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Biomedical subjects

R J Stephens

Publications and source records attributed to R J Stephens.

At least 55 records · Page 3Linked to original sources
PubMed1995

Symptoms at presentation for treatment in patients with lung cancer: implications for the evaluation of palliative treatment. The Medical Research Council (MRC) Lung Cancer Working Party.

The ten most frequently reported pretreatment symptoms on the Rotterdam Symptom Checklist, which was completed by more than 650 patients entering two MRC Lung Cancer Working Party multicentre randomised trials, included general symptoms (tiredness, lack of appetite) and psychological distress (worry, anxiety) in addition to disease-related chest symptoms (cough, shortness of breath). Although the number and severity of symptoms increased with worsening performance status, the commonest symptoms were found to be virtually the same for patients with small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and for different grades of performance status. Women with NSCLC reported more psychological symptoms than males, but this difference was much less evident in patients with SCLC. Thus, in order to assess fully the benefit of palliative treatments in patients with lung cancer, account must be taken of all symptoms at presentation, in addition to the traditionally recognised chest symptoms.

Adult↗
PubMed1995

Evidence of a locus for orofacial clefting on human chromosome 6p24 and STS content map of the region.

Orofacial clefting is genetically complex, no single gene being responsible for all forms. It can, however, result from a single gene defect either as part of a syndrome (e.g. van der Woude syndrome, Treacher-Collins syndrome, velo-cardio-facial syndrome) or as an isolated phenotypic effect (e.g. X-linked cleft palate; non-syndromic, autosomal dominant orofacial clefting). Several studies have suggested that chromosome 6p is a candidate region for a locus involved in orofacial clefting. We have used YAC clones from contigs in 6p25-p23 to investigate three unrelated cases of cleft lip and palate coincident with chromosome 6p abnormalities. Case 1 has bilateral cleft lip and palate and a balanced translocation reported as 46,XY,t(6,7)(p23;q36.1). Case 2 has multiple abnormalities including cleft lip and palate and was reported as 46,XX,del(6)(p23;pter). Case 3 has bilateral cleft lip and palate and carries a balanced translocation reported as 46,XX,t(6;9)(p23;q22.3). We have identified two YAC clones, both of which cross the breakpoint in cases 1 and 3 and are deleted in case 2. These clones map to 6p24.3 and therefore suggest the presence of a locus for orofacial clefting in this region. The HGP22 and AP2 genes, potentially involved in face formation, have been found to flank this region, while F13A maps further telomeric in 6p24.3/25.

Abnormalities, Multiple↗
PubMed1994

Binding of the lipid peroxidation product 4-hydroxynonenal to human polymorphonuclear leukocytes.

4-Hydroxynonenal (HNE) is produced during peroxidation of polyunsaturated fatty acids. It exerts a chemokinetic effect on human polymorphonuclear leukocytes (PMN). Investigations of this mechanism were performed. The results indicate that [3H]-HNE binding to PMN results both in non-specific bonds to the numerous SH groups of the cells and in binding to a saturable, reversible and specific HNE site. Scatchard analysis revealed that this is a single site with an apparent affinity constant of 319 nM and a density of 1.57 pmol (10(6))-1 cells. This specific binding site may be involved in the chemokinetic effect of HNE.

Aldehydes↗
PubMed1994

Approaches to the analysis of quality of life data: experiences gained from a medical research council lung cancer working party palliative chemotherapy trial.

Standardization in the choice of quality of life (QOL) instruments and their application in randomised clinical trials have been advocated and generally accepted. However, there is now an urgent need to address the problems relating to the analysis and presentation of the data thus generated. There are intrinsic difficulties associated with QOL data, namely its multidimensional nature, attrition and missing data, and there is no consensus as to how these problems should be dealt with. This paper therefore considers these problems using interim data from a large Medical Research Council randomised trial in patients with small cell lung cancer and a poor prognosis, in which attrition and compliance are major concerns. Three possible approaches to the analysis of these data, which use different subsets of patients, are examined in detail. The strengths and weaknesses of these three methods are discussed, and examples of their use in the literature are given and compared with other reported approaches. The need for a standard definition of compliance is also emphasised, and a method of presentation suggested. The best current advice is that QOL data should be analysed in a number of different ways, and conclusions reached only when consistency is seen.

Antineoplastic Agents↗
PubMed1994

Treatment-related deaths in small cell lung cancer trials: can patients at risk be identified? Medical Research Council Lung Cancer Working Party.

OBJECTIVES: This paper investigates the problem of treatment-related deaths in small cell lung cancer (SCLC). DESIGN: To observe and define increased hazard levels, and to identify factors relating to these excess deaths. SETTING: The United Kingdom. SUBJECTS: A total of 2196 patients entered into the series of six randomised clinical trials in SCLC conducted by the Medical Research Council (MRC) Lung Cancer Working Party (LCWP). RESULTS: In this large series of patients an increased risk of death in the second week after commencing the first cycle of chemotherapy was observed, suggesting that of the 10% of patients who died within 3 weeks of starting chemotherapy, half may have been treatment-related. Much less additional risk was associated with subsequent cycles of chemotherapy, and no additional risk with either initial surgery or radiotherapy. Radford et al. [Eur J Cancer 1993; 29A: 81-86] suggested that the risk factors for death from sepsis were a Karnofsky Performance (KP) score of < or = 50 (translated as a WHO performance grade (PS) > or = 3), age > 50 years and three or more drugs in the chemotherapy regimen utilised. Starting with this model we found that our data suggest it can be refined by omitting age and including a white blood cell count > or = 10,000/mm3 (this variable was not tested by Radford), and changing the other categories to WHO PS > or = 2 (KP < or = 70), and four or more drugs. Within our data this revised model identified a high risk group of patients with an excess death rate of more than 15% in the second week after starting chemotherapy. Radford et als' suggestion that high risk patients be given half doses of drugs at the first cycle should be tested in a randomised clinical trial.

Aged↗
PubMed1994

Does clinical experience with a treatment regimen affect survival of lung cancer patients? An analysis based on consecutive randomized trials of the Medical Research Council in small cell and non-small cell tumours. Medical Research Council Lung Cancer Working Party.

This paper investigates the influence on patient survival of an individual clinician's experience with a particular treatment regimen and the collective experience of the centre through which the patient is recruited to a particular clinical trial. Data were available from two series of randomized trials, one series in small cell and the other in non-small cell lung cancer, which were conducted by the Medical Research Council Lung Cancer Working Party. Successive small cell trials used the same chemotherapy regimen and successive non-small cell trials the same radiotherapy regimen. We found no evidence that either the degree of experience of individual clinicians with the regimen or the participation in terms of number of patients recruited to centres influenced patient survival. There is a strong suggestion, in non-small cell lung cancer that, as clinicians' experience with the regimen extended, they became increasingly likely to admit patients in poor condition to the trials. We stress how important it is to take account of patient prognostic characteristics in such an analysis, as we found that unadjusted comparisons suggested negative influences of increasing experience with the regimen. The implications for routine audit are self evident, in particular that it is not a substitute for the randomized controlled trial.

Aged↗
PubMed1994

Can long-term survival be improved in patients with small-cell lung cancer (SCLC) and good performance status? Medical Research Council Lung Cancer Working Party.

Results from a long-term follow-up suggest that in patients with limited small-cell lung cancer (SCLC) and normal performance status intensive alternating chemotherapy and radiotherapy improve long-term survival rates. In a non-randomised study, 22 patients with SCLC of limited extent and good performance status were prescribed six cycles of etoposide, doxorubicin, cisplatin and cyclophosphamide at 4 week intervals with doses of thoracic radiotherapy following the second, third and fourth cycles. Although only six patients received all their prescribed treatment, nine (41%) were alive at 1 year, seven (32%) at 2 years, six (27%) at 3 years, and four are still alive at, respectively, 42, 47, 50, and 61 months, all four being in the subgroup of eight patients with WHO performance status grade 0 at the start of treatment. In a comparison with similar patients receiving conventionally scheduled chemotherapy and radiotherapy in a concurrent trial, no difference in survival was seen in the patients with performance status grade 1 or 2, but a large difference in favour of the alternating schedule in those with grade 0 status was seen. We encourage other investigators to report the results achieved with intensive treatment in patients with WHO grade 0 performance status at the start of treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party.

A total of 458 eligible patients, from 21 centres, with histologically or cytologically confirmed SCLC were allocated at random to three chemotherapy regimens, each given at 3-week intervals. In two regimens, etoposide, cyclophosphamide, methotrexate and vincristine were given for a total of either three courses (ECMV3) or six courses (ECMV6). In the third regimen, etoposide and ifosfamide were given for six courses (EI6). Patients with limited disease (56% of the total) also received radiotherapy to the primary site after the third course of chemotherapy in all three groups. A partial response occurred in 45% of 144 ECMV3 patients, 48% of 141 ECMV6, and 53% of 141 EI6 patients assessed, and a complete response in a further 15%, 9%, and 13% respectively, giving total response rates of 60%, 57%, and 67%, respectively. There was no overall survival advantage to any of the three regimens. At 1 year, 24%, 29%, and 30% of patients were alive, and at 2 years 7%, 8%, and 9%, respectively. The median survival time was 7.4 months in the ECMV3 group, 8.6 months in the ECMV6 group and 8.8 months in the EI6 group. The individual factors: poor performance status, extensive disease, the presence of dysphagia and a raised white blood cell count on admission adversely affected prognosis. The results do not exclude the possibility of a minor survival advantage with the two 6-course regimens. The findings on quality of life are presented in the companion paper (MRC Lung Cancer Working Party, 1993b).

Adult↗
PubMed1993

A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). II: Quality of life. Medical Research Council Lung Cancer Working Party.

A total of 458 eligible patients, from 21 centres, with microscopically confirmed SCLC were allocated at random to three chemotherapy regimens, each given at 3-week intervals. In two regimens, etoposide, cyclophosphamide, methotrexate and vincristine were given for a total of either three courses (ECMV3) or six courses (ECMV6). In the third regimen, etoposide and ifosfamide were given for six courses (E16). Patients with limited disease also received radiotherapy to the primary site after the third course of chemotherapy in all three groups. As reported by clinicians, 59% of the ECMV3, 67% of the ECMV6 and 63% of the EI6 patients experienced moderate or severe adverse reactions to their chemotherapy. The major symptoms of disease, cough, haemoptysis, chest pain, anorexia, and dysphagia, were palliated in 63% or more of patients and the median duration of palliation was 63% or more of survival, the results being similar in the three groups. Among patients with poor overall condition, physical activity and breathlessness on admission, the proportions who improved were higher in the EI6 group but the differences were small. In all three groups, levels of anxiety fell substantially during treatment. Levels of depression were lower and showed little change. As assessed by patients using a daily diary card, the patterns of nausea, vomiting, activity and mood, associated with courses of chemotherapy were very similar in the three groups. In the EI6 group there was less dysphagia and better overall condition between courses, but these advantages need to be weighed against the inconvenience of the 24-h infusions required, compared with the 30-min infusions of the other two regimens. As reported in the companion paper (MRC Lung Cancer Working Party, 1993a) there was no statistically significant survival advantage to any of the three regimens, although the results do not exclude the possibility of a minor survival advantage with the two six-course regimens. In conclusion, there was no major clinical gain from continuing chemotherapy beyond three courses or from using the ifosfamide regimen.

Adult↗
PubMed1993

How reliable is the diagnosis of lung cancer using small biopsy specimens? Report of a UKCCCR Lung Cancer Working Party.

BACKGROUND: A study was undertaken to investigate the accuracy of typing of a series of bronchial carcinomas by experienced pathologists with an interest in lung cancer from the examination of bronchoscopic biopsy specimens. METHODS: Eighty bronchial biopsy specimens showing positive results for bronchial carcinoma were circulated to five pathologists, who recorded diagnostic criteria and diagnosis for each. Diagnoses were then compared with the diagnosis agreed from the resection specimen corresponding to each biopsy specimen. A "non-small cell carcinoma, not further specified" classification group was introduced for small biopsy specimens. RESULTS: A diagnostic accuracy of 75% was achieved for squamous cell carcinomas, 66% for small cell carcinomas, and 50% for adenocarcinomas. There was diagnostic confusion between small cell and non-small cell carcinoma in less than 10% of cases. The introduction of a non-specific non-small cell classification improved diagnostic accuracy by 10-15% for each non-small cell tumour group. CONCLUSIONS: There are appreciable inaccuracies in applying the World Health Organisation's 1981 classification of lung cancer to the diagnosis of bronchial carcinoma from small biopsy specimens and these inaccuracies have been measured. They can be diminished by introducing a less specific "non-small cell" category for use with this sort of biopsy material. Care should be taken not to overinterpret small biopsy specimens in lung cancer.

Biopsy↗
PubMed1992

Quantitative determination of hydroxy fatty acids as an indicator of in vivo lipid peroxidation: oxidation products of arachidonic and docosapentaenoic acids in rat liver after exposure to carbon tetrachloride.

An improved gas chromatography-mass spectrometry method has been applied to the quantitation of both in vitro and in vivo products of lipid peroxidation in rat liver stimulated with carbon tetrachloride. The method avoids problems of autoxidation of unsaturated fatty acids during sample preparation, and the sensitivity permits assays on as little as 1 mg of tissue. This permits small samples of tissue to be obtained by biopsy from the same organ, thus making it possible to perform in vivo time studies on a single animal. Lipids from whole tissue or cell preparations are simultaneously extracted and reduced by catalytic hydrogenation and then saponified and derivatized to their pentafluorobenzyl esters and trimethylsilyl ethers. Quantitation is accomplished by negative ion chemical ionization gas chromatography-mass spectrometry, using either deuterated compounds or naturally occurring fatty acid metabolites as internal standards. Hydroxy fatty acids which result from reduction of the hydroperoxides of arachidonic and docosapentaenoic acids are found to increase within 20 min after exposure of liver or hepatocyte suspensions to carbon tetrachloride.

Animals↗
PubMed1991

Quantitative determination of hydroxy fatty acids as an indicator of in vivo lipid peroxidation: gas chromatography-mass spectrometry methods.

A new method has been developed for the quantitation of lipid peroxidation products by gas chromatography-mass spectrometry. An important advantage over existing gas chromatography-mass spectrometry methods is the elimination of autoxidation during sample preparation. The sensitivity is sufficient to permit measurement of lipid peroxidation products under normal physiological conditions on as little as 1 mg of tissue. Lipids from whole tissue samples or cell preparations are reduced by catalytic hydrogenation during extraction. The hydrogenation stabilizes the compounds by saturating the double bonds and reducing the hydroperoxides to hydroxy derivatives. The saturated lipids are then saponified and the resulting fatty acids are converted to pentafluorobenzyl esters. Hydroxy fatty acids are further converted to trimethylsilyl ether derivatives. Quantitation is accomplished by negative ion chemical ionization gas chromatography-mass spectrometry, using deuterated internal standards. Specific products from polyunsaturated fatty acids can be quantitated, and the method differentiates between products produced by free-radical and photooxidation mechanisms. Increased levels of lipid peroxidation products, above normal physiological levels, that result from prooxidant conditions, such as exposure of animals to carbon tetrachloride, can be measured.

Animals↗
PubMed1991

Assessment of quality of life in small-cell lung cancer using a Daily Diary Card developed by the Medical Research Council Lung Cancer Working Party.

Three hundred and sixty-nine patients in an MRC study of combination chemotherapy and radiotherapy for small-cell lung cancer of limited extent were asked to complete a Daily Diary Card which enabled an assessment of their quality of life to be made during and after treatment. The information derived from the card suggests that although cytotoxic chemotherapy has an adverse effect upon quality of life, this impairment only affects the first 2 or 3 days following each course of treatment, although there is also a small deterioration which may be associated with the 'nadir' effect of the blood counts about 10 days after each course. These results should assist physicians in counselling patients about the likely effects of treatment. Just over half of the patients (196) were subsequently randomised to either a further six courses of maintenance chemotherapy or no further chemotherapy, and it is also shown that the patients allocated to no maintenance chemotherapy experienced a gradually deteriorating quality of life, as opposed to the brief but more severe adverse effects which occurred following each course in the maintenance chemotherapy group; this supports the hypothesis of a palliative effect in this latter group. The findings demonstrate that the Daily Diary Card is a sensitive instrument capable of yielding useful information.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

A Medical Research Council phase II trial of alternating chemotherapy and radiotherapy in small-cell lung cancer. The Medical Research Council Lung Cancer Working Party.

In a non-randomised study in six centres in the UK, 24 patients with previously untreated small-cell lung cancer of limited extent were treated with a regimen of alternating chemotherapy and radiotherapy to assess response, toxicity, and the feasibility of applying such a regimen on a multicentre basis in the UK. The intention was to give six courses of chemotherapy on five consecutive days at 4-week intervals: etoposide 75 mg m-2 on days 1, 2, and 3; doxorubicin 40 mg m-2 on day 1; cisplatin 100 mg m-2 on day 2; and cyclophosphamide 300 mg m-2 on days 2, 3, 4 and 5. A dose of 20 Gy thoracic radiotherapy was to be given following the 2nd and the 3rd courses, and one of 15 Gy following the 4th course. After 12 patients had been admitted, the cisplatin dosage was reduced to 80 mg m-2 because of unacceptable toxicity. Two patients were withdrawn during treatment on review of their histology because their diagnosis was found to be incorrect. Only one patient of the 12 treated with cisplatin 100 mg m-2 was able to complete treatment, compared with five of the eligible ten given the lower dosage. Among the 22 patients with confirmed small-cell disease, a complete response was reported in 14 (64%) and a partial response in a further three (total response rate 77%). Myelosuppression was the commonest serious adverse effect. It occurred in 19 of the 24 patients and gave rise to septicaemia in five, four of whom were receiving the higher cisplatin dose. Sixteen patients required blood transfusion and ten platelet transfusion. Vomiting, oesophagitis, and peripheral neuropathy occurred in 12, four and four patients, respectively, and radiation pneumonitis developed in two. Treatment was considered a contributory cause of death in four. The working party concluded that the alternating regimen was feasible in only a small proportion of centres in the UK, and decided not to embark on a multicentre randomised trial comparing alternating with conventional scheduling.

Activities of Daily Living↗
PubMed1989

The thermogenic actions of alpha 2-adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic alpha 2-adrenoceptor mechanism.

1. The dose-related effects of the selective alpha 2-adrenoceptor agonists clonidine, UK-14,304 and B-HT 933 on the body temperature of untreated and reserpine-treated mice were investigated. 2. In untreated mice all three agonists induced a dose-related hypothermia. The highest doses of UK-14,304 and B-HT 933, 3 and 100 mg kg-1 respectively, elicited a marked (10 degrees C) hypothermia, whereas the maximal hypothermic effect of clonidine (5.5 degrees C) was less pronounced and reached a plateau at a dose of 0.5 mg kg-1 i.p. 3. Reserpine (2.5 mg kg-1, s.c.) induced a marked hypothermia in the mouse; 18 h after injection body temperature had decreased to only slightly (0.5-1.5 degrees C) above ambient (19 degrees C). 4. All three alpha 2-agonists produced a partial dose-related reversal of reserpine-induced hypothermia; maximal thermogenic responses (9-10 degrees C increases in body temperature) were elicited by doses of 0.2, 0.5 and 16 mg kg-1 i.p. of clonidine, UK-14,304 and B-HT 933 respectively, and the log dose-response curves for all 3 agonists were bell-shaped. 5. Following intracerebroventricular administration to reserpine-treated mice, the thermogenic response to clonidine was more rapid in onset, and the agonist was 20 fold more potent than when injected i.p. 6. The selective alpha 2-adrenoceptor antagonists, idazoxan (0.05-0.5 mg kg-1), Wy 26392 (0.3-5.0 mg kg-1) and yohimbine (0.1-1.6 mg kg-1) given orally attenuated the thermogenic responses to all 3 agonists in reserpinized mice in a dose-related manner. Pretreatment with a single dose of idazoxan (0.3 mg kg-1, orally) elicited a 6 fold parallel shift to the right in the dose-response curve to clonidine. 7. The selective alpha 1-adrenoceptor antagonists, prazosin (10 mg kg-1) and indoramin (3-10 mg kg-1), and the beta-adrenoceptor antagonist, propranolol (10 mg kg-1), only partially attenuated the thermogenic responses to the alpha 2-agonists in reserpinized mice. These effects were variable and not clearly dose-related. 8. Pretreatment of reserpinized mice with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, markedly attenuated (60-95%) the thermogenic response to the noradrenaline uptake inhibitor, desipramine (0.13-12.5 mg kg-1, i.p.), but only slightly reduced (10-35%) that to clonidine (0.032-0.5 mg kg-1, i.p.). 9. These results suggest that alpha2-adrenoceptor agonists reverse reserpine-induced hypothermia via a central mechanism involving activation of postsynaptic alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗