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Biomedical subjects

M E O'Brien

Publications and source records attributed to M E O'Brien.

At least 19 recordsLinked to original sources
PubMed2000

Flow cytometric visualisation of cytokine production by CD3-CD56+ NK cells and CD3+CD56+ NK-T cells in whole blood.

BACKGROUND: Natural killer (NK) cells produce multiple cytokines with potential immune regulatory roles. We standardised a whole-blood flow cytometry method to visualise intracellular cytokine production by NK cells for the study of NK cell biology and for clinical monitoring. METHODS: With a three-colour fluorescent labelling technique, specific cytokine production by NK or T cells was visualised directly in whole blood in the same sample after stimulation by phorbol 12-myristate 13-acetate (PMA) and ionomycin and by electronically gating on the CD3-ve/CD56+ve NK population or on the CD3+/CD56+ NK-T-cell population. RESULTS: Detectable levels of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) but not of interleukin-2 (IL-2) or IL-4 were easily observed in NK cells. The visualisation of the cytokine production by NK cells was dependent on the addition of a Golgi transport inhibitor, Brefeldin A. Other known stimuli for NK cells (IL-2 and CD16 monoclonal antibody and incubation with K562, the NK-sensitive cell line) promoted IFN-gamma and TNF-alpha production in NK cells to a lesser extent than did PMA and ionomycin stimulation. CONCLUSIONS: This whole-blood flow cytometric assay appears to be an useful and easy method to examine cytokine production by NK cells and/or by CD3+CD56+ NK-T lymphocytes in patients with relevant diseases.

Brefeldin A↗
PubMed2000

Large-scale UK audit of blood transfusion requirements and anaemia in patients receiving cytotoxic chemotherapy.

Cancer patients receiving cytotoxic chemotherapy often become anaemic and may require blood transfusions. A large-scale audit of patients with a variety of solid tumours receiving chemotherapy at 28 specialist centres throughout the UK was undertaken to quantify the problem. Data were available from 2719 patients receiving 3206 courses of cytotoxic chemotherapy for tumours of the breast (878), ovary (856), lung (772) or testis (213). Their mean age was 55 years (range 16-87). Overall, 33% of patients required at least one blood transfusion but the proportion varied from 19% for breast cancer to 43% for lung. Sixteen per cent of patients required more than one transfusion (7% for breast, 22% in lung). The mean proportion of patients with Hb < 11 g dl(-10 rose over the course of chemotherapy from 17% before the first cycle, to 38% by the sixth, despite transfusion in 33% of patients. Of the patients receiving transfusions, 25% required an inpatient admission and overnight stay. The most common symptoms reported at the time of transfusion were lethargy, tiredness and breathlessness. Further research is needed to evaluate the role of blood transfusions in patients receiving cytotoxic chemotherapy.

Adolescent↗
PubMed1999

Docetaxel in the community setting: an analysis of 377 breast cancer patients treated with docetaxel (Taxotere) in the UK. UK Study Group.

BACKGROUND: Given as first- or second-line chemotherapy docetaxel appears to have great potential in advanced breast cancer. PATIENTS AND METHODS: Three hundred and seventy-seven locally advanced or metastatic breast cancer patients received docetaxel (Taxotere) as part of a named patient programme under the care of 108 oncologists from 61 cancer units across the UK. The recommended starting dose was 100 mg/m2, but patients at higher risk of toxicity started at 75 mg/m2. All patients received corticosteroid premedication. The modal number of prior chemotherapy regimens was 2 (range 1-7). 342 patients (91%) had at least one prior anthracycline-based regimen. RESULTS: Response was graded according to the managing clinician's best judgement without formal criteria. The overall response rate (ORR) was 46% among the 331 evaluable patients. 46% among the 299 patients who were anthracycline resistant and 35% among the 82 patients who were anthracycline refractory (progressive disease being the best response obtained to the most recent anthracycline containing regimen). One hundred and ninety-three patients started at the full dose of 100 mg/m2 with an ORR of 55% and 129 started at 75 mg m2 with an ORR of 33%. In October 1997, some two years after the programme had started, 26 of 377 patients were still alive, although no complete remissions have lasted to this date. Kaplan-Meier survival analysis yielded a median survival of 194 days (95% CI: 178-218 days). Haematological parameters were checked before each course of docetaxel and additionally as clinically indicated. The safety data confirmed that docetaxel has a manageable, predictable side effect profile; 29 of 377 (7.7%) patients were hospitalised as a result of neutropenic sepsis. CONCLUSIONS: The results of this named patient programme over a two year timespan confirm that docetaxel is an effective chemotherapy option in patients with locally advanced and/or metastatic breast cancer, including an 'anthracycline refractory' population.

Adult↗
PubMed1999

Pre-operative chemotherapy in early stage resectable non-small-cell lung cancer: a randomized feasibility study justifying a multicentre phase III trial.

Surgical resection offers the best chance for cure for early stage non-small-cell lung cancer (NSCLC, stage I, II, IIIA), but the 5-year survival rates are only moderate, with systemic relapse being the major cause of death. Pre-operative (neo-adjuvant) chemotherapy has shown promise in small trials restricted to stage IIIA patients. We believe similar trials are now appropriate in all stages of operable lung cancer. A feasibility study was performed in 22 patients with early stage (IB, II, IIIA) resectable NSCLC; randomized to either three cycles of chemotherapy [mitomycin-C 8 mg m(-2), vinblastine 6 mg m(-2) and cisplatin 50 mg m(-2) (MVP)] followed by surgery (n = 11), or to surgery alone. Of 40 eligible patients, 22 agreed to participate (feasibility 55%) and all complied with the full treatment schedule. All symptomatic patients achieved either complete (50%) or partial (50%) relief of tumour-related symptoms with pre-operative chemotherapy. Fifty-five per cent achieved objective tumour response, and a further 27% minor tumour shrinkage; none had progressive disease. Partial pathological response was seen in 50%. No severe (WHO grade III-IV) toxicities occurred. No significant deterioration in quality of life was detected during chemotherapy. Pre-operative MVP chemotherapy is feasible in early stage NSCLC, and this study has now been initiated as a UK-wide Medical Research Council phase III trial.

Adult↗
PubMed1998

A highly sensitive whole blood natural killer cell assay.

The assessment of natural killer cell activity at baseline and the monitoring of this activity during treatment is important in many diseases especially in patients with cancer and AIDS. An optimised and standardised whole blood chromium release assay is described using K562 cells, the standard target erythroleukaemic cell line. The tumour cell lysis observed using whole blood is comparable to that obtained with the standard 4 h lysis assay using peripheral blood mononuclear cells as effector cells. Results with the whole blood assay are reproducible when the incubation with K562 cells is performed over a period of 18 h. The assay necessitates only 0.6 ml of blood collected in 10 IU/ml of sodium heparin as the anticoagulant. In this report, depletion experiments, also standardised using whole blood, show that the effector cells in the whole blood assay are contained within the CD56 + cell population. This assay will be of interest where the immunological status of patients with different diseases need to be frequently monitored.

Anticoagulants↗
PubMed1998

Hutchinson-Gilford progeria: faithful DNA maintenance, inheritance and allelic transcription of beta(1-4) galactosyltransferase.

Hutchinson-Gilford progeria syndrome (HGPS) is a fatal segmental aging disorder affecting children. There is a paucity of prior data at the nucleotide level on DNA maintenance in HGPS. We have examined the specific nucleotide sequences and production of allelic transcripts from the locus GGTB2 encoding beta(1-4) galactosyltransferase. Quantitative Northern blots of mRNA from HGPS and control fibroblasts indicated identical mature beta(1-4) galactosyltransferase transcript sizes and amounts, regardless of their altered glycosylation status. DNA sequencing of cDNA derived from HGPS beta(1-4) galactosyltransferase mRNA populations confirmed the encoded amino acid sequence was unaffected. Population studies of 41 unrelated individuals provided allelic frequency estimates for a novel FokI polymorphism, which was identified in two of six progeria cell strains. The polymorphism was faithfully inherited in a progeria pedigree in a Mendelian manner. Furthermore, the polymorphism provided direct evidence through sequencing of reverse transcription polymerase chain reaction products that both alleles were transcribed and generated mature mRNA. Any defects in transcripts were below detectable levels over the lengths of coding sequences examined, despite multiple replication events from conception leading to the production and maintenance of patient-derived cells. These results indicate faithful transcription in HGPS.

Alleles↗
PubMed1998

Good symptom relief with palliative MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in malignant mesothelioma.

PURPOSE: To evaluate the therapeutic impact of a simple combination chemotherapy regimen on symptoms related to malignant mesothelioma. MATERIALS AND METHODS: Between October 1986 and June 1997, 39 patients with advanced inoperable malignant mesothelioma were treated with palliative MVP (mitomycin-C 8 mg/m2 q. six weeks, vinblastine 6 mg/m2 q. three weeks and cisplatin 50 mg/m2 q. three weeks) chemotherapy and assessed for objective response and relief of symptoms. RESULTS: Eight of 39 patients (20%) achieved an objective partial response with a median duration of nine months: only five patients had progression of disease during chemotherapy. Twenty-four of 39 (62%) had an overall improvement in their symptomology with particularly good responses for pain (79%). These benefits were independent of performance status. Resolution of symptoms was achieved in all responding patients within two treatment cycles. There was no statistically significant difference in duration and incidence of symptom response in those patients achieving radiological PR compared with those with no change and more than 60% of patients with radiological no change obtained useful symptom control. The treatment was well tolerated with only four patients developing grade 3 leucopenia and three with grade 3 nausea. CONCLUSIONS: MVP is a well tolerated regimen and its use in malignant mesothelioma provides useful symptomatic benefit. These results should be the basis for further trials of MVP in the management of mesothelioma with symptom control as a principal endpoint.

Aged↗
PubMed1998

A pilot study of MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in small-cell lung cancer.

MVP chemotherapy (mitomycin C 8 mg m(-2), courses 1, 2, 4 and 6, vinblastine 6 mg m(-2), cisplatin 50 mg m(-2)) is an active low-toxicity regimen in non-small-cell lung cancer (NSCLC). Based on the single-agent activity of these agents in SCLC, we have conducted a phase II trial of MVP in SCLC. Fifty chemo-naive patients with SCLC were entered in this trial. There were 33 men and 17 women with median age 66 years (range 46-83 years); 18 patients had limited disease (LD) and 32 extensive disease (ED). WHO performance status (PS) was: three patients PS 0, 33 patients PS 1, ten patients PS 2, four patients PS 3. A maximum of six cycles was given in responding patients. On completion of chemotherapy, patients with LD obtaining complete response (CR)/good partial response (PR) received thoracic irradiation and those obtaining CR were offered entry into the ongoing MRC Prophylactic Cranial Irradiation Trial. The overall response was 79% with 17% CR and 62% PR. For LD patients, 38% obtained CR but for ED only one patient achieved CR. Median response duration for LD patients was 8 months and for ED patients 5 months. Median survival was 10 months for LD patients and 6 months for ED patients. There was complete resolution of symptoms in 24%, partial improvement in 68%, no change in 2% and progressive symptoms in 6%. As regards toxicity, 24% developed WHO grade 3/4 neutropenia, 16% grade 3/4 thrombocytopenia and 6% significant hair loss. Two patients died during the first week of treatment with neutropenic infection. Quality of life using the EORTC questionnaire (QLC-C30) with lung cancer module demonstrated significant improvements from baseline levels in emotional and cognitive functioning, global QOL, of pain, dyspnoea and cough. MVP, an effective palliative regimen for NSCLC, is also active against SCLC with low toxicity and merits comparison with more toxic conventional schedules.

Aged↗
PubMed1998

Clinical benefit from palliative chemotherapy in non-small-cell lung cancer extends to the elderly and those with poor prognostic factors.

The intention of this study was to identify the pretreatment characteristics predicting for the survival, objective response and symptom relief in patients with non-resectable, non-small-cell lung cancer (NSCLC) managed in the Lung Unit at the Royal Marsden Hospital. This analysis included 290 patients with advanced NSCLC generally treated with a cisplatin-based chemotherapy regimen in one of a series of trials. Thirty-seven pretreatment variables, response and survival data were collected prospectively and analysed using univariate and multivariate methods. By multivariate analysis performance status, disease extent and pattern of metastases along with certain biochemical features were influential independent variables for survival, objective and symptom response. Older age was positively associated with objective response (P = 0.04). When the independent factors for symptom response were used to group patients into prognostic categories, 30-48% of patients with an adverse set of factors had symptom relief. Similarly using the relative risk of death to subgroup the patient population, 54% of patients at high risk of death (greater than 8.0), with a median survival of 2.5 months, had symptom relief. The data are consistent with other studies in identifying the pretreatment factors predicting for survival and objective response. Additionally, older age is positively associated with objective response and the majority of patients with the worst prognosis have symptom relief from treatment with chemotherapy.

Adult↗
PubMed1998

Plasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans.

The purpose of this study was to characterize the absorption and transport of phylloquinone (vitamin K1) by plasma lipoproteins. Twenty-six healthy subjects (11 men and 15 women) aged 20-78 y received phylloquinone in the amount of either 1.43 or 50 microg/kg body wt orally with a fat-rich meal containing 1.0 g/kg body wt of fat, carbohydrate, and protein and 7.0 mg cholesterol/kg body wt. Blood was obtained at baseline (0 h) and 3, 6, 9, and 12 h after the meal for the measurement of plasma lipid and phylloquinone concentrations in plasma and lipoprotein subfractions. In both groups of subjects, triacylglycerol concentrations peaked after 3 h in plasma and in the triacylglycerol-rich lipoprotein fraction, composed of chylomicrons and VLDLs. Plasma phylloquinone concentrations peaked at 6 h. At baseline and during the postprandial phase, > 53% of plasma phylloquinone was carried by the triacylglycerol-rich lipoprotein fraction. In 9 of the 11 subjects supplemented with 50 microg phylloquinone/kg, plasma lipoproteins were isolated by sequential ultracentrifugation. In these subjects the fraction of plasma phylloquinone carried by LDLs and by HDLs increased progressively from 3% and 4% at 3 h to 14% and 11% at 12 h, respectively. Our data indicate that whereas triacylglycerol-rich lipoproteins are the major carriers of phylloquinone, LDL and HDL may carry small fractions of this vitamin.

Administration, Oral↗
PubMed1998

Interaction between vitamin K nutriture and bacterial overgrowth in hypochlorhydria induced by omeprazole.

Subjects taking a hydrogen pump blocking agent (omeprazole) develop bacterial overgrowth of the small intestine. We tested the hypothesis that this bacterial overgrowth produces menaquinones, which would meet the vitamin requirement in situations of vitamin K deficiency. In a crossover-type design, 13 healthy volunteers eating a phylloquinone-restricted diet for 35 d were randomly assigned to take omeprazole during the first period of study or starting on day 15 until the end of the study. Coagulation times, serum osteocalcin [total osteocalcin and undercarboxylated osteocalcin (ucOC)], plasma phylloquinone, urinary gamma-carboxyglutamic acid, and plasma undercarboxylated prothrombin (PIVKA-II) were measured. Plasma phylloquinone concentrations declined 82% with dietary phylloquinone restriction (P < 0.05) and were not significantly different in the period when the diet was combined with omeprazole treatment (P > 0.05). The mean value for PIVKA-II during the phylloquinone-restricted diet significantly increased 5.7-fold from baseline (P < 0.05); however, the combination of omeprazole treatment and the phylloquinone-restricted diet significantly reduced PIVKA-II values by 21% (P < 0.05) compared with the diet period alone. There were no alterations in total or percentage ucOC concentrations during the phylloquinone-restricted diet or during the period of diet plus omeprazole treatment. Our data support the hypothesis that bacterial overgrowth results in the synthesis and absorption of menaquinones. These menaquinones contribute to vitamin K nutriture during dietary phylloquinone restriction, but not enough to restore normal vitamin K status.

1-Carboxyglutamic Acid↗
PubMed1998

Molecular biology of alcohol dependence, a complex polygenic disorder.

Alcohol dependence, and the medical conditions which arise from prolonged excessive alcohol use, have no single cause. Like other complex diseases, they result from a combination of social, personal and genetic contributions; but within any society genetic variation has a substantial influence on individual risk. The genes presently known to affect alcohol dependence produce variation in alcohol metabolism; other genes which affect personality or susceptibility to intoxication are likely to be significant but so far reproducible evidence is scanty. Designs which include related subjects have advantages for the study of complex diseases, because any association effects can be placed in the context of overall heritability and because linkage analysis can also be included. Examples of our studies of alcohol metabolism, consumption and dependence are presented.

Adult↗
PubMed1997

Idiopathic pneumonia syndrome after high-dose chemotherapy for relapsed Hodgkin's disease.

The risk of idiopathic pneumonia syndrome (IPS) in patients with Hodgkin's disease (HD) undergoing high-dose chemotherapy (HDC) is significant, and once developed IPS is potentially fatal. The aim of this study was to quantify this risk accurately and determine prognostic factors for its development and course. Using a computerized database, all patients with HD treated with BCNU (carmustine) containing HDC and haematopoietic support at The Royal Marsden between November 1985 and March 1994 were identified. Patient characteristics, previous treatments, disease status at HDC, dose of BCNU, incidence and severity of IPS and survival were all determined and analysed. During the study period, 94 patients received HDC, of whom 26 (28%) had a first episode of IPS within a year of HDC and 23 within 6 months. The median time to presentation after HDC was 93 days (range 12-336 days). The only factors that significantly increased the risk of developing IPS on multivariate analysis were dose of BCNU (P for trend = 0.03) and female sex (P = 0.04). Of these 26 patients, 14 had complete resolution of all symptoms, three had persisting pulmonary symptoms at 6 months and the remaining nine died of IPS at a median of 74 days (19-418 days). All the patients who died from IPS had the first symptoms within 6 months of HDC and all received doses of BCNU > 475 mg m(-2) (P for trend = 0.001). For women receiving > 475 mg m(-2) the risk of death was significantly higher than for men (P = 0.035) but not for those receiving < 475 mg m(-2). Previous lung disease, persisting residual disease before HDC, previous bleomycin or previous mantle radiotherapy did not increase either the incidence of IPS or risk of a fatal outcome. We conclude that the main avoidable risk factor for fatal IPS after HDC is dose of BCNU, and this is especially true for women. If < 475 mg m(-2) is given, even patients with previous mantle radiotherapy and/or previous bleomycin have a very low risk of developing fatal lung toxicity if lung function tests are normal.

Adolescent↗
PubMed1997

Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects.

The response of osteocalcin and other biochemical markers of vitamin K status to diets formulated to contain different amounts of phylloquinone was assessed in nine healthy subjects aged 20-33 y. Subjects resided in a metabolic ward for two 15-d cycles with a minimum of 6 wk between cycles. A mixed diet containing 100 micrograms phylloquinone/d was fed throughout both cycles; however, the phylloquinone content of one of the cycles was increased to a total of 420 micrograms/d on days 6 through 10 by fortifying corn oil in the diet with phylloquinone (supplemented diet). Total serum osteocalcin concentrations were not affected by either of the dietary treatments. The percentage of undercarboxylated osteocalcin increased an average of 28% over the 15-d cycle with the mixed diet (P < 0.05) and declined significantly an average of 41% with 5 d of the supplemented diet (day 6: 21.9 +/- 1.3%, day 11: 12.8 +/- 1.1%; P = 0.0001) with a rise after the return to the mixed diet (16.7 +/- 1.3%, P < 0.001). Plasma phylloquinone concentrations increased significantly with supplementation (day 6: 0.95 +/- 0.16 nmol/L, day 11: 1.40 +/- 0.29 nmol/L; P < 0.001) and then rapidly returned to presupplementation concentrations on returning to the mixed diet. Twenty-four-hour ratios of urinary gamma-carboxyglutamic acid to creatinine were unchanged with the supplemented diet; however, excretion declined to 91 +/- 2% of baseline after 10 d on the mixed diet (P = 0.01). These results show that undercarboxylated osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid excretion appear to be sensitive measures of vitamin K nutritional status because all of these variables were responsive to changes in dietary intake.

1-Carboxyglutamic Acid↗
PubMed1997

Effect of vitamin K1 supplementation on vitamin K status in cystic fibrosis patients.

BACKGROUND: Patients with cystic fibrosis are at risk for impaired vitamin K status due to fat malabsorption from pancreatic insufficiency. This study was designed to assess vitamin K status and measure the effect of vitamin K1 supplementation in cystic fibrosis patients. METHODS: Eighteen outpatients participated in a crossover study to determine the effect of vitamin K1 (phylloquinone) supplementation. After obtaining initial data, each subject was randomly assigned to either a 4-week study treatment of 5 mg oral vitamin K1 supplementation per week, or no supplementation and then crossed over to the other treatment for a second 4 week period. Plasma, serum and urine samples were collected and analyzed pre-study and at the end of each study period. RESULTS: The mean concentration of plasma vitamin K1 for the supplemented group was significantly higher than the unsupplemented group, [0.34 nmol/L and 0.21 nmol/L, respectively (p < 0.05)]. The percent of undercarboxylated osteocalcin increased on supplementation from 17% to 31%, (p < 0.005). Prothrombin induced in vitamin K absence (PIVKA-II) increased on supplementation from 5 ng/mL to 22 ng/mL, (p < 0.005). The ratio of urinary gamma-carboxyglutamic acid/creatinine was similar for both study periods. CONCLUSIONS: In contrast to other studies in cystic fibrosis, this study demonstrated a need for vitamin K1 supplementation. The carboxylation state of osteocalcin and PIVKA-II were the most sensitive indices of changes in vitamin K1 status. Although the 5 mg vitamin K1/week dose improved these vitamin K parameters, normal levels were not achieved.

1-Carboxyglutamic Acid↗
PubMed1996

Epirubicin, cisplatin, and protracted venous infusion of 5-fluorouracil for esophagogastric adenocarcinoma: response, toxicity, quality of life, and survival.

BACKGROUND: The results of chemotherapy for patients with esophagogastric carcinoma have generally been modest but regimens developed more recently have produced higher response rates, and rekindled interest in neoadjuvant chemotherapy. One such regimen is epirubicin, cisplatin, and 5-fluorouracil (ECF). This study evaluates its efficacy, toxicity, impact on quality of life (QL), and impact on survival in a large consecutive series of patients with metastatic and locally advanced disease (LAD). METHODS: Patients with histologically confirmed esophagogastric carcinoma were treated with ECF (epirubicin 50 mg/m2 and cisplatin 60 mg/m2 every 3 weeks with continuous infusion of 5-fluorouracil (5-FU) 200 mg/m2/d). Responses were evaluated with computed tomography (CT) scan and endoscopy. QL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. RESULTS: A total of 235 patients were treated, 173 with metastatic disease and 62 with LAD. The mean number of cycles delivered was 6 (range: 1-11) and patients were followed-up for a median of 8 months. Response was observed in 135 of 220 (61%) evaluable patients, with a complete response (C(R)), 11% of the patients and a partial response in 50% of the patients. Patients with moderately differentiated adenocarcinomas and LAD responded most favorably. Symptomatic improvement was achieved in the majority of cases (63-78% depending on the symptom). Toxicity was generally only mild to moderate, with severe non hematologic toxicity in less than 12% of the patients and only 6 (2.5%) treatment related deaths. QL assessment showed no significant negative impact on emotional functioning and good symptomatic control. Surgery following response to ECF was performed in 29 of the LAD patients, and in 19 cases (66%) a potentially curative resection was possible, with histologic CR in 32% of the patients. CONCLUSIONS: ECF is a highly active regimen with acceptable toxicity in patients with esophagogastric adenocarcinoma. In a proportion of patients with LAD, chemotherapy enabled potentially curative surgery to be performed. The results justify further investigation of this regimen in a neoadjuvant setting.

Adenocarcinoma↗