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Biomedical subjects

J M Dixon

Publications and source records attributed to J M Dixon.

At least 19 recordsLinked to original sources
PubMed2004

Diagnostic delay in breast cancer.

BACKGROUND: Delay in the diagnosis of breast cancer has important clinical and medicolegal implications. This study assessed the frequency, causes and effects of delay in the diagnosis of breast cancer in a specialist breast unit. METHODS: Details of women who attended the breast clinic between 1988 and 1999 inclusive, and for whom the interval between first attendance and diagnosis of invasive breast cancer was greater than 2 months, were reviewed. Potential causes of delay were identified and the consequence of the delay assessed. The clinical features were compared with those of patients diagnosed with breast cancer during a 2-year period from 1999 and 2001. RESULTS: Breast cancer was diagnosed in 5283 women during the interval reviewed; delay in diagnosis was suggested in 72 women (1.4 per cent). Women with a delayed diagnosis were younger (P < 0.001) and had a smaller tumour at diagnosis (P = 0.011) compared with all women diagnosed with breast cancer between 1999 and 2001. There were no differences in the rate of axillary node positivity or the need for mastectomy. Women unsuitable for conservation therapy in the delayed group had a significantly longer interval to diagnosis (P = 0.006). CONCLUSION: The likelihood that conservation therapy will be appropriate is reduced when the hospital delay in the diagnosis of breast cancer is more than 240 days. All patients with a palpable mass require triple assessment to minimize delay in diagnosis of breast cancer.

Adult↗
PubMed2003

Non-Gaussian statistics of the vibrational fluctuations of myoglobin.

Experiments on the dynamics of vibrational fluctuations in myoglobin revealed an interesting behavioral cross-over occurring in the range 180-200 K. In this temperature range the mean square displacement of atomic positions versus temperature sharply increases its slope, indicating the dissociation of CO from the heme group. In this paper we develop a theoretical model that provides a framework for the quantitative description of this phenomenon. The basis of our calculations is an assumption of an effective potential with multiple local minima. In particular, we consider a quartic potential in place of the simple quadratic. We then use non-Gaussian statistics to obtain a relationship between the mean square displacement and model parameters. We compare our model to published experimental data and show that it can describe the data set using physically meaningful parameters which are fitted to the experimental data. In the process we verify the Gaussian approximation's applicability only to the low-temperature régime. In the high-temperature limit, however, deviations from the Gaussian approximation are due to the double-well nature of our effective potential. We find that the published datasets showing the thermal transition display the qualitative trends predicted by appropriate algebraic approximations to our predicted myoglobin behavior.

Computer Simulation↗
PubMed2003

Models of spatial and orientational self-organization of microtubules under the influence of gravitational fields.

Tabony and co-workers [C. Papaseit, N. Pochon, and J. Tabony, Proc. Natl. Acad. Sci. U.S.A. 97, 8364 (2000)] showed that the self-organization of microtubules from purified tubulin solutions is sensitive to gravitational conditions. In this paper, we propose two models of spatial and orientational self-organization of microtubules in a gravitational field. First, the spatial model is based on the dominant chemical kinetics. The pattern formation of microtubule concentration is obtained (1) in terms of a moving kink in the limit when the disassembly rate is negligible, and (2) for the case of no free tubulin and only assembled microtubules present. Second, the orientational pattern of striped microtubule domains is consistent with predictions from a phenomenological Landau-Ginzburg free energy expansion in terms of an orientational order parameter.

Animals↗
PubMed2003

Breast cancer risk among the survivors of atomic bomb and patients exposed to therapeutic ionising radiation.

Radiation induced breast cancer is a highly complex phenomenon, which most likely involves the accumulation of several genetic and epigenetic events. Studies of atomic bomb survivors, patients who underwent multiple fluoroscopic examinations during treatment for pulmonary tuberculosis, those who received therapeutic radiation for benign breast disease, such as acute post-partum mastitis, or those with an enlarged thymus or skin haemangioma and patients with Hodgkin's disease treated by mantle radiotherapy established that the risk of breast cancer increases with exposure to ionising radiation. The carcinogenic effect of therapeutic or accidental radiation is highest when exposure occurs during childhood and exposure after age 40 imparts low or minimal risk. The risk of bilateral breast cancer is not significantly increased in the survivors of atomic bomb and therapeutic radiations. Fractionated exposures for therapeutic radiation are similar to a single exposure of the same total dose in their ability to induce breast cancer; this risk remains high for many years after exposure. Younger age at first full term pregnancy confers a protective effect against the risk of breast cancer in the survivors of atomic bomb but long-term data on this beneficial effect after therapeutic radiation is not available.

Age Factors↗
PubMed2003

Pathological features of breast cancer response following neoadjuvant treatment with either letrozole or tamoxifen.

Morphological characteristics, grading features, proliferation marker MIB1, apoptosis (by Tdt-mediated duTP-biotin nick-end labelling (TUNEL)), Bcl-2 expression, oestrogen receptor (ER) and progesterone receptor (PgR) status were compared in ER-positive breast cancers before and after 3 months of neoadjuvant therapy with either letrozole or tamoxifen. Daily treatment was with letrozole 2.5 mg (12 patients) or 10 mg (12 patients), or with tamoxifen 20 mg(24 patients). Letrozole treatment was associated with a pathological response in 17 of 24 (71%) patients. The predominant change in grading features was a decrease in mitosis, and the expression of MIB1 was reduced in all of the 22 evaluable cases. Whilst only marginal changes were observed in ER expression following letrozole therapy, PgR reactivity was reduced in 20 of 21 evaluable cases which were initially PgR-positive, becoming undetectable in 16 patients. Tamoxifen treatment was associated with pathological response in 15 of 24 (63%) tumours. In contrast to letrozole, the dominant change in grading feature was an increase in tubule formation, ER score was markedly reduced in most cases, and the most common effect on PgR was an increased expression. Following treatment with either tamoxifen or letrozole, variable effects were observed on the apoptotic index and expression of Bcl-2. These results indicate that both letrozole and tamoxifen have marked influences on the pathological features of breast cancer during neoadjuvant therapy. However, the effects of the two agents varied such that the phenotypes of letrozole- and tamoxifen-treated tumours differ markedly. Effects on clinical, pathological and biological endpoints were frequently disconcordant--future studies will therefore require the evaluation of multiple parameters in order to fully assess tumour response.

Antineoplastic Agents↗
PubMed2003

An integrated view of aromatase and its inhibition.

Aromatase inhibition has become a major treatment strategy for postmenopausal women with oestrogen-dependent breast cancer. Its optimal application is, however, dependent upon (i) the accurate identification of cancers which are ultimately dependent upon the activity of the aromatase enzyme, (ii) the use of the best method/inhibitor by which to blockade aromatase activity. The single best predictor of response to aromatase inhibitors is the presence of tumour oestrogen receptors; receptor-negative cancers rarely respond whereas those with high levels seem particularly likely to benefit. However, there is a need for additional discriminatory markers. The use of microarray technology coupled with neoadjuvant therapy is likely to yield promising candidate genes. The finding that, amongst peripheral tissues, the tumour itself may have high activity has led to the suggestion that the tumour aromatase measurements may be predictive; however, in situ studies and the lack of robust assays for tumour aromatase suggest that tumour aromatase may not be an influential marker. Whilst drugs such as anastrozole, exemestane, formestane and letrozole are all effective and specific inhibitors of aromatase, they differ in structure, potency and mechanism of action. Thus, differential sensitivity of tissues/tumours and non-cross resistance mean inhibitors are not equivalent and individual agents may have differing roles according to the setting in which they will be used. Aromatase inhibitors have evolved as key endocrine agents in the treatment of breast cancer. They offer the promise of rational treatment management based on the accurate identification of individual cohorts of tumours responsive to specific drugs.

Aromatase↗
PubMed2003

Neoadjuvant tamoxifen and aromatase inhibitors: comparisons and clinical outcomes.

Neoadjuvant hormonal therapy for oestrogen receptor (ER) and/or progesterone receptor (PgR) positive large operable or locally advanced breast cancer is effective and a safe alternative to chemotherapy in postmenopausal women. A randomised trial has demonstrated that the response rate and the incidence and degree of downstaging with the aromatase inhibitor letrozole is significantly greater than with tamoxifen [J. Clin. Oncol. 19 (2001) 3808]. Tumours at all levels of ER appear to respond better to letrozole than tamoxifen but at low levels of ER responses are seen only with letrozole and not with tamoxifen. Patients most likely to benefit from neoadjuvant therapy and those who achieve the greatest reduction in tumour volume are those patients with tumours that express very high levels of ER (ALLRED category score 8). Both letrozole and anastrozole appear effective in both erbB2 positive and negative breast cancers. Three months of treatment is adequate to determine if a tumour will respond. Following breast-conserving surgery and radiotherapy, local recurrence rates appear satisfactory.

Anastrozole↗
PubMed2003

The pharmacology of letrozole.

Recent clinical trials indicate that the third-generation aromatase inhibitors may be more effective than tamoxifen as first line endocrine therapy in ER+ metastatic breast cancer in postmenopausal women. This review will focus exclusively on the pharmacology of the non-steroidal inhibitor letrozole. Aromatase derived from a variety of sources is inhibited at low nM concentrations of the drug. In non-cellular systems, letrozole is 2-5 times more potent than anastrozole and exemestane in its inhibition of aromatase, whilst in cellular systems it is 10-20 times more potent. Anti-tumour effects of letrozole have been demonstrated in several animal models. In postmenopausal women, letrozole commonly suppresses circulating concentrations of estrone and estradiol to below the sensitivity limit of the assays used to measure them. In a recent randomized cross-over study, letrozole (2.5mg daily) achieved a significantly greater suppression of the plasma concentrations of both estrone and estrone sulphate than anastrozole (1mg daily) and a greater inhibition of in vivo aromatization. Letrozole appears to have a small effect on adrenal steroidogenesis such that a small number of patients exhibit an abnormal response to synthetic ACTH during letrozole therapy. This is unlikely to have any clinical significance. In short-term studies letrozole has been shown to increase markers of bone resorption indicating the need to monitor bone integrity when the drug is used for extended periods of time. A consistent effect of letrozole on serum lipids has not been demonstrated.

Adrenocorticotropic Hormone↗
PubMed2003

Does local surgery have a role in the management of stage IV breast cancer?

AIMS: There are no uniformly agreed guidelines regarding the treatment of local breast cancer in patients who have stable metastatic disease. The aim of this study was to define the role of breast surgery in the management of stage IV disease by reviewing the clinical outcome in patients with stage IV disease submitted to surgery in a regional breast cancer unit. METHODS: All patients who underwent breast surgery from 1993 to 1999 and had known metastatic disease or who were diagnosed with metastases within one month of surgery were identified and their clinical outcome was studied using death and local recurrence as end points. RESULTS: Median survival after breast surgery was 23 months. Ten of the 20 patients were alive with no local disease at 20 months mean follow-up. Three of 10 patients who died developed local recurrence and had local disease at the time of death. CONCLUSION: The local surgery does have a role in controlling the primary cancer and controlling local symptoms in a selected group of patients with stable metastatic disease.

Breast Neoplasms↗
PubMed2003

Imprint cytology of axillary lymph nodes as an intraoperative diagnostic tool.

AIMS: Frozen section histology of lymph nodes intraoperatively is associated with a false negative rate of twenty-five per cent. Imprint cytology is reported to have greater accuracy than frozen section. Accurate intraoperative examination of lymph nodes could help to prevent some patients from having a second axillary operation in breast cancer. This study assesses the sensitivity of imprint cytology to lymph node metastases using two different staining techniques. METHODS: Imprint cytology of 238 freshly excised axillary lymph nodes in 53 patients with stage T1-2, N0, M0 breast cancer was performed. Imprints were stained using toluidine blue dye and anti-pancytokeratin immunoglobulin to compare the two staining methods. A consultant histopathologist blinded to the routine histology results examined each set of imprints. A non-pathologist also examined each set of imprints to determine whether a technician could be used to screen slides in order to decrease the workload of the pathologist. RESULTS: Sensitivity was 82% with toluidine blue and 36.4% with anti-pancytokeratin immunoglobulin. Positive predictive values were 100% and 57% respectively for toluidine blue and anti-pancytokeratin. The false-negative rate was 18% for toluidine blue and 63.6% for anti-pancytokeratin antibody when examined by a consultant histopathologist. CONCLUSIONS: Imprint cytology using toluidine blue is as sensitive as frozen section in the detection of axillary lymph node metastases. A positive result may be acted upon with acceptable safety. Immunohistochemistry using antibody to pancytokeratin did not improve imprint sensitivity in this study. Imprint cytology could help to prevent a second operation in 80% of breast cancer patients with positive lymph nodes.

Adult↗
PubMed2003

Increases in spinal fluid osmolarity induced by mannitol.

OBJECTIVE: Mannitol is widely used in hospitals worldwide to treat patients with high intracranial pressure and/or cerebral edema. One of the mechanisms by which mannitol is thought to affect intracranial pressure is by increasing the patient's serum osmolarity, but not the osmolarity in the brain or cerebrospinal fluid. In this way, mannitol is thought to increase the osmolarity gap between the brain and the blood, which in turn leads to removal of excess water from the brain. However, relatively little is known regarding long-term effects of mannitol on osmolarity of cerebrospinal fluid. We therefore sought to determine the effects of mannitol administration on the osmolarity of cerebrospinal fluid. DESIGN: Controlled trial. SETTING: University teaching hospital. PATIENTS: Patients with severe head injury and patients with subarachnoid bleeding who required insertion of an intracranial probe. MEASUREMENTS AND MAIN RESULTS: Serum and cerebrospinal fluid osmolarity were measured before and during mannitol administration in ten patients treated with mannitol for >or=72 hrs (group 1), ten patients treated for 24 to 48 hrs (group 2), and ten controls (group 3). Serum osmolarity increased quickly in all patients receiving mannitol (groups 1 and 2), whereas remaining constant in controls. Average cerebrospinal fluid osmolarity slowly increased in all patients receiving mannitol; cerebrospinal fluid osmolarity increased from (mean +/- sd) 291.5 +/- 4.0 to 315.5 +/- 4.5 mOsm/kg after 96 hrs in group 1 (p <.01), and from 288.9 +/- 3.5 to 296.9 +/- 6.2 mOsm/kg after 48 hrs in group 2 (p <.01). Cerebrospinal fluid osmolarity remained constant in controls (p <.01 for group 1 vs. group 3 and for group 2 vs. group 3, respectively). In group 1, the gap between serum and cerebrospinal fluid osmolarity initially increased (which was the desired effect), but later decreased first to baseline values and then to below-normal levels. CONCLUSIONS: Long-term administration of mannitol can induce significant increases in cerebrospinal fluid osmolarity in patients with subarachnoid hemorrhage or severe head injury. This may be an undesirable and potentially dangerous effect. Therefore, cerebrospinal fluid osmolarity should be measured regularly in all patients receiving mannitol for longer than 24 hrs. If cerebrospinal fluid osmolarity increases, discontinuation or tapering of mannitol therapy should be considered.

Adolescent↗
PubMed2003

Safety issues surrounding the use of aromatase inhibitors in breast cancer.

Third generation aromatase inhibitors (AIs) are now established therapy in advanced oestrogen receptor (ER)-positive breast cancer. As the use of AIs expands to include adjuvant treatment of early breast cancer and breast cancer prevention, tolerability and effects on other organs such as bone will become as important as the antitumour properties of the drugs. In direct comparisons with tamoxifen, AIs have a better toxicity profile with fewer patients stopping therapy because of drug-related side effects. There is a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen. Although published information about the side effects of AIs is scarce, it is likely that they will have adverse effects on bone and possibly also on lipid metabolism. Subprotocols of ongoing adjuvant trials are investigating these effects. It is likely that the choice of which third generation AI to use will be largely determined by its tolerability and safety profile, since it is likely that the currently available drugs have similar efficacy.

Anastrozole↗
PubMed2002

Anastrozole ('Arimidex') blocks oestrogen synthesis both peripherally and within the breast in postmenopausal women with large operable breast cancer.

The effect of anastrozole on peripheral and tumour aromatase activity and oestrogen levels in postmenopausal patients with oestrogen receptor-rich breast tumours was investigated. Twenty-six patients were randomly allocated to treatment with anastrozole 1 mg (n=13) or 10 mg (n=13), once daily. Before and after 12 weeks' treatment, patients were infused with 3H-Delta4 androstenedione (20 MBq) and 14C-oestrone (E1) (1 MBq) for 18 h. Oestrogens were purified from excised tumours and plasma samples taken after each infusion. Peripheral and tumour aromatase activity and tumour E1 uptake were calculated from levels of 3H and 14C in purified E1 fractions from tumour and plasma. Endogenous tumour oestrogens were measured by radioimmunoassay. Twenty-three patients were available for analysis (1 mg group, n=12; 10 mg group, n=11). Following treatment, anastrozole (1 and 10 mg) markedly inhibited peripheral aromatase in all patients (the difference between pre- and on-treatment values being highly significant P<0.0001). In situ aromatase activity was also profoundly decreased by anastrozole treatment in 16 of 19 tumours (the difference with treatment also being highly significant P=0.0009). Most tumours were able to concentrate E1 beyond levels in the circulation; anastrozole treatment had no consistent effect on uptake of E1. Endogenous tumour levels of both E1 and oestradiol (E2) were significantly reduced with therapy (P=0.028 for E1 and P=0.0019 for E2). Anastrozole (1 and 10 mg daily) effectively suppresses aromatase activity, and subsequently oestrogen levels, within the breast tissue of postmenopausal women with large or locally advanced, operable, oestrogen receptor-rich breast cancers.

Aged↗
PubMed2002

Effect of neoadjuvant treatment with anastrozole on tumour histology in postmenopausal women with large operable breast cancer.

Anastrozole is an orally active, non-steroidal aromatase inhibitor which appears effective as neoadjuvant treatment of breast cancer. Histological changes have been evaluated in biopsies from large, oestrogen-receptor rich, operable breast tumours in postmenopausal women following 12 weeks of neoadjuvant anastrozole treatment (1 mg (n=12) or 10 mg (n=11)). Of the 23 patients, 18 had a clinical response following treatment. Compared with pre-treatment biopsies anastrozole-treated specimens displayed decreased cellularity and/or increased fibrosis in 15 tumours; changes in gland formation, nuclear pleomorphism, or mitoses, in 12 cases; and a reduction in Mib1 score in all tumours. Marked changes in apoptotic scores were seen following treatment but the direction of effect was inconsistent. In all 17 tumours which were positive for progesterone receptors before therapy, treatment was associated with reduced staining for progesterone receptors. There was no consistent effect of treatment on oestrogen-receptor expression. It is concluded that neoadjuvant anastrozole treatment in this patient group has marked effects on tumour histopathology but these do not always correlate with clinical response.

Aged↗
PubMed2002

Outcome after extended follow-up in a prospective study of operable breast cancer: key factors and a prognostic index.

In 1990, 215 patients with operable breast cancer were entered into a prospective study of the prognostic significance of five biochemical markers and 15 other factors (pathological/chronological/patient). After a median follow-up of 6.6 years, there were 77 recurrences and 77 deaths (59 breast cancer-related). By univariate analysis, patient outcome related significantly to 13 factors. By multivariate analysis, the most important of nine independent factors were: number of nodes involved, steroid receptors (for oestrogen or progestogen), age, clinical or pathological tumour size and grade. Receptors and grade exerted their influence only in the first 3 years. Progestogen receptors (immunohistochemical) and oestrogen receptors (biochemical) were of similar prognostic significance. The two receptors were correlated (r=+0.50, P=0.001) and displaced each other from the analytical model but some evidence for the additivity of their prognostic values was seen when their levels were discordant.

Biomarkers, Tumor↗
PubMed2002

Neoadjuvant endocrine therapy of breast cancer: a surgical perspective.

Neoadjuvant treatment with chemotherapy or endocrine agents is being used increasingly to downstage locally advanced and large operable breast cancers. Following these treatments, inoperable breast cancer often becomes fully resectable, and initially operable tumours requiring mastectomy may be successfully removed by breast-conserving surgery. Patient selection is important to optimise neoadjuvant endocrine therapy: only patients with oestrogen receptor (ER)-rich breast cancer are candidates, and postmenopausal women are likely to benefit the most. Such patients can expect a high probability of responses over a 3-month treatment period. Response to therapy should be monitored by clinical examination as well as by ultrasound, mammography, or other imaging procedures. Third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen in this treatment setting. In a large randomised trial of neoadjuvant endocrine therapy in postmenopausal women, letrozole achieved significantly higher response rates than tamoxifen, and a correspondingly higher rate of breast-conserving surgery was possible in the letrozole-treated patients. There is some evidence to suggest that the nature of the tumour response is different for preoperative endocrine therapy compared with chemotherapy. This difference may result in a higher rate of complete tumour excisions following breast-conserving surgery after neoadjuvant endocrine treatment. There appears to be a low rate of subsequent local recurrence in patients having breast-conserving therapy after neoadjuvant endocrine therapy.

Antineoplastic Agents, Hormonal↗
PubMed2002

Anti-tumor effects of letrozole.

The use of drugs, which inhibit estrogen biosynthesis, is an attractive treatment for postmenopausal women with hormone-dependent breast cancer. Estrogen deprivation is most specifically achieved using inhibitors which block the last stage in the biosynthetic sequence, i.e., the conversion of androgens to estrogens by the aromatase enzyme. Recently, a new generation of aromatase inhibitors has been developed. Among these, letrozole (Femara) appears to be the most potent. When given orally in milligram amounts per day to postmenopausal women, the drug almost totally inhibits peripheral aromatase and causes a marked reduction in circulating estrogens to levels that are often undetectable in conventional assays. Similarly, neoadjuvant studies demonstrate that letrozole substantially inhibits aromatase activity in both malignant and nonmalignant breast tissues, and markedly suppresses endogenous estrogens within the breast cancers. These studies also illustrate anti-estrogenic and anti-proliferative effects of letrozole in estrogen receptor (ER)-rich tumors. Thus, tumor expression of progesterone receptors and the cell-cycle marker Ki67 is significantly and consistently reduced with treatment. Additionally, clear pathological responses as evidenced by decreased cellularity and increased fibrosis are seen in the majority of cases. These results translated into clinical benefit in a series of 24 breast cancers treated neoadjuvantly with letrozole (either 2.5 or 10 mg): tumor volume reductions > 25% were observed in 23 women, and > 50% reductions in 18 patients. Pathological and clinical effects are seen much more consistently than with tamoxifen. Thus, in a multicenter randomized trial of letrozole vs. tamoxifen (PE 024), clinical study outcomes were superior for letrozole in comparison with tamoxifen with regard to overall tumor response and an increase in the proportion of patients treated by breast conserving surgery. Letrozole has also been used in advanced breast cancer, both as second-line hormone treatment following tamoxifen failure, and more recently as first-line therapy. Trials of second-line treatment in which letrozole has been compared with either older aromatase inhibitors or progestins have shown equivalent or superior clinical activity and improved tolerability favoring letrozole. In first-line comparison with tamoxifen in metastatic disease, a phase III trial of over 900 postmenopausal women showed letrozole to be significantly better than tamoxifen in terms of overall tumor response rates, clinical benefit, and time to treatment failure. In summary, letrozole is an exceptionally potent and specific endocrine agent. In patients with ER-rich tumors, high rates of pathological and clinical response have been documented, and large phase III trials against established treatments such as tamoxifen and progestin suggest superior (or at least equivalent) clinical efficacy. Letrozole is a drug of immense potential and in the future is likely to occupy a central role in the management of postmenopausal women with hormone-dependent breast cancer.

Antineoplastic Agents↗