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Biomedical subjects

M Moriarty

Publications and source records attributed to M Moriarty.

At least 19 recordsLinked to original sources
PubMed2005

Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

AIMS: To standardize the pathological analysis of total mesorectal excision specimens of rectal cancer following neoadjuvant chemoradiotherapy for locally advanced disease (T3/T4), including tumour regression. METHODS AND RESULTS: Standardized dissection and reporting was used for 60 patients who underwent total mesorectal excision following long-course chemoradiotherapy. Tumour regression was scored by two pathologists (K.S., D.G.) using both an established 5-point tumour regression grade (TRG), and a novel 3-point grade. Both scores were evaluated for interobserver variability. A complete or near-complete pathological response (3-point TRG 1) was found in 10 patients (17%). Using the 5-point TRG, there was good agreement between both pathologists (kappa = 0.64). Using the 3-point grade, agreement was excellent (kappa = 0.84). No disease recurrence has been reported in patients with a complete, or near complete pathological response (3-point TRG 1), after a mean follow-up of 22 months. CONCLUSION: Tumour regression grade is a useful method of scoring tumour response to chemoradiotherapy in rectal cancer. TRG 1 and 2 can be regarded as a complete pathological response (ypT0). A modified 3-point grade has the advantage of better reproducibility, with similar prognostic significance.

Adult↗
PubMed2004

Improvement in efficacy of chemoradiotherapy by addition of an antiangiogenic agent in a murine tumor model.

BACKGROUND: Chemoradiotherapy improves survival for some cancer patients. Methods of enhancing treatment response would further enhance survival rates. The effect of the addition of an antiangiogenic agent to a chemoradiotherapy regime has not previously been examined. MATERIALS AND METHODS: C57B16 mice were inoculated with 1 x 10(6) Lewis lung carcinoma cells into the flank and randomized to 1 of 10 treatment groups when tumor volume approached 1000 mm(3). Animals received combinations of standard doses of intraperitoneal cisplatin, 5-fluorouracil, and the antiangiogenic agent genistein, together with 10 or 20 Gy of external beam radiotherapy. Animals were sacrificed at day 6 when tumor volume, microvessel density, and serum VEGF were determined. RESULTS: Mean (SEM) tumor volume in the chemoradiotherapy group was 762 (212) mm(3) versus 565 (79) mm(3) in the chemoradiotherapy plus genistein group (P = 0.04, unpaired t-test). The addition of genistein produced a significant reduction in tumor microvessel density (P = 0.01) as well as serum VEGF levels (P < 0.05) compared to those animals receiving chemoradiation alone. CONCLUSIONS: This study provides proof of principle that chemoradiation can be enhanced by the addition of an antiangiogenic agent to the regime and suggests that further examination of such regimes is warranted.

Angiogenesis Inhibitors↗
PubMed2003

Monoamine oxidase inhibitors l-deprenyl and clorgyline protect nonmalignant human cells from ionising radiation and chemotherapy toxicity.

l-Deprenyl (R-(-)-deprenyl, selegiline) is an inhibitor of monoamine oxidase-B (MAO-B) that is known to protect nerve cells from a variety of chemical and physical insults. As apoptosis is a common mechanism of radiation-induced cell death, the effect of l-deprenyl on the survival of cultured cells and tissue explants was studied following exposure to gamma radiation. The results obtained were compared with the effects of the less-selective MAO-B inhibitor pargyline and the MAO-A inhibitor clorgyline. l-Deprenyl at a concentration of 10(-9) M protected the nontumorigenic cell line (HaCaT) and normal human urothelial explants from the effects of cobalt-60 gamma radiation, but did not protect tumorigenic human cell lines HaCaT-ras, HPV-transfected human keratinocytes (HPV-G cells), or PC3. Human bladder carcinoma explants were not protected. Clorgyline showed a smaller protective effect of normal cells, whereas pargyline had no effect. Radiation-induced delayed effects (genomic instability measured as delayed cell death) were prevented in normal cells by l-deprenyl but, interestingly, deprenyl appeared to increase the amount of delayed death in the tumorigenic cell lines. Studies using l-deprenyl prior to the exposure of nonmalignant cells to cisplatin showed that cell death due to this agent was also reduced. Treatment of cultures of nontumorigenic cells with l-deprenyl or clorgyline significantly increased the levels of the protein Bcl-2 following irradiation, but there was no such effect on the already-elevated levels of this protein in the tumour samples. Since the Bcl-2 has been shown to be an inhibitor of apoptosis or programmed cell death, this would imply that the protective effects of l-deprenyl and clorgyline involve activation of antiapoptotic pathways within the normal cell. This hypothesis is supported by data showing reduced levels of apoptosis in HaCAT cells and in normal bladder explant cultures following treatment with l-deprenyl.

Animals↗
PubMed2001

BB-10010, an analog of macrophage inflammatory protein-1alpha, protects murine small intestine against radiation.

Irradiation of the small intestine can result in depletion of the epithelial stem cell compartment and is often the dose-limiting factor for radiotherapeutic treatment of tumors in the abdominal and pelvic region. Since mitotic cells are most sensitive to radiation, significant radioprotection can be achieved by reducing the number of cells in mitosis at the time of irradiation. We have previously shown that administration of macrophage inflammatory protein (MIP) -1alpha induces a transient 50% reduction in the number of mitotic cells in small intestinal crypts, including the stem cell region, and therefore, MIP-1alpha pretreatment before radiation exposure could result in a substantial reduction of the side effects associated with radiotherapy. Groups of adult mice were exposed to different doses of radiation (6, 8, 10, or 12 Gy), with or without prior administration of 200 microg BB-10010/kg 3 hr before irradiation and radiation damage was assessed by means of the microcolony survival assay. MIP-1alpha pretreatment resulted in significantly increased numbers of surviving crypts (10%) when compared to untreated irradiated animals. The observed radioprotective effects of MIP-1alpha in the small intestine should translate into reduced side effects in a clinically relevant radiotherapy context and could allow larger doses of radiation to be delivered to patients with tumors in the abdominal or pelvic region.

Animals↗
PubMed2000

Value of a contrast agent in equivocal carotid ultrasound studies: pictorial essay.

The aim of the present study was to assess the use of an echo-enhancing agent (Levovist; Schering AG) in equivocal carotid bifurcation ultrasound studies and compare the information obtained with digital subtraction angiography (DSA). Contrast-enhanced carotid ultrasound studies were performed on 30 carotid bifurcations in 28 patients. The standard carotid ultrasound examinations were considered equivocal for two reasons: apparent acute internal carotid artery occlusions (n = 10), and possibly patent but critically stenosed internal carotid arteries with the residual flow lumen being incompletely visualized (n = 20). All patients underwent subsequent carotid digital subtraction angiography. All patients with apparent acute carotid occlusions (n = 10) were correctly characterized on contrast-enhanced ultrasound when compared with DSA. The majority were complete occlusions (n = 8) although in two cases there were critical carotid stenoses requiring surgical endarterectomy. In the 'incompletely visualized lumen' group (n = 20), the majority (n = 16) were correctly characterized on contrast enhanced ultrasound: 13 cases of critically stenotic but patent internal carotid arteries, two cases without a haemodynamically significant stenosis and one case of a carotid occlusion with patent vasa vasorum. One of the critical carotid stenoses was prospectively reported as occluded on the 'gold standard' angiography. In three cases the flow lumen was still incompletely visualized due to calcified plaque despite an echo-enhancing agent; angiography revealed no significant stenosis in all cases. There was one false negative for internal carotid occlusion. This occurred early in the series and could be considered to be a technical error. Importantly, there were no false positives for carotid occlusion. Contrast-enhanced carotid ultrasound significantly improves diagnostic confidence in equivocal carotid ultrasound studies. In appropriate clinical settings this may reduce the need for subsequent carotid angiography.

Acute Disease↗
PubMed1999

Quality-of-life measurement in advanced cancer: assessing the individual.

PURPOSE: Despite the increasing importance of assessing quality of life (QoL) in patients with advanced cancer, relatively little is known about individual patient's perceptions of the issues contributing to their QoL. The Schedule for the Evaluation of Individual Quality of Life (SEIQoL) and the shorter SEIQoL-Direct Weighting (SEIQoL-DW) assess individualized QoL using a semistructured interview technique. Here we report findings from the first administration of the SEIQoL and SEIQoL-DW to patients with advanced incurable cancer. PATIENTS AND METHODS: QoL was assessed on a single occasion using the SEIQoL and SEIQoL-DW in 80 patients with advanced incurable cancer. RESULTS: All patients were able to complete the SEIQoL-DW, and 78% completed the SEIQoL. Of a possible score of 100, the median QoL global score was as follows: SEIQoL, 61 (range, 24 to 94); SEIQoL-DW, 60.5 (range, 6 to 95). Psychometric data for SEIQoL indicated very high levels of internal consistency (median r =.90) and internal validity (median R(2) = 0.88). Patients' judgments of their QoL were unique to the individual. Family concerns were almost universally rated as more important than health, the difference being significant when measured using the SEIQoL-DW (P =.002). CONCLUSION: Patients with advanced incurable cancer were very good judges of their QoL, and many patients rated their QoL as good. Judgments were highly individual, with very high levels of consistency and validity. The primacy given to health in many QoL questionnaires may be questioned in this population. The implications of these findings are discussed with regard to clinical assessment and advance directives.

Adult↗
PubMed1997

Trp64Arg substitution in the beta 3-adrenergic receptor does not relate to body weight in healthy, premenopausal women.

OBJECTIVE: To examine the contribution of the substitution of arginine for tryptophan at amino acid position 64 (Trp64Arg) of the beta 3-adrenergic receptor to body weight and weight-related factors in healthy, premenopausal women. SUBJECTS: Five hundred and five healthy, premenopausal women 44-50 y, body mass index (BMI) 20-40 kg/m2. MEASUREMENTS: Subjects were genotyped for the Trp64Arg substitution using restriction fragment length polymorphism (RFLP) analysis. Measurements for weight and weight-related factors (for example, weight, waist-hip ratio, lipid levels) were also taken. RESULTS: Two women were homozygous Arg/Arg, 75 women were heterozygous Trp/Arg, and 428 women were homozygous Trp/Trp. The frequency of the Arg substitution was 0.078. When subjects with and without the arginine substitution were compared, no significant differences were found on measures of weight or weight-related risk factors. CONCLUSION: The results confirm previous studies suggesting that the Trp64Arg substitution of the beta 3-adrenergic receptor is not related to weight or weight-related phenotypes in healthy, premenopausal women.

Alleles↗
PubMed1997

Cancer of the pyriform fossa: hyperfractionated radiotherapy as a primary treatment modality.

Carcinoma of the pyriform fossa carries one of the worst prognoses of all head and neck cancers. A prospective trial was set up to study the efficacy of hyperfractionated radiotherapy as a primary treatment modality in the management of these patients. Seventeen patients entered the trial and were followed for up to 3 years. Results for local control, regional control and survival compare favourably with patients treated primarily with surgery with or without radiotherapy. Hyperfractionated radiotherapy offers a logical and standardized approach to the management of this tumour and reduces the significant morbidity associated with the use of surgery as a primary treatment.

Carcinoma, Squamous Cell↗
PubMed1997

A 25 year review of parotid surgery.

At a single institution over 25 years, 110 patients were operated upon for a mixture of parotid disease. The mean duration of symptoms for benign disease was 40.8 months compared with 15.6 months for malignant disease. Pain was a significant feature of malignant parotid disorders (46.1% compared with 17.8% for benign conditions). The pathology of these masses was diverse, with pleomorphic adenoma being the commonest (44%). Superficial parotidectomy was the commonest procedure employed (69/110) with local excision being performed only prior to 1984 (15/110). There were five cases of permanent facial palsy, all following radical resection for malignancy. One patient developed Frey's syndrome. Recurrence rate for pleomorphic adenomas was 7/48 (15%), three following enucleations prior to 1984. In primary malignancy of the parotid, 3/21 (14%) developed recurrences. Parotid tumours have a low incidence. Surgery for these tumours can be safely performed by those with a special interest in parotid surgery.

Female↗
PubMed1996

Absence of correlation between chemo- and radioresistance in a range of human tumour cell lines.

The correlation between cellular resistance to radiation and to chemotherapeutic drugs has been investigated in a number of solid tumour cell lines, and preliminary results indicate no direct relationship. The acquisition of a multidrug resistance (MDR) profile by adriamycin-selected variants of a human squamous lung carcinoma, an ovarian carcinoma, a cervical carcinoma and by a colchicine-selected variant of a Chinese hamster ovarian carcinoma resulted in alterations to their radiosensitivity. However, the degree of change in the radiosensitivity of the MDR cell lines could not be predicted from their level of resistance to adriamycin. Clonal populations derived from DLKP-A, an adriamycin-selected MDR variant of the human lung carcinoma cell line DLKP, exhibited individual radiosensitivity profiles, which did not correlate with their chemoresistance. Exposure of DLKP to consecutive increasing doses of radiation did not confer cross-resistance to chemotherapeutic drugs.

Animals↗
PubMed1996

Thyroid disorders and breast cancer.

We have investigated the controversial association between diseases of the thyroid gland and breast carcinoma using methodology which allows positive exclusion of cases of breast disease from control groups and the detection of subclinical alterations in thyroid volume using high resolution ultrasonography, thus addressing the deficiencies of earlier studies. Whereas the prevalence of hyperthyroidism and hypothyroidism in patients with breast carcinoma and in healthy controls without clinical evidence of breast disease was similar, non-toxic goitre was more than twice as common in the breast carcinoma patients. Thyroid volumes were also significantly higher in breast carcinoma patients than in controls; using World Health Organisation criteria, 45.5% of breast carcinoma patients had thyroid enlargement compared with only 10.5% of controls. Finally, antithyroid peroxidase autoantibodies were twice as common in breast cancer patients than in controls. These findings provide clear evidence of a relationship between thyroid disease and breast carcinoma, although the mechanisms underlying this relationship require further study, future studies of breast cancer risk factors should therefore include assessment of thyroid function, antibody status and volume.

Breast Neoplasms↗
PubMed1994

Neuropeptide Y analog with selective antagonism of effects mediated by postjunctional Y1 receptors.

Neuropeptide, a 36 amino acid peptide, is one of the most ubiquitous neuropeptides in the nervous system. It is released during stimulation of sympathetic nerves and is implicated as an important neurotransmitter regulating cardiovascular activity. Administration of neuropeptide Y results in vasoconstriction and inhibition of neurotransmitter release. However, the absence of any effective inhibitors of neuropeptide Y action have precluded the examination of its possible role in hypertension. Here we describe a synthetic hexapeptide (BRC 672), corresponding to residues 22-27 of neuropeptide Y. Following the administration of BRC 672 (6.7 mumol/kg), neuropeptide Y-induced pressor responses were reduced by 32-48% in a dose-dependent fashion. The inhibition was specific for neuropeptide Y, as the pressor response to phenylephrine, an alpha-adrenoceptor agonist, was unchanged. It was selective for the postsynaptic (neuropeptide Y Y1 receptor-mediated) vasoconstrictor activity, because the presynaptic (neuropeptide Y Y2 receptor-mediated) cardiac vagal inhibition evoked by injection of neuropeptide Y to rats was not affected. The hexapeptide inhibited the neuropeptide Y-induced increase in cytosolic free Ca2+ in mammalian cells expressing the cloned human neuropeptide Y Y1 receptor. Injections of BRC 672 significantly reduced blood pressure in anaesthetised rats and in conscious spontaneously hypertensive rats. Resting arterial blood pressure decreased from 136 +/- 4 mm Hg to 122 +/- 3 mm Hg and remained depressed 2 h after the administration of the hexapeptide in anaesthetised rats. In spontaneously hypertensive rats blood pressure was decreased for up to 4 h.

Animals↗
PubMed1994

The influence of continuous ambulatory peritoneal dialysis connection technique on peritonitis rate and technique survival.

Peritonitis is still the most common complication of continuous ambulatory peritoneal dialysis (CAPD). Several measures have been used to prevent peritonitis, including prophylactic antibiotics and a variety of connection techniques. This study was designed to evaluate the effects of different connection techniques, age at the start of CAPD, sex, and diabetic status on peritonitis rate and technique survival. Three hundred twenty-seven patients treated with CAPD and followed for 8,804.4 patient-months at the Vancouver General Hospital between February 13, 1978, and August 31, 1992, were reviewed. The mean age of the patients was 57.1 +/- 16.3 years. The overall peritonitis rate was 16.6 patient-months per episode. The overall technique survival was 79.6%, 60.2%, and 41.8%, at 1, 2, and 3 years, respectively. Patients using "standard" spike technique (group A, n = 87), Luer lock connector (group B, n = 77), and Luer lock with iodine instillation at the dialysis bag connection site (group C, n = 120) had peritonitis rates of 10.4, 14.7, and 33.3 patient-months per episode, respectively. The relative risk (RR) of peritonitis was 3.5 for group A (95% confidence interval, 2.1 to 4.5) and 2.6 for group B (95% confidence interval, 1.7 to 3.9) compared with group C. Patient age at the start of CAPD, sex, and diabetic status had no effect on the RR of peritonitis. None of the variables studied, except patient age, affected technique survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1993

Clinical significance of cellular resistance in tumours to cytotoxic chemotherapy and radiotherapy.

Cellular resistance is a significant component of tumour treatment failure. More detailed understanding of resistance mechanisms has enabled us to plan circumvention strategies, though these are not yet in routine clinical use. Such resistance is, however, only one of several factors which render cure of advanced malignant disease difficult. It is important for researchers in this field to see not only therapeutic opportunities but also limitations of these approaches. It is hoped that increased cooperation between clinicians and scientists in the field of cellular resistance will yield further improvement in tumour response rates and cure.

Antineoplastic Agents↗
PubMed1993

Pharmacological separation of cardio-accelerator and vagal inhibitory capacities of sympathetic nerves.

Prolonged attenuation of vagal action at the heart, proposed to be due to release of the sympathetic cotransmitter neuropeptide Y (NPY), follows stimulation of cardiac sympathetic nerves. It has been shown that pretreatment with reserpine depletes cardiac and neuronal stores of both noradrenaline and NPY, while combined pretreatment with reserpine and the ganglion blocking agent chlorisondamine reduces depletion of NPY, while still depleting noradrenaline. The effects of reserpine pretreatment and combined chlorisondamine and reserpine pretreatment on the inhibition of cardiac vagal action evoked by cardiac sympathetic nerve stimulation (16 Hz, 2 min) were compared in anaesthetised dogs. In dogs with no pretreatment (n = 6), sympathetic stimulation evoked an immediate cardio-acceleration, and a prolonged inhibition of cardiac vagal action, with a maximum percent inhibition (MPI) and time to half-recovery (T50) of 78 +/- 6% and 16 +/- 2 min respectively. In dogs pretreated with reserpine (n = 6, 1 mg/kg, 24 h), the immediate cardio-acceleration (ANOVA, P < 0.01), and the magnitude (MPI = 31.8%, ANOVA, P < 0.001) and duration (T50 = 6 +/- 1 min, ANOVA, P < 0.05) of inhibition of cardiac vagal action following sympathetic stimulation were significantly attenuated. In dogs with combined chlorisondamine (n = 5, 2 mg/kg, 48 and 24 h) and reserpine pretreatment, there was again significantly reduced cardio-acceleration (ANOVA, P < 0.01), but the inhibition of cardiac vagal action following sympathetic stimulation did not significantly differ from untreated animals (MPI = 79 +/- 8%, T50 = 21 +/- 6 min). Intravenous injections of NPY (25-50 micrograms/kg) evoked prolonged inhibition of cardiac vagal action in untreated and both groups of pretreated animals. These experiments indicate that the cardio-accelerator and vagal inhibitory capacities of sympathetic nerve stimulation can be separated, and are consistent with the sympathetic vagal inhibitory factor being NPY.

Animals↗
PubMed1993

Desensitization by neuropeptide Y of effects of sympathetic stimulation on cardiac vagal action in anaesthetised dogs.

The effects of a long-lasting intravenous infusion of neuropeptide Y (NPY, 180 +/- 8 min, 53 +/- 4 micrograms/kg/h) on the prolonged inhibition of cardiac vagal action evoked by cardiac sympathetic nerve stimulation and bolus intravenous injections of NPY were investigated in anaesthetised dogs. Sympathetic stimulation and NPY injection were performed on four separate occasions; once in control conditions, then once early and again late in the period of NPY infusion, and then on a final occasion 60-90 min after the cessation of NPY infusion. The maximum inhibition of cardiac vagal action evoked by an injection of NPY was significantly less late in the NPY infusion when compared with the other three injection groups (ANOVA, P < 0.001). Also the time to half-recovery of this response was significantly less than that seen in the other three injection groups (ANOVA, P < 0.001). The maximum inhibition of cardiac vagal action evoked by sympathetic stimulation was significantly reduced late in the NPY infusion when compared with the other three stimulation groups (ANOVA, P < 0.0001). The time for half-recovery of this response was also less than that of the other three stimulation groups (ANOVA, P < 0.001). The results indicate that desensitisation of the vagal attenuation to both exogenous NPY and sympathetic stimulation occurred during a long-lasting period of NPY infusion. This is consistent with the proposal that NPY is a mediator of this sympathetic-evoked vagal attenuation.

Anesthesia↗
PubMed1993

Galanin antagonist effects on cardiac vagal inhibitory actions of sympathetic stimulation in anaesthetized cats and dogs.

1. Galantide, a putative galanin antagonist composed of twenty amino acids, caused a significant reduction in the vagal attenuating action of galanin injection (20 micrograms/kg; 6.2 nmol/kg) in anaesthetized cats at both ten times (137 micrograms/kg; 62 nmol/kg) and twenty-five times (343 micrograms/kg: 156 nmol/kg) the molar dose of galanin. Galantide did not block the depressor action of galanin in these animals. 2. Galantide, at both doses, also significantly reduced the vagal attenuating action of a 5 min period of cardiac sympathetic stimulation at 16 Hz in anaesthetized cats. 3. In anaesthetized dogs, galantide, at the same dose used in cats (137 micrograms/kg; 62 nmol/kg) had no significant effect on the vagal attenuation evoked by cardiac sympathetic stimulation or injection of neuropeptide Y (35 micrograms/kg; 8.2 nmol/kg). 4. This study therefore demonstrates antagonist properties of galantide on the vagal inhibitory action of galanin. It supports the hypothesis that the vagal inhibitory factor released by cardiac sympathetic nerve stimulation in the cat, but not the dog, is galanin, although it does not exclude the possibility of other factors playing a more minor role. Because galantide was not shown to block the depressor action of galanin, this study also suggests that there may be more than one galanin receptor subtype.

Animals↗