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Biomedical subjects

D Parkin

Publications and source records attributed to D Parkin.

At least 19 recordsLinked to original sources
PubMed2006

SCOTROC 2A: carboplatin followed by docetaxel or docetaxel-gemcitabine as first-line chemotherapy for ovarian cancer.

The feasibility of sequential carboplatin followed by docetaxel-based therapy for untreated ovarian cancer was determined. Patients received four q3w cycles of carboplatin AUC 7, then four q3w cycles of either docetaxel 100 mg m(-2) (day 1) (arm A); docetaxel 75 mg m(-2) (day 8) and gemcitabine 1250 mg m(-2) (days 1,8) (arm B) or docetaxel 25 mg m(-2) and gemcitabine 800 mg m(-2) (both given weekly (days 1,8,15)) (arm C). A total of 44 patients were randomised to each treatment arm. None of the arms demonstrated an eight cycle completion rate (70.5/72.7/45.5% in arms A/B/C, respectively), which was statistically greater than 60% (P=0.102, P=0.056, P=0.982) which was our formal feasibility criteria, although only the completion rate in arm C was clearly worse than this level. The overall response rate (ORR) after carboplatin was 65.7% in 70 evaluable patients. In evaluable patients, ORRs after docetaxel-based cycles were: arm A 84.0% (21 out of 25); arm B 77.3% (17 out of 22); arm C 69.6% (16 out of 23). At follow-up (median 30 months), median progression-free survival times were: arm A 15.5 months (95% CI: 10.5-20.6); arm B 18.1 months (95% CI: 15.9-20.3); arm C, 13.7 months (95% CI: 12.8-14.6). Neutropenia was the predominant grade 3-4 haematological toxicity: 77.8/85.7/54.4% in arms A/B/C, respectively. Dyspnoea was markedly increased in both gemcitabine-containing arms (P=0.001) but was worse in arm C. Although just failing to rule out eight cycle completion rates less than 60%, within the statistical limitations of these small cohorts, the overall results for arms A and B are encouraging. Larger phase III studies are required to test these combinations.

Adult↗
PubMed2005

A randomised comparison of treosulfan and carboplatin in patients with ovarian cancer: a study by the Scottish Gynaecological Cancer Trials Group (SGCTG).

The management of older and unfit women with advanced ovarian cancer requires post-operative chemotherapy but many of these patients are not suitable for high-dose cisplatin-based regimes. Carboplatin has been an easier alternative and can be given in the ambulatory setting. Historical data suggests that oral alkylating agents to be just effective with similar efficacy. In this study we have compared platinum-based carboplatin to the alkylating agent treosulfan in a population unfit to receive high-dose cisplatin. The trial randomised patients to either intravenous carboplatin or treosulfan as single agent. The trial was stopped prematurely after the interim analysis showed improved survival and response rates in the carboplatin arm. We conclude that carboplatin is a safe and effective drug in a population that is unfit for high-dose cisplatin. Treosulfan showed limited activity but may be considered along with other oral drugs in limited circumstances. With the exception of myelosuppression, toxicity was mild in both arms. Carboplatin remains the gold standard in this older and less fit group of patients.

Aged↗
PubMed2002

Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies.

OBJECTIVE: Immunosuppressive agents have become the standard of therapy for proliferative lupus nephritis, but some patients may relapse after discontinuing treatment. We reviewed the cases of renal flares in a cohort of patients who participated in 2 randomized controlled clinical trials at the National Institutes of Health and explored the prevalence, outcome, and predictive factors of renal flares. METHODS: Data were obtained on 145 patients treated with pulse cyclophosphamide, pulse methylprednisolone, or the combination of both. Patients had not received immunosuppressive therapy for at least 6 months and had experienced complete or partial response according to defined criteria. Renal flares were classified as either proteinuric or nephritic based on changes in urinary protein and sediment. Most patients who experienced a flare received additional immunosuppressive therapy. RESULTS: Seventy-three patients had a complete response, and 19 had partial response/stabilization. Forty-one of these patients (45%) experienced renal flares (nephritic in 33, proteinuric in 8) after a mean followup of 117 months; 31 of them received additional immunosuppressive therapy. The median time to renal flare was 36 months in the complete responders and 18 months in the partial responders. Eleven of the 41 patients (27%) progressed to end-stage renal disease (ESRD); 9 had nephritic flares (all severe except for 1) and 2 had proteinuric flares (1 in each responder group). Compared with patients who had a complete response, those with a partial response were more likely to experience a flare, to have a severe nephritic flare, or to progress to ESRD. Low C4 at the time of response and African American ethnicity were significant independent risk factors for renal flare, by multivariate Cox proportional hazards analysis. CONCLUSION: Nephritic flares are common in patients with proliferative lupus nephritis, even in those with a complete response to therapy, but they do not necessarily result in loss of renal function if treated with additional immunosuppressive agents. Renal flares are an important feature of the natural history of lupus nephritis and provide an opportunity for additional preventive strategies, as well as measures of efficacy in future therapeutic trials.

Adult↗
PubMed2002

A case of B-cell lymphoblastic lymphoma involving the uterus.

A 59-year-old postmenopausal woman presented with vaginal bleeding, lower abdominal pain, severe anaemia, leucocytosis, and an ultrasonographic finding of a large mass arising within the pelvis, most likely ovarian in origin. The patient was taken to the operating theatre with the possible diagnosis of acute haemorrhage into an ovarian cyst. At laparotomy there was a large mass at the posterior uterine wall extending retroperitoneally into the left pelvic side-wall. There was also significant paraaortic lymphadenopathy. The tumor was not resectable and biopsies were taken for pathological examination which showed a precursor B cell lymphoblastic lymphoma. Although the existence of lymphomas involving the uterus is well documented, the presentation of the lymphoma in this case was very unusual and this is the first reported case of a confirmed precursor B-cell lymphoblastic lymphoma involving the uterus.

Fatal Outcome↗
PubMed2001

Cytochrome P450 CYP1B1 over-expression in primary and metastatic ovarian cancer.

Ovarian cancer is the most frequent cause of death from gynaecological malignancies world wide. Little improvement has been made in the long-term outcome of this disease, with the 5-year survival of patients only 30%. This poor prognosis is due to the late presentation of the disease and to the unpredictable response of ovarian cancer to chemotherapy. The cytochrome P450 enzymes are a superfamily of haemoproteins, known to be involved in the metabolic activation and/or detoxification of a number of anti-cancer drugs. CYP1B1 is a tumour-related form of cytochrome P450 which is over expressed in a wide variety of primary tumours of different histological type. The presence of CYP1B1 may be of importance in the modulation of these tumours to anti-cancer drugs. We have conducted a comprehensive immunohistochemical investigation, into the presence of cytochrome P450 CYP1B1 in primary and metastatic ovarian cancer. The key findings of this study are the increased expression of CYP1B1 in the majority of ovarian cancers investigated (92%), with a strong correlation demonstrated between CYP1B1 expression in both primary and metastatic ovarian cancer (P = 0.005 Spearman's rank correlation test). In contrast no detectable CYP1B1 was found in normal ovary.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Docetaxel-carboplatin as first line chemotherapy for epithelial ovarian cancer.

A prospective, non-randomized, multicentre, open, dose-finding study of a carboplatin-docetaxel (C-D) combination as first-line chemotherapy in FIGO stage Ic-IV epithelial ovarian cancer. C-D was given 3-weekly for 6 planned cycles, with a 3-day prophylactic dexamethasone regimen (8 mg b.i.d.). 139 eligible patients (Pts) (median age 56 years, range 28-85) were given a total of 750 cycles of chemotherapy in 5 cohorts: Co1, 32 pts, 169 cycles (C at AUC 5 + D 60 mg/m(2)); Co2, 22 pts, 122 cycles (5 + 75), Co3, 29 pts, 156 cycles (6 + 75), Co4, 27 pts, 146 cycles (7 + 75), Co5, 30 pts, 157 cycles (6 + 85). 110 patients (79%) completed 6 cycles; 17 (12%) stopped due to toxicity. 104 patients (75%) had CTC grade IV neutropenia, and 5 patients (4%) had this associated with fever. There were 2 probable treatment-related deaths. Only 8 patients (6%) experienced grade II-III neurotoxicity (all sensory; no motor > grade I). The maximum tolerated dose was reached in cohorts 4 and 5, and the dose limiting toxicities were myelosuppression and diarrhoea. The overall response rate for the study was 66% (49/74); CA125 response was 75% (70/93). Median progression-free survival was 16.6 months (95% CI 13.3-19.1). Recommended doses are carboplatin AUC 5 (via(51)Cr EDTA) or AUC 6 (if calculated) plus docetaxel 75 mg/m(2). A randomized trial comparing this regimen with carboplatin-paclitaxel has just completed recruitment.

Adenocarcinoma↗
PubMed2001

The efficiency of the delivery of neonatal care in the UK.

BACKGROUND: A recent paper in Journal of Public Health Medicine (O'Neill et al., 2000; 22(1): 108-115) used regression modelling to determine the average costs of neonatal care services for a sample of 49 units in the United Kingdom in 1990-1991, and concluded that economies of scale were present in the sample as a whole. Although this form of modelling is useful, analysis of the efficiency of production for individual units is also important. METHODS: Data envelopment analysis (DEA) was used to analyse the data set published by O'Neil et al., to determine technical efficiency of neonatal units, measuring efficiency compared with a benchmark efficient frontier, and estimating economies of scale for each unit. Potential cost savings if units were to operate efficiently are estimated. RESULTS: There is evidence of substantial levels of technical inefficiency. Economies of scale varied between units, with increasing returns in the 36 inefficient units, and mainly constant returns in the 13 efficient units. This suggests that the presence of technical inefficiency was as important as scale inefficiencies. Total cost savings, if all units were operating efficiently, are estimated at ł10.4 million, equivalent to 10 extra units producing 57,000 additional days of care. CONCLUSIONS: DEA is a technique of great potential value in analysing the efficiency of health care production. As well as inefficiencies in the production of neonatal care in the United Kingdom due to differences in the scale of production, there appears to have been considerable technical inefficiency, which was not due to differences in case mix. The potential cost savings from efficiency gains are large.

Data Interpretation, Statistical↗
PubMed2001

How patients with atrial fibrillation value different health outcomes: a standard gamble study.

BACKGROUND AND PURPOSE: The assessment of any health care intervention should consider both risks and benefits and take patients' preferences about these into account. The study reported in this paper aimed to elicit patient valuations of health states relevant to assessment of the prevention of stroke by warfarin anticoagulation therapy for patients with atrial fibrillation. METHODS: A sample of patients over the age of 60 years with atrial fibrillation from three family practices in North-East England was interviewed. Their health state values were elicited using the standard gamble method for general practitioner (GP)-managed warfarin treatment, hospital-managed warfarin treatment, major bleed, mild stroke and severe stroke. RESULTS: Of 180 patients, 69 (38%) agreed to participate, of whom 57 (83%) completed interviews. Median (mean) utility values were for GP-managed warfarin treatment 0.986 (0.948), hospital-managed warfarin treatment 0.984 (0.941), major bleed 0.880 (0.841), mild stroke 0.675 (0.641) and severe stroke 0 (0.189). There was wide variation in values between patients and the distributions were highly skewed. CONCLUSIONS: The results are of value in applying decision analysis to groups of patients. They should be used with caution in reaching decisions about appropriate treatment for individual patients, but may provide a starting point for necessary further exploration of those patients' individual preferences.

Anticoagulants↗
PubMed2000

Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation.

BACKGROUND: Clinical guidelines are needed on whether or not to use anticoagulant therapy to prevent stroke in patients with non-valvular atrial fibrillation. We did a Markov decision analysis to model decision-making with regard to warfarin treatment in patients with atrial fibrillation, and used the model to develop evaluative guidelines. METHODS: The decision analysis involved a systematic literature review supplemented by patients' estimates of the quality of life associated with different states of health, secondary analysis of stroke-registry data, and estimation of service costs; it also incorporated a sensitivity analysis. The derived guidelines were subsequently applied to a cohort of patients with atrial fibrillation. FINDINGS: We constructed decision tables for 12 age and sex groups. For most risk combinations, warfarin treatment would have decreased health-care costs and increased quality-of-life years, although the clinical decision was sensitive to patients' preferences and to the estimate of warfarin's effectiveness. 97% of women with atrial fibrillation older than 75 years, and 69% aged 65-74 would have been recommended for treatment; for men, the corresponding figures would have been 75% and 53%. With the upper quartile for the loss of quality of life associated with being on warfarin treatment (1.00), all but two of the 116 patients without contraindications would have been treated, whereas with the lower quartile (0.92), only 27 of 116 would have been treated. INTERPRETATION: Decision analysis is useful in the incorporation of complex probabilistic data into informed decision-making, the identification of factors influencing such decisions, and the subsequent development of evaluative guidelines.

Aged↗
PubMed2000

Treatment of multiple sclerosis with interferon beta: an appraisal of cost-effectiveness and quality of life.

OBJECTIVE: To evaluate the cost-effectiveness of interferon beta-1b (IFbeta-1b) for relapsing-remitting multiple sclerosis (RRMS). METHODS: Construction of a cost-effectiveness model using published data on IFbeta-1b effectiveness and the natural history of RRMS, and new data on costs and quality of life (QoL) from a sample of 102 patients with RRMS and resident in northern England. RESULTS: Poorer QoL was found for patients with multiple sclerosis compared with the general population; those who had had a relapse; those with worse states identified by a clinical measure (expanded disability status scale (EDSS)). Relapses have effects over several months. Health state valuations were higher than in the general population. Costs were higher in relapse than remission and for worse EDSS states. IFbeta-1b costs were larger than cost savings. The best cost-effectiveness estimate was pound28 700 per relapse avoided, which is pound809 900 per QALY gained; or pound328 300 per QALY gained allowing for effects of progression over 5 years. Estimates were robust to changes in assumptions. CONCLUSIONS: The impact of multiple sclerosis on QoL is substantial. Future trials should base outcomes measurement on QoL and be better linked to natural history and cost data. IFbeta-1b produces important occasional short term QoL gains, but small gains in QALYs overall and large additional costs.

Adjuvants, Immunologic↗
PubMed1999

Non- and semi-parametric estimation of age and time heterogeneity in repeated cross-sections: an application to self-reported morbidity and general practitioner utilization.

Patterns of self-reported morbidity and general practitioner (GP) utilization exhibit complex age, sex and time heterogeneity. Underlying patterns are often obscured by data which are overly 'rough' because of noise associated with adjacent year fluctuations. In this paper we describe methods to obtain smoothed estimates of age, time and birth-cohort effects using data from the General Household Survey (GHS), covering the period 1984-1995/6 inclusive. The methods outlined offer powerful analytic tools to research complex profiles or trends, particularly over age or time. The relationships of the morbidity and GP utilization measures with age, sex and survey year characteristics are estimated non-parametrically using roughness penalized least squares (RPLS). A semi-parametric extension of this model is used to estimate the effect of the morbidity variables on GP utilization. Tests are employed for various forms of age and time heterogeneity including birth-cohort effects. Linear age specifications are rejected for all variables and evidence is found of time heterogeneity in one of the morbidity measures--limiting long-standing illness (LS)--and GP utilization. The advantages of employing non- and semi-parametric estimations in the presence of complex relationships such as those observed for age and time profiles are discussed. Adoption of these techniques by applied econometricians working in health economics is encouraged.

Adult↗
PubMed1999

Models of commissioning health services in the British National Health Service: a literature review.

The commissioning of health services is an under-researched area and yet it is critical to the way services meet health needs and to the quality of care. Recent emphasis in the United Kingdom and elsewhere has been on a 'primary care led National Health Service', particularly on locality commissioning through primary care groups. However, there are other models of commissioning using 'programmes of care' (focused on diseases or patient groups rather than geography) which may offer greater benefits. There is little research comparing the benefits and costs of these models, and most are not even clearly enough described to be replicated. There will always be a political dimension to models of commissioning, dependent, for example, on the balance of power in the decision-making process. None the less, a broader knowledge of possible models and a willingness to evaluate rigorously are needed if commissioning of health services is to result in better patient care.

Health Care Reform↗
PubMed1999

A comparison of the plasma disappearance of iohexol and 99mTc-DTPA for the measurement of glomerular filtration rate (GFR) in diabetes.

BACKGROUND: Changes in glomerular filtration rate (GFR) provide a valuable indicator of the progression of diabetic nephropathy. GFR is most commonly measured by the plasma clearance of radioisotopes, however, use of iohexol, a non-ionic radiocontrast medium, is a recently described alternative and has shown good agreement with inulin clearance. A one-compartment model is used for calculating GFR in most Australian centres but a two-compartment model is more accurate. AIMS: To set up a non-radioisotopic method for assessment of GFR using iohexol, and to compare this with the currently used 99mTc-diethylene-triamine-penta-acetic acid (DTPA) method. Secondly, to compare GFR results using an unmodified one-compartment model with a one-compartment model subjected to the Brochner-Mortensen modification. METHODS: Twenty-one patients with diabetes had assessment of GFR with simultaneous measurements of 99mTc-DTPA and iohexol plasma clearance. Plasma clearance was determined by the slope intercept method and then modified according to the Brochner-Mortensen equation. Plasma iohexol concentrations were determined by capillary electrophoresis. RESULTS: There was no significant difference between iohexol and 99mTc-DTPA derived GFR values, difference 4.3+/-7.7 mL/minute (mean+/-SD). This was despite 99mTc-DTPA protein binding demonstrated in the range of 5-10%. Comparison of GFR results using an unmodified one-compartment model with a Brochner-Mortensen corrected one-compartment model showed higher GFR values with the former, in the range of 20-30% for GFR values > 100 mL/minute. CONCLUSION: Iohexol provides an efficient alternative to radioisotopic methods for serial measurement of GFR in diabetic patients with hyperfiltration, incipient and overt nephropathy. A one-compartment model with its inherent overestimation of GFR should be replaced by the Brochner-Mortensen modified one-compartment model.

Adult↗
PubMed1998

Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin.

Our previous randomised trial in patients with advanced ovarian cancer indicated a significant response and survival advantage for those receiving high-dose (100 mg/m2) as compared with low-dose (50 mg/m2) cisplatin in combination with cyclophosphamide (750 mg/m2). However, this was accompanied by more toxicity; peripheral neuropathy was troublesome, with 32% of patients experiencing > or = WHO grade 2 at the cisplatin dose of 100 mg/m2. Nimodipine is a calcium-channel antagonist that has provided protection from cisplatin-induced neurotoxicity in a rat model system. We performed a pilot study in 50 patients that demonstrated the feasibility of co-administration of nimodipine in a chronic oral dosing schedule with cisplatin-based chemotherapy in an open-label non-randomised trial. This led us to initiate a double-blind, placebo-controlled, randomised trial in patients with ovarian cancer, which was prematurely discontinued because of problems with nausea and vomiting, leading to poor patient compliance, that were not predicted by the pilot study. These studies did not demonstrate a neuroprotective effect for nimodipine. The primary efficacy variable, i.e, the neurotoxicity score at the end of treatment, gave a significantly lower mean for placebo patients than for nimodipine patients. This report details our experience and discusses the reasons for premature termination of the randomised trial.

Adult↗