Search PubMed⌕ Search

Biomedical subjects

P Harper

Publications and source records attributed to P Harper.

At least 37 records · Page 2Linked to original sources
PubMed2003

A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies.

BACKGROUND: Oral eniluracil/5-fluorouracil (5-FU) was shown in early clinical studies to have promising activity against gastrointestinal malignancies. Oxaliplatin in combination with 5-FU also has activity against these tumour types. The primary objective of this study was to determine a tolerable dose for oral eniluracil/5-FU in combination with oxaliplatin. PATIENTS AND METHODS: Twenty-three patients with advanced gastrointestinal malignancies were recruited into this open-label study. Patients received a fixed dose of oxaliplatin (130 mg/m(2) on the first day of a 21-day cycle), and the dose intensity of oral eniluracil/5-FU was gradually increased by escalating the number of days of treatment per course. RESULTS: The maximum tolerated dose intensity was eniluracil/5-FU 10.0/1.0 mg/m(2) twice daily for 16 days in combination with oxaliplatin 130 mg/m(2) on the first day of a 21-day cycle. Dose-limiting toxicities included vomiting and diarrhoea. The objective tumour response rate was 26% with a median duration of response of 15.3 weeks (95% confidence interval 8.5-22.1). Twenty-two patients (96%) experienced neurotoxicity (sensory neuropathy or cold-related dysaesthesia), although only two events were severe (grade 3). CONCLUSIONS: The recommended dose for future study in patients with advanced gastrointestinal cancer is 10.0/1.0 mg/m(2) oral eniluracil/5-FU twice daily for 14 days in combination with oxaliplatin 130 mg/m(2) on the first day of each treatment cycle.

Administration, Oral↗
PubMed2002

Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer.

PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) with the combination of mitomycin, cisplatin, and PVI 5-FU (MCF) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Five hundred eighty patients with adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma were randomized to receive either ECF (epirubicin 50 mg/m(2) every 3 weeks, cisplatin 60 mg/m(2) every 3 weeks and PVI 5-FU 200 mg/m(2)/d) or MCF (mitomycin 7 mg/m(2) every 6 weeks, cisplatin 60 mg/m(2) every 3 weeks, and PVI 5-FU 300 mg/m(2)/d) and analyzed for survival, response, toxicity, and quality of life (QOL). RESULTS: The overall response rate was 42.4% (95% confidence interval [CI], 37% to 48%) with ECF and 44.1% (95% CI, 38% to 50%) with MCF (P =.692). Toxicity was tolerable, and there were only two toxic deaths. ECF resulted in more grade 3/4 neutropenia and grade 2 alopecia, but MCF caused more thrombocytopenia and plantar-palmar erythema. Median survival was 9.4 months with ECF and 8.7 months with MCF (P =.315); at 1 year, 40.2% (95% CI, 34% to 46%) of ECF and 32.7% (95% CI, 27% to 38%) of MCF patients were alive. Median failure-free survival was 7 months with both regimens. Global QOL scores were better with ECF at 3 and 6 months. CONCLUSION: This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.

Adult↗
PubMed2002

A randomized trial of specialist genetic assessment: psychological impact on women at different levels of familial breast cancer risk.

The aim was to compare the psychological impact of a multidisciplinary specialist genetics service with surgical provision in women at high risk and those at lower risk of familial breast cancer. Women (n=735) were randomized to a surgical consultation with (trial group) or without (control group) specialist genetic risk assessment and the possible offer of presymptomatic genetic testing. Participants completed questionnaires before and immediately after the consultation to assess anxiety, cancer worry, perceived risk, interest in genetic testing and satisfaction. Responses of subgroups of women stratified by clinicians as low, moderate, or high risk were analyzed. There were no significant main effects of study intervention on any outcome variable. Regardless of risk information, there was a statistically significant reduction in state anxiety (P<0.001). Reductions in cancer worry and perceived risk were significant for women at low or moderate risk (P<0.001) but not those at high risk, and satisfaction was significantly lower in the high risk group (P<0.001). In high risk women who received specialist genetic input, there was a marginally significant trend towards increased perceived risk. The effect of risk information on interest in genetic testing was not significant. Breast care specialists other than geneticists might provide assessments of breast cancer risk, reassuring women at reduced risk and targeting those at high risk for specialist genetic counselling and testing services. These findings are discussed in relation to the existing UK Calman-Hine model of service delivery in cancer genetics. DOI: 10.1038/sj/bjc/6600051 www.bjcancer.comCopyright 2002 The Cancer Research Campaign

Adult↗
PubMed2002

Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene.

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial deficit of porphobilinogen deaminase (PBGD), the third of eight enzymes in the haem biosynthetic pathway. The overt disease is characterized by neuropsychiatric symptoms that are often triggered by exogenous factors such as certain drugs, stress, and alcohol. The aim of this work has been to identify the underlying genetic defect in each AIP-affected family in order to provide early counselling to assist in the avoidance of precipitating factors. The prevalence of AIP in Sweden is in the order of 1:10 000. The major mutation in Sweden, W198X, is due to a founder effect in the northern part of the country. This mutation, together with a further 11 mutations, have been reported previously. The present communication encompasses the great majority of AIP kindreds in Sweden and includes a further 27 mutations within the PBGD gene. This includes 14 completely new mutations, as well as 11 known mutations detected for the first time in Sweden. The majority of the mutations are located in exons 10 and 12 with fewer in exon 7. The clinical and biochemical outcomes in some patients are described. We also use the three-dimensional structure of the porphobilinogen deaminase enzyme to predict the possible molecular and functional consequences of the new Swedish missense and nonsense mutations.

Codon, Nonsense↗
PubMed2002

Non-viral mediated gene transfer of porphobilinogen deaminase into mammalian cells.

Acute intermittent porphyria (AIP) is an inborn error of heme synthesis in which the third enzyme, porphobilinogen deaminase (PBGD), is deficient. The disease is characterized by recurrent attacks of acute abdominal pain often accompanied by neuropsychiatric symptoms. Current therapeutic treatment with heme is only palliative and no curative alternative exists. The present report describes the first step towards a gene therapy treatment for AIP. Mouse cDNA encoding the PBGD enzyme was cloned and four vectors containing the full-length mouse and human cDNA of the housekeeping and erythroid PBGD isoforms under the control of a cytomegalovirus promoter were constructed. The vectors, condensed to polyethylenimine, were successfully transfected to NIH 3T3 and HeLa cells as determined by enzymatic activity measurements. Thus, the PBGD activity was increased 3-10 times in NIH 3T3 cells and 95-240 times in HeLa cells. The expression was shown to be dose and time dependent, with the highest level of activity observed in HeLa cells after 72 h posttransfection. Non-viral gene transfer was also undertaken in PBGD-deficient fibroblasts established from an AIP patient. Complete normalization of the PBGD activity was accomplished after the addition of 2.5 microg DNA per well. Further addition of DNA increased the PBGD activity up to threefold the normal value. The study documents a successful gene transfer and a high degree of PBGD expression in different cell-lines, indicating a potential for future gene therapy in AIP.

3T3 Cells↗
PubMed2002

A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil (5-FU) with PVI 5-FU plus mitomycin C in patients with inoperable oesophago-gastric cancer.

BACKGROUND: This randomised study compared protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin C (MMC) in patients with advanced oesophago-gastric cancer. PATIENTS AND METHODS: Two hundred and fifty-four patients with adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma involving the oesophagus, oesophago-gastric junction or the stomach were randomised. The major end points were tumour response, survival, toxicity and quality of life. RESULTS: The median age of patients treated was 72 years and the two arms were well-balanced for baseline demographic factors. The overall response rate was 16.1% [95% confidence interval (CI) 9.5% to 22.7%] in patients treated with PVI 5-FU alone compared with 19.1% (95% CI 12.0% to 26.0%) for those treated with PVI 5-FU plus MMC (P = 0.555). Median time to treatment failure was 3.9 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P = 0.195). Median survival was 6.3 months for PVI 5-FU and 5.3 months for PVI 5-FU plus MMC (P = 1.0). Toxicity was mild for both treatments. Symptomatic benefit measured by improvement in pain control, weight loss, dysphagia and oesophageal reflux was observed in over 64% of patients in each arm. Quality of life scores were comparable in each arm. CONCLUSIONS: PVI 5-FU is a safe, effective form of palliation for patients with advanced oesophago-gastric cancer although the addition of MMC adds little extra benefit.

Aged↗
PubMed2002

The scope of guidelines to prevent healthcare-associated infections.

As care is increasingly delivered in the community rather than acute settings, there has been concern that this might be accompanied by a rise in healthcare-associated infection. Consequently, the National Institute for Clinical Excellence (NICE) has commissioned a set of infection prevention guidelines for healthcare workers in community and primary care. The guideline developers were anxious to concentrate this guidance on the areas of most concern to practitioners, particularly in relation to devices. This article describes how a survey and focus groups were employed to identify the areas for guideline development, namely standard principles, long-term indwelling urinary catheters, enteral feeds and central intravascular devices.

Community Health Services↗
PubMed2002

Malignant by name or malignant by nature: a case of Wegener's granulomatosis diagnosed as adenocarcinoma of unknown primary.

Most malignancies are characterised by malignant behaviour at some point in the disease trajectory. However, non-malignant diseases may exhibit malignant behaviour. A diagnosis of malignancy based on fine needle aspiration cytology (FNAC) can be misleading. We report a case of Wegener's granulomatosis initially diagnosed by FNAC as adenocarcinoma of unknown primary. The limitations of FNAC, the disparate prognoses of the two diagnoses despite a compatible clinical picture and the need for clinical vigilance in monitoring a disease course are highlighted.

Adenocarcinoma↗
PubMed2001

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study.

PURPOSE: To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil (5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m(2) administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity. RESULTS: The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P =.65); median time to treatment failure was 4.2 and 4.0 months (log-rank P =.89); and median overall survival was 13.2 and 12.1 months (log-rank P =.33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P <.00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P <.00001). Capecitabine also resulted in lower incidences (P <.00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 hand-foot syndrome (P <.00001) and uncomplicated grade 3/4 hyperbilirubinemia (P <.0001) were reported more frequently with capecitabine. CONCLUSION: Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.

Adenocarcinoma↗
PubMed2001

Highly heterogeneous nature of delta-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria.

The properties of 9 delta-aminolevulinate dehydratase (ALAD) mutants from patients with ALAD porphyria (ADP) were examined by bacterial expression of their complementary DNAs and by enzymologic and immunologic assays. ALADs were expressed as glutathione-S-transferase (GST) fusion proteins in Escherichia coli and purified by glutathione-affinity column chromatography. The GST-ALAD fusion proteins were recognized by anti-ALAD antibodies and were enzymatically active as ALAD. The enzymatic activities of 3 ALAD mutants, K59N, A274T, and V153M, were 69.9%, 19.3%, and 41.0% of that of the wild-type ALAD, respectively, whereas 6 mutants, G133R, K59N/G133R, F12L, R240W, V275M, and delTC, showed little activity (< 8%). These variations generally reflect the phenotype of ALAD in vivo in patients with ADP and indicate that GST-ALAD fusion protein is indeed useful for predicting of the phenotype of ALAD mutants. The location of F12L mutation in the enzyme's molecular structure indicates that its disturbance of the quaternary contact of the ALAD dimer appears to have a significant influence on the enzymatic activity. Mouse monoclonal antibodies to human ALAD were developed that specifically recognized a carboxy terminal portion of ALAD, or other regions in the enzyme. This study represents the first complete analysis of 9 mutants of ALAD identified in ADP and indicates the highly heterogeneous nature of mutations in this disorder.

Adolescent↗
PubMed2001

The rapid whole blood agglutination d-dimer assay has poor sensitivity for use as an exclusion test in suspected deep vein thrombosis.

AIMS: Several clinical studies have proposed using d-dimer as an initial screening test to exclude thrombosis in cases of suspected (DVT). In published series, these assays have variable sensitivity, raising concerns that they may not be sufficiently robust for clinical practice. The aim of the study was to examine the sensitivity of two commercially available d-dimer assays and to assess their value and safety as initial screening tests in suspected DVT. METHODS: In this prospective study, blood samples were collected for d-dimer measurement (SimpliRED assay and IL test d-dimer) in all patients presenting to the emergency department over a twelve month period. All patients underwent compression ultrasound scanning as the primary diagnostic procedure. RESULTS: 235 patients were included in the study. 51(22.8%) had a DVT confirmed on ultrasound. The SimpliRED assay was positive in only 33 cases, with seventeen cases of confirmed DVT giving a negative result (six cases with proximal vein thrombosis). Assay sensitivity was 66%, with a negative predictive value of 88.9%. The IL test gave three false negatives (all below knee thromboses) giving assay sensitivity and negative predictive value of 94.1% and 96.8% respectively. CONCLUSIONS: The precise role of d-dimer testing in the diagnosis of venous thrombosis has yet to be established. From our results and a review of published series, we conclude that the SimpliRED assay is too insensitive to use as a reliable exclusion test in cases of suspected DVT, however, the more sensitive automated IL test d-dimer may have a role in the initial assessment. We propose that the IL d-dimer test is used in conjunction with a pre-test probability score to identify patients at low risk of DVT and recommend that this approach is tested in a clinical study before introduction into practice.

Diagnosis, Differential↗
PubMed2001

Erythrocytes and the transfer of anticancer drugs and metabolites: a possible relationship with therapeutic outcome.

Blood functions as a mobile tissue in an exchange system, with the remaining body tissue as a stationary phase. The equilibrium among plasma water, plasma proteins, and blood cells is described by models, but little consideration has been given to the substance-binding capacity of erythrocytes. There are numerous reasons for this, including bioanalytical limitations (ie, it has been difficult to study erythrocytes in the laboratory in their natural state). Erythrocyte monitoring requires accurate blood sampling and quantitative isolation of erythrocytes without disturbing the equilibrium of substances of interest between erythrocytes and plasma or other blood constituents. This became possible with the advent of the measurement of sediment device. The mass of a given substance available in blood can be described by M(Blood) = M(Plasma) + M(ERY) (+ M(REM)). M(ERY) is the mass of a substance present in erythrocytes and it is shown that for several oxazaphosphorines, such as iphosphoramide mustard, that M(ERY) determines M(Blood) with great superiority over M(Plasma). The impact of erythrocyte monitoring on therapeutic outcome has to be defined, but is an important area of research.

Antineoplastic Agents↗
PubMed2001

Developments in cytotoxic chemotherapy: advances in treatment utilising vinorelbine.

Vinorelbine is a third generation vinca alkaloid which has been in clinical development for 15 years. Recent exploration of its pre-clinical activity has revealed unexpected evidence of potential synergy with taxane compounds and early clinical results support the suggestion of enhanced efficacy particularly in breast cancer. The initial studies establishing the clinical activity of vinorelbine in breast cancer and non-small cell lung cancer have been extended to encompass a thorough evaluation of its contribution to combination chemotherapy for these disorders. In the treatment of breast cancer useful activity has been established for vinorelbine in combination with anthracyclines, anthracenediones, antimetabolites and the taxanes; additive toxicity is not a limiting factor. The activity of vinorelbine in the treatment of non-small cell lung cancer is significantly extended by incorporation into schedules utilising cisplatin and other agents. Vinorelbine has also demonstrated useful activity in the treatment of a wide range of other malignancies including prostatic carcinoma, multiple myeloma, cancer of the ovary, cervix and head and neck and malignant lymphomas.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Is there any place for cytotoxic chemotherapy in endometrial cancer?

Cytotoxic chemotherapy has an established role in the treatment of many solid tumours that are considered to be incurable with any modern treatment method. Such treatment may result in an improvement in quality of life without influencing overall survival. In this chapter the evidence to support the use of chemotherapy in patients with advanced or recurrent endometrial adenocarcinoma is reviewed. The most effective single agent and combination treatments are outlined. Although evidence from randomized trials is limited, combination chemotherapy can lead to response rates of over 40% in patients with advanced disease. The role of chemotherapy as adjuvant treatment in patients with early-stage disease is less well defined and this treatment is not recommended outside a clinical trial. The role of chemotherapy for treatment of the aggressive histological variant, uterine papillary serous carcinoma is also discussed.

Adenocarcinoma↗
PubMed2001

The epic project: developing national evidence-based guidelines for preventing healthcare associated infections. Phase I: Guidelines for preventing hospital-acquired infections. Department of Health (England).

In 1998, the Department of Health (England) commissioned the first phase of national evidence-based guidelines for preventing healthcare associated infections. These focused on developing a set of standard principles for preventing infections in hospitals together with guidelines for preventing hospital-acquired infections (HAI) associated with the use of short-term indwelling ureteral catheters in acute care and with central venous catheters in acute care. These guidelines are systematically developed broad statements (principles) of good practice that all practitioners can use and which can be incorporated into local protocols. A nurse-led, multi-professional team composed of infection prevention practitioners, clinical microbiologists/retrovirologist, epidemiologists, and researchers developed the guidelines. A rigorous guideline development process was used to inform the systematic reviews, the clinical and critical appraisal of relevant evidence, and linking that evidence to evolving guidelines. Both general and specialist clinical practitioners were involved in all stages of developing these guidelines, as were representatives from relevant Royal Colleges, learned societies, other professional organisations and key stakeholders. The introduction to these guidelines describes a robust and validated guideline development model that can be used by others to develop future guidelines. This model is described in more detail in the associated technical reports that can be found on the project web site http://www.epic.tvu.ac.uk. Locating and appropriately using good quality evidence to inform guideline development in this field is challenging. Evidence from rigorously conducted experimental studies was frequently limited and consequently a range of other types of evidence were systematically retrieved and carefully appraised. The concluding discussion on implementation highlights potential issues for clinical governance and areas for future research and suggests issues that need to be addressed to allow practitioners to successfully incorporate these guidelines into routine clinical practice.

Acute Disease↗
PubMed2001

An acoustic model of the respiratory tract.

With the emerging use of tracheal sound analysis to detect and monitor respiratory tract changes such as those found in asthma and obstructive sleep apnea, there is a need to link the attributes of these easily measured sounds first to the underlying anatomy, and then to specific pathophysiology. To begin this process, we have developed a model of the acoustic properties of the entire respiratory tract (supraglottal plus subglottal airways) over the frequency range of tracheal sound measurements, 100 to 3000 Hz. The respiratory tract is represented by a transmission line acoustical analogy with varying cross sectional area, yielding walls, and dichotomous branching in the subglottal component. The model predicts the location in frequency of the natural acoustic resonances of components or the entire tract. Individually, the supra and subglottal portions of the model predict well the distinct locations of the spectral peaks (formants) from speech sounds such as /a/ as measured at the mouth and the trachea, respectively, in healthy subjects. When combining the supraglottic and subglottic portions to form a complete tract model, the predicted peak locations compare favorably with those of tracheal sounds measured during normal breathing. This modeling effort provides the first insights into the complex relationships between the spectral peaks of tracheal sounds and the underlying anatomy of the respiratory tract.

Acoustics↗