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Biomedical subjects

Ian E Smith

Publications and source records attributed to Ian E Smith.

At least 37 records · Page 2Linked to original sources
PubMed2005

Chronic treatment with modafinil may not be beneficial in patients with chronic fatigue syndrome.

Fourteen patients (7 male, 7 female, 22-63 years), classified as having chronic fatigue syndrome (CFS), but without concurrent major depression, significant sleepiness or use of psychoactive medication, completed a double-blind, placebo-controlled, crossover study of the effects of the selective wakefulness-promoting agent, modafinil (200 and 400mg/day). The treatment periods were each 20 days, with washout periods of 2 weeks. The primary aim was to determine effects on cognition and the secondary aim was to determine effects on self-ratings of fatigue, quality of life and mood. Modafinil had mixed effects in two cognitive tasks. In a test of sustained attention, treatment with 200mg reduced the latency to correctly detect sequences, but 400mg increased the number of missed targets. In a test of spatial planning, the 200mg dose resulted in a slower initial thinking time for the easiest part of the task, whereas 400mg reduced the initial thinking time for the hardest part of the test. Lastly, in a test of mental flexibility and one of motor speed, patients performed worse whilst on modafinil (400mg), compared with the placebo period. No effects were observed on the performance of other psychometric tests or on self-ratings of fatigue, quality of life or mood, but this may have been due to insufficient statistical power. It is discussed whether the limited and mixed cognitive effects that we observed could have occurred by chance, or whether a subgroup of CFS patients with daytime sleepiness would have shown greater benefits.

Adult↗
PubMed2004

Aromatase inhibitors--extending the benefits of adjuvant therapy beyond tamoxifen.

Adjuvant tamoxifen is still considered standard care for postmenopausal women with early stage hormone receptor-positive breast cancer. However, efficacy and safety of tamoxifen are limited by its partially estrogenic properties. Aromatase inhibitors have proven highly effective in advanced breast cancer and are currently being investigated in the adjuvant setting, either as an alternative to or in sequence with tamoxifen, or as extended adjuvant therapy following tamoxifen. Results of several adjuvant aromatase inhibitor trials have been published and strongly indicate that efficacy may be increased compared with tamoxifen alone. This review will examine the published data, discuss ongoing trials, and address the question of how to best integrate the aromatase inhibitors into adjuvant treatment.

Antineoplastic Agents, Hormonal↗
PubMed2004

Factors associated with a delay in the diagnosis of narcolepsy.

BACKGROUND: There can be a long interval from the onset of symptoms before a diagnosis of narcolepsy is made. There are no multivariate analyses reported in the literature of factors that may contribute to this delay. The aims of this study were to describe the delay in diagnosis of people with narcolepsy living in the UK and to identify associated factors. METHODS: The study comprised a postal survey of 500 members of the Narcolepsy Association UK, which included questions regarding age of onset of symptoms, year of diagnosis and subject demographics. Cox's proportional hazards regression was performed. RESULTS: A total of 313 questionnaires were returned of which 219 had been completed sufficiently for analysis. The interval between symptom onset and diagnosis ranged from within 1 to 61 years with a median of 10.5 years. Multivariate analysis showed that the presence of cataplexy as one of the initial symptoms and a more recent year of symptom onset were the only factors associated with time to diagnosis. CONCLUSIONS: We have confirmed that the diagnosis of narcolepsy can be delayed for many years particularly when cataplexy is absent initially. The delay in diagnosis in the UK appears to be decreasing, probably through greater doctor and patient awareness of the clinical manifestations of narcolepsy.

Adolescent↗
PubMed2004

Circulating tumour cells in breast cancer.

By use of modern immunological and molecular analytical techniques, cells with the characteristics of tumour cells can be detected in the blood of many patients with breast cancer. The ability to detect and characterise such cells routinely could have a profound influence on the early diagnosis of breast cancer, risk stratification in the adjuvant setting, early detection of relapse, and the development of new targeted strategies. In this review we discuss current techniques to detect circulating breast-cancer cells and the limitations of these approaches. We also review the clinical studies in breast cancer and discuss the potential relevance of this research to the future management of the disorder.

Breast Neoplasms↗
PubMed2004

Aromatase inhibitors in early breast cancer therapy.

Third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, are active and well tolerated in postmenopausal patients with hormone-sensitive advanced or metastatic breast cancer, as either first- or second-line therapy. These agents are being investigated as neoadjuvant therapy of locally advanced breast cancer and as adjuvant therapy of early breast cancer. In a large neoadjuvant study, letrozole resulted in significantly more responses than tamoxifen, with significantly more patients becoming eligible for breast-conserving surgery. Greater letrozole responses were associated with high and low levels of estrogen receptor expression and with coexpression of ErbB-1 and/or ErbB-2. Neoadjuvant anastrozole, in two studies, was also significantly superior to tamoxifen in rendering patients eligible for breast-conserving surgery. In the adjuvant setting, the Arimidex, Tamoxifen Alone or in Combination trial compared 5 years of anastrozole versus tamoxifen versus the combination. At 47 months' median follow-up, disease-free survival was significantly improved with anastrozole compared with the other arms. In the Intergroup Exemestane Study, switching to exemestane after 2 to 3 years of tamoxifen significantly improved disease-free survival compared with remaining on tamoxifen for 5 years. The MA.17 trial evaluated switching to letrozole versus placebo following 5 years of adjuvant tamoxifen, and letrozole was significantly superior to placebo in disease-free survival. While all three aromatase inhibitors as adjuvant therapy were well tolerated, long-term effects on bone health and lipids are being monitored. Ongoing trials will better define the optimum use of aromatase inhibitors as adjuvant therapy.

Antineoplastic Agents↗
PubMed2004

Efficacy and safety of trastuzumab.

The human epidermal growth factor receptor (HER) 2 is overexpressed in approximately 20-25% of human breast cancers and is an independent adverse prognostic factor. Targeted therapy directed against this receptor has been developed in the form of a humanised monoclonal antibody, trastuzumab. This antibody has shown activity as a single agent in metastatic breast cancer both prior to chemotherapy and in heavily pretreated patients. A pivotal Phase III trial has demonstrated that its use in combination with an anthracycline or paclitaxel results in a significant improvement in survival, time to progression, and response. This has recently been reinforced by another trial with docetaxel. The HER2 status of a tumour is a critical determinant of response to trastuzumab-based treatment. Those that express HER2 at the highest level on immunohistochemistry (IHC), 3+, derive more benefit from treatment with trastuzumab than those with overexpression at the 2+ level. Benefit correlates best with tumours that are positive on fluorescence in situ hybridisation for HER2, regardless of IHC status. Treatment with trastuzumab is generally well tolerated with a low incidence of adverse events. Some patients may experience fever, chills, dyspnoea and pain, particularly with the first administration. Unexpectedly, cardiac toxicity has developed in some patients treated with trastuzumab, and this has a higher incidence in those treated in combination with an anthracycline. 'Cross-talk' between the oestrogen receptor and HER2 pathway has stimulated interest in using trastuzumab in combination with endocrine therapy. Current clinical trials are investigating the role of this agent in the adjuvant setting.

Antibodies, Monoclonal↗
PubMed2004

Obstructive sleep apnoea in the elderly: recognition and management considerations.

Obstructive sleep apnoea is characterised by repetitive interruptions of breathing during sleep due to upper airway collapse. It affects sleep quality, daytime alertness and quality of life. It is associated with increased cardiovascular morbidity and mortality and an increased risk of road traffic accidents. Sleep apnoea is common among older people and its effects can be more severe than in younger people. The added impact is because of a physiological decline in sleep quality with age in most people and the increasing frequency of other comorbidities with increasing years that affect both sleep and daytime function. It is important to be alert to the diagnosis, bearing in mind these other influences on sleep quality. The diagnosis is generally straightforward once appropriate tests are performed. Treatment is aimed at minimising upper airway obstruction during sleep and the most effective therapy is continuous positive airway pressure. Weight loss can also be effective. Other management options, including surgery, mandibular advancement devices and drug treatment, are less effective, but there are interesting advances in the understanding of the pharmacology of the upper airway. Specific serotonergic agonists hold the greatest potential for a useful drug treatment for this widespread and debilitating condition.

Aged↗
PubMed2004

Pharmacotherapies for obstructive sleep apnoea: where are we now?

Obstructive sleep apnoea (OSA) is common, causes considerable morbidity and probably contributes to mortality particularly through associated cardiovascular disease. The physical therapy of continuous positive airway pressure (CPAP) is extremely effective in the majority of patients but most patients would prefer an alternative. Intuitively, OSA should be amenable to pharmacotherapy. The upper airway of affected individuals can be narrowed but is patent during wakefulness. Collapse of the airway during sleep occurs when negative intra-luminal pressure generated by inspiratory effort exceeds the tone of the upper airway dilators. This mismatch may be in part due to respiratory drive instability but the state-dependent fall in drive to the airway dilator muscles is the biggest factor in most patients. Various drugs have been investigated as treatment for OSA. Acetazolamide, theophylline, nicotine, opioid antagonists and medroxyprogesterone have been used to increase respiratory drive. Clonidine has been tested with the aim of reducing rapid eye movement sleep when OSA is often most severe. Various antidepressants have been used to suppress rapid eye movement sleep and to preferentially activate the upper airway dilators. The drug trials have often been of poor design and none has included more than a few patients. Most of the drugs have been found to be ineffective and those that have worked for some patients (acetazolamide and protriptyline) have produced intolerable adverse effects. There have been recent advances in the understanding of the neurotransmitters involved in the control of sleep and the upper airway motor neurones, offering the possibility of novel approaches to the drug treatment of OSA for those patients who cannot tolerate or do not benefit from CPAP. It seems likely that a better understanding of the mechanisms of OSA in individual patients and tailoring of drug therapy will be the way forward.

Clinical Trials as Topic↗
PubMed2003

Cell filtration-laser scanning cytometry for the characterisation of circulating breast cancer cells.

BACKGROUND: Epithelial cells may be detected in the circulation of the majority of patients with metastatic breast cancer. Quantification of such presumptive cancer cells might allow for the monitoring of patients with early or late stage disease as an early index of relapse. Additionally, biomarker analysis may allow a more rational approach to therapeutics. We have developed a new method for the detection and characterisation of these cells. METHODS: Blood was filtered through polycarbonate membranes containing cylindrical pores, 8 microm in diameter. All the red cells and a large majority of the white blood cells passed through the filter while the larger epithelial cells were trapped. Cells on the membrane were fixed in ethanol, stained with propidium iodide and anti-pan-cytokeratin-FITC (to identify epithelial cells). The filters were then examined by laser scanning cytometry (LSC), which allowed enumeration and localisation of cells. RESULTS: With normal blood spiked with cells from breast carcinoma cell lines, 99.9% of the leukocytes passed through the membrane, while close to 100% of the epithelial cells were trapped, with a detection limit of less than one epithelial cell/ml of blood. All of 20 samples from patients with widespread metastatic disease contained cytokeratin-positive cells with the morphological characteristics of carcinoma cells, the number of cells ranging from 0.2 to 5.7/ml of blood. CONCLUSIONS: Cell filtration-LSC is a viable technique for detecting and studying breast carcinoma cells in peripheral blood.

Breast Neoplasms↗
PubMed2003

Letrozole versus tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy.

Letrozole, a third generation aromatase inhibitor, has been compared with tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy. In a first-line trial in advanced disease, 939 post menopausal women were randomised double blind to receive treatment with letrozole 2.5 mg daily or tamoxifen 20 mg daily. Letrozole was significantly superior in terms of median time to progression (9.4 months versus 6.1 months, P=0.0001), objective response (30% versus 20%, P=0.0006), and clinical benefit (49% versus 38%, P=0.0001). Superiority of letrozole was independent of disease site, receptor status, or prior adjuvant anti-oestrogen therapy. In an extended phase of this trial, 200 patients were crossed over to tamoxifen after letrozole, compared with 197 crossed over to letrozole after tamoxifen. Median overall survival was 34 months for letrozole versus 30 months for tamoxifen (not significant). In a similar randomised double-blind neoadjuvant trial, 337 post menopausal patients with large ER/or PgR positive T2-T4 cancers, either requiring mastectomy or locally advanced, were randomised to preoperative letrozole or tamoxifen for 4 months prior to surgery. Overall response was 55% for letrozole versus 36% for tamoxifen (P<0.001). Conservative surgery was possible in 45% of patients treated with letrozole versus 35% with tamoxifen (P=0.022). In both trials, both treatments were well tolerated with no significant differences in side effects. These results indicate that letrozole is more active than tamoxifen both as neoadjuvant therapy and as first-line treatment in advanced disease. They support the importance of current adjuvant trials comparing the two treatments.

Adult↗
PubMed2003

Challenges in the endocrine management of breast cancer.

The goal of endocrine therapy in breast cancer is to block the action of estrogen on the tumor cells either by inhibiting estrogen from binding to the specific estrogen receptor or by inhibiting its synthesis. Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen inhibits the binding of estrogen to the receptor, resulting in inhibition of hormone action. However, as tamoxifen is also weakly estrogenic, it may not be optimally effective and increases the risk of endometrial cancer and stroke. Furthermore, patients may be refractory or may become resistant to tamoxifen treatment. Since aromatase inhibitors (AI) block the synthesis of estrogen and have no intrinsic estrogenic activity, they have the potential to be more effective than tamoxifen. Their different mechanism of action and chemical structures may also circumvent tamoxifen resistance. Consequently, AIs are currently being evaluated as an alternative to tamoxifen treatment. A preclinical model has recently been developed to compare the efficacy of AIs and antiestrogens in different treatment schemes and to assist in the design of clinical trials. Current studies with the MCF-7Ca xenograft model are exploring the effects of combination and sequential therapy on tumor growth. The efficacy of AIs in the treatment of hormone receptor-positive breast cancer was first demonstrated in five multicenter second-line trials enrolling several hundreds of postmenopausal patients with metastatic breast cancer who had failed tamoxifen treatment. More recently, anastrozole demonstrated efficacy at least equivalent to that of tamoxifen in first-line randomized, phase III clinical trials in postmenopausal women with hormone receptor-positive or unknown metastatic breast cancer, whereas letrozole demonstrated superiority. The steroidal AI exemestane is currently under evaluation. Letrozole is the only AI to have been studied in a randomized, phase III trial in the neoadjuvant setting. In this trial, more patients underwent breast-conserving surgery with letrozole than with tamoxifen. Smaller phase II studies also suggest that both anastrozole and exemestane are active in the neoadjuvant setting. Because neoadjuvant trials permit temporal sampling of breast tissue, substudies in the phase III trial with letrozole have examined the impact of such biomarkers as estrogen receptor, progesterone receptor and epidermal growth factor receptor family members, HER-1 and HER-2, on patient response. AIs are currently under evaluation in the adjuvant setting, and preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have been reported. AIs have proven as safe as tamoxifen in trials in patients with metastatic breast cancer. Ongoing clinical trials in the adjuvant setting include companion studies of end-organ effects, particularly bone metabolism and lipid metabolism evaluations. Quality-of-life assessments are also parts of major clinical trials. A head-to-head quality-of-life assessment of anastrozole compared with letrozole demonstrated patient preference for letrozole. These assessments also clearly indicated the eagerness of patients to participate actively in treatment decisions

Adult↗
PubMed2003

Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer.

Recent evidence suggests that common molecular adaptations occur during resistance to both tamoxifen and estrogen deprivation that use various signal transduction pathways, often involving cross-talk with a retained and functional estrogen receptor (ER) protein. There appear to be several different levels at which this cross-talk may occur, including peptide growth factor signaling via the type 1 tyrosine kinase growth factor receptor family [epidermal growth factor receptor (EGFR) and HER2], which may become up-regulated during endocrine treatment, ultimately being harnessed by cells to allow them hormone-independent growth. ER may remain involved in cell growth with ligand-independent phosphorylation and activation via different intracellular mitogen-activated protein kinases. ER may also become involved in non-nuclear estrogen-dependent signaling via interaction with the phosphatidylinositol 3'-kinase/Akt cell survival pathway or may interact with the stress-activated protein kinase/c-Jun-NH(2)-terminal kinase pathway. Understanding these mechanisms will permit the optimal integration of new signal transduction inhibitors (STIs) into breast cancer therapy. Preclinical approaches that have shown promise include the use of EGFR tyrosine kinase inhibitors for hormone-resistant breast cancer cells that are dependent on either EGFR or HER2 signaling. Likewise, farnesyl transferase inhibitors, mitogen-activated protein kinase inhibitors, and cell cycle inhibitors have all shown activity in experimental breast cancer models. Emerging data suggest that STIs may be more effective when given in combination with endocrine therapy either to overcome resistance or to prevent/delay emergence of the resistance phenotype. Clinical trials are in progress to determine the safety and optimal schedule for each of the various STIs, and studies of STIs in combination with aromatase inhibitors have commenced in breast cancer to see whether the therapeutic response to endocrine therapy can be enhanced further.

Antineoplastic Agents, Hormonal↗
PubMed2002

Periodic limb movement in a community population detected by a new actigraphy technique.

BACKGROUND: Periodic limb movements (PLMs) have been studied in both community and sleep clinic populations using polysomnography. An alternative detection method is actigraphy. Our aims were to determine the frequency of PLMs, measured by actigraphy in a community sample, and to assess the relationships of PLMs with age, gender, and reported sleep-related symptoms. METHODS: Volunteers had bilateral foot actigraphy (Cambridge Neurotechnology) at home and completed sleep questionnaires. Actigraphy was scored for PLMs per hour in bed (PLMI) and statistical analysis performed to assess possible associations. RESULTS: PLMI (mean of two nights) ranged from 0 to 60.3 and 37% of the sample had a PLMI> or =5. Men had significantly higher PLMIs than females (P=0.003) but PLMI was not correlated with age. There was a modest but significant correlation between subjectively reported restless leg severity and PLMI (r=0.238; P=0.003), but none with reported sleepiness. CONCLUSIONS: This actigraphy technique is a practical and reliable tool for community studies. A large proportion of this community sample, particularly men, had PLMs. PLMI was not correlated with age or Epworth Sleepiness Score.

Journal Article↗