineoplastic activity against breast and ovarian cancer, we explored its application as a peripheral blood stem cell mobilizing agent in 33 women with stage lll-IV ovarian carcinoma (n = 10) or stage ll-lV breast cancer (n = 23) who were in preparation for high-dose chemotherapy. Eleven patients had bone and/or bone marrow involvement with their disease. The median number of prior regimens received before mobilization was two (range 1-3). The three dose levels administered were 100 mg/m(2), 110 mg/m(2) and 120 mg/m(2). Patients received one dose of docetaxel in the outpatient setting followed by G-CSF (10 microg/kg/day) starting 4 days after docetaxel administration. Leukapheresis commenced when WBC >1.0 x 10(9)/l or when the WBC began to rise after reaching a nadir. Ninety-seven percent of patients began leukapheresis within 7-9 days after receiving docetaxel (range 7-10 days). The collection goal was >/=2 x 10(6) CD34(+) cells/kg. Twenty-seven (82%) patients reached this goal in a median of 2 leukapheresis days (range 1-3). No grade 2-4 nonhematologic toxicities were noted. Thirteen patients (55%) showed a WBC nadir >1.0 x 10(9)/l. None of the patients experienced neutropenic fever or required blood or platelet transfusion support. In conclusion, docetaxel + G-CSF is an effective, well-tolerated regimen for PBPC mobilization which can be safely administered in the outpatient setting with minimal toxicity.

Adult↗
PubMed2001

Absence of major peripheral neuropathy in a phase II trial of ifosfamide with vinorelbine in patients with ovarian cancer previously treated with platinum and paclitaxel.

Both ifosfamide and vinorelbine have been shown to produce responses in women with previously treated ovarian cancer. However, vinorelbine has been reported to cause severe neuropathy in patients previously treated with paclitaxel. We assessed a regimen consisting of ifosfamide 1.6 g/m2/d and vinorelbine 30 mg/m2/d for 3 days consecutively every 21 days. Because these doses resulted in severe neutropenia despite the use of granulocyte colony-stimulating factor, doses were reduced to a final level of ifosfamide 960 mg/m2/d and vinorelbine 20 mg/m2/d. Peripheral sensory neuropathy was evaluated by questionnaire. A total of 30 women were treated. All had previously been treated with both a platinum compound and paclitaxel. One partial response was observed among 23 patients with measurable disease, and two CA-125 responses were noted among seven patients without measurable disease. Severe progressive neurotoxicity was not observed. Despite the fact that almost half the patients had not been exposed to cyclophosphamide, this regimen produced few responses. Superior response rates have been reported with single-agent vinorelbine at doses that do not require growth factor support. With this dose and schedule, vinorelbine is reasonably safe therapy for patients who have received prior paclitaxel and who have have mild baseline sensory neuropathy.

Adult↗
PubMed2001

Benefits and risks of self medication.

Self medication is becoming an increasingly important area within healthcare. It moves patients towards greater independence in making decisions about management of minor illnesses, thereby promoting empowerment. Self medication also has advantages for healthcare systems as it facilitates better use of clinical skills, increases access to medication and may contribute to reducing prescribed drug costs associated with publicly funded health programmes. However, self medication is associated with risks such as misdiagnosis, use of excessive drug dosage, prolonged duration of use, drug interactions and polypharmacy. The latter may be particularly problematic in the elderly. Monitoring systems, a partnership between patients, physicians and pharmacists and the provision of education and information to all concerned on safe self medication, are proposed strategies for maximising benefit and minimising risk.

Drug Therapy↗
PubMed2001

Meta-analysis of adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy in postmenopausal women with estrogen receptor-positive, node-positive breast cancer.

Conflicting results have been published regarding the efficacy of adjuvant cyclophosphamide/methotrexate/5-fluorouracil (CMF)-type chemotherapy in postmenopausal, estrogen receptor (ER)-positive women. The Oxford overview suggests real but limited benefit of any chemotherapy in this group of patients but avoids analyzing smaller subsets. We wished to better quantitate the benefit of adding CMF to tamoxifen in postmenopausal ER-positive women with tumor involvement of axillary lymph nodes. Six randomized studies comparing CMF plus tamoxifen to tomoxifen alone in postmenopausal, ER-positive, node-positive women have been published since 1992. They include 2368 patients. We performed a meta-analysis of 6 endpoints: survival, disease-free survival, locoregional recurrence, distant recurrence, contralateral breast recurrence, and thromboembolic complications. There was a statistically significant increase in disease-free survival from the addition of CMF-type chemotherapy to tamoxifen in this population; the absolute risk of relapse was reduced by 5.5% at 5 years. Effects of locoregional recurrence were greater than those on overall recurrence. No significant survival benefit was observed.

Adult↗
PubMed2001

Phase I Trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer.

Raf-1 is a serine/threonine kinase that functions as a critical effector of Ras-mediated signal transduction via the mitogen-activated protein kinase pathway. Constitutive activation of this pathway directly contributes to malignant transformation in many human tumors. A 20-base phosphorothioate oligonucleotide complementary to c-raf-1 mRNA (ISIS 5132; CGP 69846A) has been shown to specifically suppress Raf-1 expression both in vitro and in vivo. This Phase I trial, involving 22 patients with advanced cancer, was designed to evaluate the safety, feasibility, and maximum tolerated dose of ISIS 5132 administration as a weekly 24-h i.v. infusion. Pharmacokinetic analysis was performed, and c-raf-1 mRNA levels in peripheral blood mononuclear cells were assessed using quantitative reverse transcription-PCR. This trial defined a maximum tolerated dose of 24 mg/kg/week on this schedule. Two of four patients treated at 30 mg/kg/week had serious adverse events after the first dose of ISIS 5132, including acute hemolytic anemia and acute renal failure and anasarca. There were no major responses documented. Dose-dependent complement activation was demonstrated on this schedule, but not on previously evaluated schedules, of ISIS 5132 administration. In contrast to other trials of ISIS 5132, there appeared to be no consistent suppression of peripheral blood mononuclear cell c-raf-1 mRNA level on this schedule at any of the dose levels analyzed. These data suggest that the efficacy and toxicity profiles of antisense oligonucleotides may be highly dependent on the schedule of administration and support the analysis of the putative molecular target in the evaluation of novel therapeutics.

Adult↗
PubMed2000

Development of a schedule-dependent population pharmacodynamic model for rhizoxin without quantitation of plasma concentrations.

In previous phase I reports of short bolus infusion of rhizoxin, problems in assay sensitivity prevented the description of pharmacokinetic-pharmacodynamic relationships, and a pharmacologically guided approach to dose escalation was deemed not feasible. In this report, we describe a mathematical model, which explains the schedule-dependent interpatient pharmacodynamic variability of rhizoxin administered on a continuous infusion schedule. Using patient demographic and toxicity data from 45 patients treated in a phase I dose and duration escalation study of rhizoxin, we sought to model the nadir neutrophil count. We hypothesized that a surrogate derived variable based on dose and duration would reflect a pharmacokinetic parameter that would be a significant covariate. Multiple linear regression analysis was carried out to determine the other significant covariates. Dose/m2 x Log(DUR/ALB) was significantly correlated with the LogANCnadir (Log10 neutrophil nadir; r = 0.56, P < 0.001). Other significant covariates included baseline performance status (PS), baseline serum bilirubin (BIL), and Log10 baseline neutrophil count (LogANCbaseline). Model bias and precision were assessed using the mean prediction error (MPE) and the root mean square error (RMSE) of the ANCnadir, respectively. We constructed 1-4 covariate models. The variability of ANCnadir was modeled with good precision and accuracy with a 4-covariate model (MPE and RMSE 0.113 +/- 0.182 x 10(3) cells/microl and 1.22 x 10(3) cells/microl, respectively). This model should be validated and improved on with further clinical data. We believe that such pharmacodynamic modeling should be explored further to determine its performance and clinical relevance compared with modeling using pharmacokinetic parameters.

Adult↗