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Biomedical subjects

C McArdle

Publications and source records attributed to C McArdle.

At least 19 recordsLinked to original sources
PubMed2003

Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial.

BACKGROUND: Policies of UK clinicians regarding the duration of chemotherapy for patients with advanced colorectal cancer are not consistent. We aimed to compare effectiveness of continuous and intermittent chemotherapy in such patients. METHODS: Patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich, or raltitrexed chemotherapy, were randomised to either intermittent (a break in chemotherapy, re-starting on the same drug on progression), or continuous chemotherapy until progression. FINDINGS: 354 patients (178 intermittent, 176 continuous) were enrolled from 42 UK centres. At randomisation, 41% of participants had part or complete response; 59% were stable. Only 66 (37%) patients allocated to intermittent treatment restarted as planned, after a median of 130 days. Median time on treatment after restarting was 84 days. Patients in the continuous group remained on treatment for a median of a further 92 days. Similar proportions of patients in both groups received second-line therapy. Patients on intermittent chemotherapy had significantly fewer toxic effects and serious adverse events than those in the continuous group. There was no clear evidence of a difference in overall survival (hazard ratio 0.87 favouring intermittent, 95% CI 0.69-1.09, p=0.23). INTERPRETATION: Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression. They showed that it is safe to stop chemotherapy after 12 weeks and re-start the same treatment on progression in patients with chemosensitive advanced colorectal cancer.

Adult↗
PubMed2002

Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial.

BACKGROUND: This randomised trial compared three chemotherapy regimens in the first-line treatment of advanced colorectal cancer, in terms of their effect on overall and progression-free survival; other endpoints included toxicity, symptom palliation, and quality of life. METHODS: 905 patients were randomly assigned the de Gramont regimen (n=303; folinic acid 200 mg/m(2), fluorouracil bolus 400 mg/m(2), and infusion 600 mg/m(2) on days 1 and 2, repeated every 14 days), the Lokich regimen (n=301; protracted venous infusion of fluorouracil 300 mg/m(2) daily), or raltitrexed (n=301; 3 mg/m(2) intravenously every 21 days). Analyses were by intention to treat. FINDINGS: Median follow-up of survivors was 67 weeks. For the de Gramont, Lokich, and raltitrexed groups, respectively, median survival was 294, 302, and 266 days. The hazard ratios for overall survival were 0.88 (95% CI 0.70-1.12, p=0.17) for de Gramont versus Lokich, and 0.99 (0.79-1.25, p=0.94) for de Gramont versus raltitrexed. An increase in treatment-related deaths was seen on raltitrexed (de Gramont one, Lokich two, raltitrexed 18) due to combined gastrointestinal and haematological toxicity. Patients' assessment of quality of life showed that raltitrexed was inferior to the fluorouracil-based regimens, especially in terms of palliation and functioning. INTERPRETATION: The deGramont and Lokich regimens were similar in terms of survival, quality of life, and response rates. The Lokich regimen was associated with more central line complications and hand-foot syndrome. Raltitrexed showed similar response rates and overall survival to the de Gramont regimen and was easier to administer, but resulted in greater toxicity and inferior quality of life.

Adenocarcinoma↗
PubMed2001

Evolution tunes the excitability of individual neurons.

The relationship between the genome and the evolution of the nervous system may differ between an animal like C. elegans with 302 neurons, and mammals with tens of billions of neurons. Here we report that a class of nonconserved potassium channels highly expanded in C. elegans may play a special role in the evolution of its nervous system. The C. elegans genome contains an extended gene family of potassium channels whose members fall into two evolutionary divergent classes. One class constitutes an ancient conserved "set" of K+ channels with orthologues in both humans and Drosophila and a second larger class made up of rapidly evolving genes unique to C. elegans. Chief among this second class are novel potassium channels having four transmembrane domains per subunit that function as regulated leak conductances to modulate cell electrical excitability. This inventory of novel potassium channels is far larger in C. elegans than in humans or Drosophila. We found that, unlike conserved channel genes, the majority of these genes are expressed in very few cells. We also identified DNA enhancer elements associated with these genes that direct gene expression to individual neurons. We conclude that C. elegans may maintain an exceptionally large inventory of these channels (as well as ligand-gated channels) as an adaptive mechanism to "fine tune" individual neurons, making the most of its limited circuitry.

Adaptation, Physiological↗
PubMed1999

Activity of doxorubicin covalently bound to a novel human serum albumin microcapsule.

UNLABELLED: Doxorubicin is widely used in the treatment of human malignancies, however is associated with significant cardiac, bone marrow and gastro-intestinal toxicity. Delivery systems may ameliorate this toxicity and increase treatment specificity by increasing the proportion of drug delivered to sites of disease. We have developed a novel preparation of doxorubicin (Dox) covalently linked to a heat stabilised human serum albumin microparticle (HSAM) carrier (median particle diameter of 4 microm) and assessed its activity in 4 malignant cell lines. MATERIALS AND METHODS: Doxorubicin microcapsules were compared with free doxorubicin in the rat carcinoma cell line, WRC256, and the human lines, OVCAR3, MCF7 and the Dox resistant MCF7/Dox, using a cell counting technique. IC50 were calculated from regression analysis of the resulting survival curves. Endocytosis of the microcapsules by cells in culture was observed. The rate of microcapsule uptake was assessed using dual wavelength filtered fluorescence microscopy and flow cytometry. RESULTS: The mean IC50 following incubation with the Dox microcapsules was around 5 times greater than Dox for WRC256 (p < 0.001), MCF7 (p < 0.01) and for OVCAR3 (p < 0.01). MCF7/Dox was significantly more sensitive to Dox microcapsules than free Dox (p = 0.034). A negative correlation between the rate of microcapsule uptake and the IC50 values for each cell line in culture exists (r = -0.96, p = 0.04). CONCLUSIONS: We conclude that: 1) Doxorubicin microcapsules retain activity in vitro and appear to overcome p-glycoprotein mediated Dox resistance. 2) The observed activity of Dox microcapsules correlates with the rate of particle uptake. Further studies in animal tumour models are in progress.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Controversies in the use of lower extremity sonography in the diagnosis of acute deep vein thrombosis and a proposal for a unified approach.

During the past 10 years, lower extremity venous ultrasonography (LEUS) has essentially replaced contrast venography for the evaluation of patients suspected of acute thromboembolic disease. Along with this change in technology, the number of studies performed to rule out DVT has increased dramatically, and there has been controversy in the literature regarding the most appropriate role of LEUS. Specifically, four questions have been raised: (1) What is the appropriate role of LEUS in patients with a nondiagnostic V/Q scan?; (2) Is there a need to examine the contralateral (asymptomatic) leg of patients presenting with unilateral DVT symptomatology?; (3) What role, if any, does LEUS play in the evaluation of patients with bilateral leg symptoms?; and (4) When can a limited examination of the leg be performed? The purpose of this article is to provide a balanced review of these issues and to present an algorithm for a reasonable, integrated approach to the use of LEUS among patients suspected of having acute thromboembolic disease.

Acute Disease↗
PubMed1996

The luteal heat cycle of the breast in disease.

Wearing a special thermometric brassiere, selected women self-measured their breast surface temperature. These measurements were made during one hour each evening at home for one menstrual cycle under standard conditions of overclothing and room temperature. To stage their cycle they also collected daily samples of saliva in their freezer for immuno-assay of progesterone concentration in the laboratory. A total of 82 women participated, most having young families. This total included four groups, a control group (N = 25) and three 'disease' groups, namely: family history of breast cancer (14); benign breast disease (12); and a 'cancer-associated' group (31) who had had previous cancer surgery. A significant breast temperature rhythm with a period at or about 28 days was found not only in the controls but also in the three groups of breasts designated 'disease'. Nevertheless, consistent rhythm abnormalities were found in all the disease groups. Most evident was a hyperthermia throughout the cycle, a reduction in the rhythm amplitude, and a tendency for the breast temperature rhythm to be manifest 1-2 days earlier in the menstrual cycle.

Adult↗
PubMed1996

Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group.

PURPOSE: To determine whether a combination chemotherapy regimen that contains epirubicin (fluorouracil, epirubicin, and cyclophosphamide [FEC]) is superior to the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in premenopausal women with axillary node-positive operable breast cancer. PATIENTS AND METHODS: The International Collaborative Cancer Group (ICCG) conducted a large randomized trial in which two alternative schedules were used according to participating center: CMF1 versus FEC1 and CMF2 versus FEC2. RESULTS: Seven hundred fifty-nine patients were entered onto the trial. At a median follow-up time of 4.5 years, no significant benefit for the anthracycline-containing regimen was observed in terms of relapse-free (P = .61) or overall survival (P = .13). FEC1 and CMF1 appear to be of similar efficacy, but there is a suggestion that FEC2 may be superior to CMF2, since patients who received FEC2 had improved overall (P = .02) and relapse-free survival (P = .03) rates. Nausea and vomiting and alopecia were more common in the epirubicin-containing regimen (P = .001). CONCLUSION: We conclude that the FEC2 regimen, in which epirubicin replaced the methotrexate in CMF, is the preferable adjuvant chemotherapy regimen for premenopausal patients with operable axillary node-positive breast cancer.

Adult↗
PubMed1996

Compression sonography in patients with indeterminate or low-probability lung scans: lack of usefulness in the absence of both symptoms of deep-vein thrombosis and thromboembolic risk factors.

OBJECTIVE: We sought to determine whether compression sonography could be eliminated in the evaluation of patients who lacked both thromboembolic risk factors and symptoms of deep-vein thrombosis and who had an indeterminate or low-probability lung scan. MATERIALS AND METHODS: The medical records of 155 consecutive patients who underwent bilateral lower-extremity sonography after an indeterminate or low-probability lung scan were reviewed. The presence of thromboembolic risk factors and deep-vein thrombosis symptoms and the result of sonography were recorded. Patients were divided into two groups: group 1 consisted of patients with either thromboembolic risk factors or deep-vein thrombosis symptoms, and group 2 consisted of patients without thromboembolic risk factors and without deep-vein thrombosis symptoms. The incidences of deep-vein thrombosis in groups 1 and 2 were compared by use of a two-tailed Fisher's exact test. RESULTS: Thromboembolic risk factors or deep-vein thrombosis symptoms were found in 109 of 155 patients (70%) (group 1). Deep-vein thrombosis was found in nine of 108 patients (8%) in group 1. Both thromboembolic risk factors and deep-vein thrombosis symptoms were absent in 47 of 155 patients (30%) (group 2). Deep-vein thrombosis was found in none of 47 patients (95% confidence interval, 0-8%) in group 2. The difference in the incidences of deep-vein thrombosis in groups 1 and 2 approached statistical significance (p = .0579). The negative predictive value of the absence of both thromboembolic risk factors and deep-vein thrombosis symptoms in excluding deep-vein thrombosis was 100% (95% confidence interval, 93-100%). CONCLUSION: If both symptoms of deep-vein thrombosis and thromboembolic risk factors are absent, the usefulness of lower-extremity sonography in detecting deep-vein thrombosis in patients with an indeterminate or low-probability lung scan is low. The manner in which these findings may be used to modify individual practice patterns will undoubtedly depend on the rate of detection of deep-vein thrombosis at a given institution.

Algorithms↗
PubMed1995

A non-invasive test for the pre-cancerous breast.

This paper describes a non-invasive, self-measured procedure by which the precancerous breast can be distinguished from the normal breast. The method involves wearing a specially designed thermometric brassiere for 90 min each evening at home through one menstrual cycle. Profiles of progesterone through the cycle, obtained from daily saliva sampling, and determination of the steroid content by radioimmunoassay, are made to allow the status and calendar date timing of the luteal phase to be established. Thus, cycles can be synchronised across subjects. In this study, two types of breast were compared: 50 normal breasts and 41 age-matched precancerous breasts. Differences between the groups were striking in terms of amplitude, phasing and average temperature during the luteal heat cycle. When these parameters and others were used as predictors in a linear discrimination and/or neural net analysis, a sensitivity and specificity of > 90% was achieved.

Adult↗
PubMed1995

Pituitary adenylate cyclase activating peptide-38 (PACAP-38), PACAP-27, and PACAP related peptide (PRP) in the rat median eminence and pituitary.

Pituitary adenylate cyclase activating peptide (PACAP) is a member of the vasoactive intestinal peptide-like peptide family. It is found in the hypothalamus, where the PACAP precursor is processed to form PACAP-38, the C-terminal truncated PACAP-27 and PACAP related peptide (PRP). Both PACAPs are potent stimulators of anterior pituitary adenylate cyclase activity, but the physiologically relevant anatomical sources of PACAP and possible importance of PRP in this regard are poorly understood. Using immunocytochemistry with epitope-specific antisera, we now show that PACAP38-, PACAP27- and PRP-positive nerve fibres are all present in the rat median eminence. The major immunoreactive species present was PACAP38. Numerous PACAP38-immunoreactive nerve fibres were observed in the internal layer and a few were present in the posterior pituitary lobe. The external layer of the median eminence contained a few PACAP-38-immunoreactive fibres and PACAP-38-positive nerve terminals were rarely seen in the perivascular portal spaces. Surprisingly, delicate PACAP-38-positive nerve fibres were identified in the anterior pituitary lobe intermingled between the pituitary cells although none of the secretory pituitary cells contained immunoreactive PACAP38, PACAP27 or PRP and preproPACAP mRNA was not detected in the gland by Northern blotting or in situ hybridization. PACAP-27- and PRP-immunoreactive nerve fibres and terminals were found in the same locations as PACAP-38 although generally in lower numbers. Specific radioimmunoassays and HPLC revealed that PACAP-38 accounts for the vast majority of the adenohypophyseal PACAP-immunoreactivity, whereas PACAP-27 and PRP were found in low to undetectable concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The luteal heat cycle of the breast in health.

Wearing a special thermometric brassiere, twenty-five normal women self-measured their breast surface temperature. The subjects averaged 39 years of age and all were parous. Observations were made for one hour each evening for one menstrual cycle under semi-standardized domestic conditions. They also collected daily samples of saliva for radioimmunoassay of progesterone concentration. The surface temperature of the breast is relatively cold around mid-cycle; thereafter, and without interruption in averaged data, the temperature increases steadily by about 1 degree C over the 12 days of the luteal phase; around the time of the menses, it falls rapidly. This heat rhythm does not occur in peri-menopausal low progesterone menstrual cycles or in patients where the breast tissue has been irradiated for cancer treatment.

Adult↗
PubMed1993

Coincidental occurrence of primary hyperparathyroidism and cancer-associated hypercalcaemia in a middle-aged man.

Primary hyperparathyroidism (PHPT) is found not uncommonly in patients with cancer. In this report, however, we describe a patient where both humoral hypercalcaemia of malignancy and PHPT were present coincidentally. A 47-year-old man was found to have PHPT due to parathyroid hyperplasia. Serum parathyroid hormone (PTH) levels, which were elevated before parathyroidectomy, were undetectable post-operatively; however, hypercalcaemia persisted. Nephrogenous cyclic adenosine monophosphate was elevated along with this undetectable PTH, indicative of the presence of a PTH-like factor in the serum. This was confirmed by the finding of an elevated level of PTH-related protein (PTHrP) in plasma (9.1 pmol/l, normal < 2.6 pmol/l). Secondary carcinoma was identified in a lesion in the region of the manubrium sternii. This stained positively for PTHrP by immunocytochemistry and PTHrP messenger RNA was detected by in-situ hybridization. This case illustrates the value of sensitive PTH assays in distinguishing PHPT from other causes of hypercalcaemia and also shows the importance of considering primary hyperparathyroidism in the differential diagnosis of the patient with cancer and hypercalcaemia.

Bone Neoplasms↗
PubMed1992

Removal of retained intrauterine contraceptive devices in pregnancy.

Using real-time ultrasound and clinical expertise gained from chorionic villus sampling, we describe a technique for ultrasound-guided intrauterine device removal in those cases in which the string is not visible. Utilizing a stone clamp for intrauterine manipulation, we were easily able to extract the device without interrupting the pregnancy. We concur with recent recommendations advocating all intrauterine devices can be removed if pregnancy termination is declined.

Adult↗