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Ian E Smith

Publications and source records attributed to Ian E Smith.

At least 19 recordsLinked to original sources
PubMed2007

Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer.

Tumor expression of the proliferation antigen Ki67 is widely used to assess the prognosis of cancer patients. A change in the expression of Ki67 after short-term exposure of patients to therapeutic agents is frequently used as a pharmacodynamic marker of efficacy, particularly among breast cancer patients before undergoing surgery. To determine the clinical significance of the level of tumor cell proliferation during endocrine therapy for breast cancer, we measured the expression of Ki67 in tumor biopsy samples taken before and after 2 weeks of presurgical treatment with anastrozole or tamoxifen or the combination of anastrozole plus tamoxifen in 158 patients with hormone receptor-positive primary disease. In a multivariable analysis, we found that higher Ki67 expression after 2 weeks of endocrine therapy was statistically significantly associated with lower recurrence-free survival (P = .004) whereas higher Ki67 expression at baseline was not. Larger baseline tumor size and lower estrogen receptor level after 2 weeks of treatment were also statistically significantly associated with poorer recurrence-free survival (P < .001 and P = .04, respectively). Our data indicate that measurements of tumor Ki67 level after short-term endocrine treatment may improve the prediction of recurrence-free survival by integrating the prognostic value of Ki67 level at baseline with changes in Ki67 level that are associated with treatment benefit.

Adult↗
PubMed2006

The effect of the stromal component of breast tumours on prediction of clinical outcome using gene expression microarray analysis.

INTRODUCTION: The aim of this study was to examine the effect of the cellular composition of biopsies on the error rates of multigene predictors of response of breast tumours to neoadjuvant adriamycin and cyclophosphamide (AC) chemotherapy. MATERIALS AND METHODS: Core biopsies were taken from primary breast tumours of 43 patients prior to AC, and subsequent clinical response was recorded. Post-chemotherapy (day 21) samples were available for 16 of these samples. Frozen sections of each core were used to estimate the proportion of invasive cancer and other tissue components at three levels. Transcriptional profiling was performed using a cDNA array containing 4,600 elements. RESULTS: Twenty-three (53%) patients demonstrated a 'good' and 20 (47%) a 'poor' clinical response. The percentage invasive tumour in core biopsies collected from these patients varied markedly. Despite this, agglomerative clustering of sample expression profiles showed that almost all biopsies from the same tumour aggregated as nearest neighbours. SAM (significance analysis of microarrays) regression analysis identified 144 genes which distinguished high- and low-percentage invasive tumour biopsies at a false discovery rate of not more than 5%. The misclassification error of prediction of clinical response using microarray data from pre-treatment biopsies (on leave-one-out cross-validation) was 28%. When prediction was performed on subsets of samples which were more homogeneous in their proportions of malignant and stromal cells, the misclassification error was considerably lower (8%-13%, p < 0.05 on permutation). CONCLUSION: The non-tumour content of breast cancer samples has a significant effect on gene expression profiles. Consideration of this factor improves accuracy of response prediction by expression array profiling. Future gene expression array prediction studies should be planned taking this into account.

Adult↗
PubMed2006

Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines.

PURPOSE: Aromatase inhibitors (AIs) are now established as adjuvant therapy for early hormone receptor-positive breast cancer in postmenopausal women. Their use is sometimes extended to younger women after chemotherapy-induced amenorrhoea; we have audited this in one institution's breast unit, and we propose guidelines for use in such circumstances. PATIENTS AND METHODS: The use of aromatase inhibitors as adjuvant therapy in younger women age > or = 40 with hormone receptor-positive early breast cancer and chemotherapy-induced amenorrhea has been audited clinically and biochemically. Results A total of 45 such women were identified in the audit, with a median age of 47 years (range, 39 to 52 years). Twelve women (27%) showed a return of ovarian function (10 renewed menses, one pregnancy, one biochemically premenopausal) after starting an AI. Median age at restart of ovarian function was 44 years (range, 40 to 50 years). CONCLUSION: AIs may promote recovery of ovarian function in some women with chemotherapy-induced amenorrhea and should be used with caution. Biochemical monitoring of ovarian function requires highly sensitive immunoassays. Guidelines for the selection and delivery of adjuvant endocrine therapy in such patients are proposed.

Adult↗
PubMed2006

A phase II study of weekly docetaxel in patients with anthracycline pretreated metastatic breast cancer.

BACKGROUND: Docetaxel has significant activity in metastatic breast cancer and weekly schedules are associated with less myelosuppression than 3-weekly schedules. We evaluated the toxicity and the activity of weekly docetaxel in anthracycline-pretreated patients. PATIENTS AND METHODS: A total of 42 patients were studied. Treatment consisted of docetaxel 35 mg/m2 weekly as a 30-min infusion for 6 weeks followed by a 2-week rest, with dexamethasone 8 mg i.v. pre-medication and 4 mg orally 12-hourly for 48 h following treatment. RESULTS: The median age of the patients was 53 years (range 34-74). Twenty-six (62%) patients had received prior chemotherapy for advanced disease. Patients received a median 10 weeks of treatment (range 1-24). 11 had a partial response (ORR 26%; 95% CI 13-39%), five of whom had relapsed <12 months since the end of previous anthracycline-based chemotherapy. In addition six patients (14%) had stable disease for >16 weeks. Myelosuppression was rare with only 2 patients (5%) experiencing grade 3 neutropenia (no grade 4 neutropenia). Non-haematological grade III toxicities were as follows: fatigue 17%, neuropathy 0%, hyperlacrimation 5%, stomatitis 7%, diarrhoea 14%, and cutaneous toxicity 19%. Skin toxicity consisted of limb/palmar-plantar erythematous reactions, or fixed-plaque erythrodysaesthesia. CONCLUSIONS: Weekly docetaxel has moderate activity in women with anthracycline pre-treated breast cancer. Although the level of myelosuppression is lower than 3-weekly regimens, this weekly regimen cannot be recommended due to the significant non-haematological toxicities associated with the treatment.

Adult↗
PubMed2006

Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer.

The study of changes in proliferation as a marker of treatment benefit during presurgical endocrine treatment of breast cancer has become increasingly popular, particularly using the nuclear marker Ki67, and holds the potential for prioritizing new treatments for full clinical development. There are weakly significant relationships between Ki67 change and clinical response that differ according to data handling. In the neoadjuvant Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen trial, suppression of Ki67 at both 2 and 12 weeks was greater with the aromatase inhibitor anastrozole than with either tamoxifen or the combination of anastrozole and tamoxifen. We report here that absolute values of Ki67 after 2 weeks were also significantly lower with anastrozole than with tamoxifen and the combination. This indicates that it may be possible to make such comparisons using surgical samples only. We argue that these changes in proliferation and concurrent changes in apoptosis may be expected to be more predictive of adjuvant benefit from endocrine therapy than clinical response.

Anastrozole↗
PubMed2006

Rhythmic movement disorder (head banging) in an adult during rapid eye movement sleep.

Sleep-related rhythmic movements (head banging or body rocking) are extremely common in normal infants and young children, but less than 5% of children over the age of 5 years old exhibit these stereotyped motor behaviors. They characteristically occur during drowsiness or sleep onset rather than in deep sleep or rapid eye movement (REM) sleep. We present a 27-year-old man with typical rhythmic movement disorder that had persisted into adult life and was restricted to REM sleep. This man is the oldest subject with this presentation reported to date and highlights the importance of recognizing this nocturnal movement disorder when it does occur in adults.

Adult↗
PubMed2006

Neoadjuvant treatment for early-stage breast cancer: opportunities to assess tumour response.

Primary, preoperative, or neoadjuvant chemotherapy was introduced in the early 1970s as part of an integrated therapeutic approach to treat inoperable locally advanced breast cancer. The approach resulted in high responses, and sufficient downstaging to allow mastectomy in some patients. In addition, a small number of pathological complete responders were reported. Gradually, the idea of preoperative chemotherapy was extended to include patients with large but operable early-stage breast cancer, with the possibility in some cases of downstaging the primary tumour to avoid mastectomy, and to allow breast-conserving surgery to be done. This approach allows the tumour to be used as a measure of treatment response in vivo. More recently, the possibility has opened up for neoadjuvant chemotherapy to provide information on the use of clinical, pathological, and molecular endpoints, which can be used as surrogate markers to predict long-term outcome in the adjuvant setting. In addition, the anatomical accessibility of the breast provides the potential for serial biopsies to investigate molecular changes during treatment.

Antibodies, Monoclonal↗
PubMed2006

Overview of gemcitabine activity in advanced breast cancer.

Gemcitabine, an antimetabolite that is incorporated as a triphosphate into DNA, is active as a single agent in first- and subsequent-line treatment of breast cancer, with an overall objective response rate of 26%. It is relatively well tolerated, and its dose-limiting toxicity has usually been neutropenia. Gemcitabine has proven active in combination with paclitaxel and, on this basis, a phase III trial showed a significantly higher response rate than paclitaxel alone (39.3% v 25.6%). The combination also showed a significantly longer median time to progression (5.2 v 2.9 months) and significantly improved median overall survival time (18.5 v 15.8 months). Apart from neutropenia, there was no significant increase in toxicity for the combination. Gemcitabine has also been shown to be active in combination with docetaxel, and a phase III trial has shown that gemcitabine plus docetaxel is as effective as capecitabine plus docetaxel, but with significantly less nonhematologic toxicity. Two-week schedules of gemcitabine plus paclitaxel or docetaxel are currently being investigated, as are combinations with paclitaxel plus trastuzumab, and paclitaxel plus anthracyclines. These results have prompted ongoing trials of gemcitabine in early breast cancer as neoadjuvant and adjuvant therapy.

Antimetabolites, Antineoplastic↗
PubMed2006

Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab.

We aim to investigate the incidence, patterns and timing of brain metastases in advanced breast cancer patients who have previously received trastuzumab. Eighty-seven patients who had received trastuzumab for advanced breast cancer from November 1999 to September 2003 at the Royal Marsden Hospital were assessed. With a median follow-up period of 11 months from commencing trastuzumab, 23 patients developed brain metastases (30% at 1 year; 95% CI 58-82%). Among 57 patients who had clinical benefits on trastuzumab, 12 (21%) patients developed first disease progression in brain with 75% of them had isolated CNS progression. Moreover, among patients who received trastuzumab as first line treatment, isolated brain metastases were the initial site of progression in 17% patients. Nearly all patients developed parenchymal brain disease. This study shows brain metastases are common phenomenon in HER2 positive advanced breast cancer patients receiving trastuzumab and also may implicate the brain as a sanctuary site for early relapse in this patient cohort.

Adult↗
PubMed2006

Prolonged invasive ventilation following acute ventilatory failure in COPD: weaning results, survival, and the role of noninvasive ventilation.

BACKGROUND: Invasive ventilation for COPD has significant mortality, and weaning can be difficult. At Papworth Hospital, we provide a specialist weaning service using noninvasive ventilation (NIV) for patients requiring prolonged invasive ventilation after recovery from acute illness. We analyzed our results for patients with COPD to identify factors associated with weaning outcome and survival. METHODS: A retrospective analysis was conducted of COPD patients admitted for weaning from invasive ventilation, from 1992 to 2003. Weaning success and survival were assessed. Associations were sought between these outcomes and age, sex, spirometry, arterial blood gas levels, APACHE (acute physiology and chronic health evaluation) II score, length of stay (LOS), and the use of NIV and long-term oxygen therapy. RESULTS: Sixty-seven patients were identified, all of whom were receiving tracheostomy ventilation on transfer to the Respiratory Support and Sleep Centre (RSSC). Sixty-four patients (95.5%) were weaned, and 62 patients survived to hospital discharge. NIV was used in weaning 40 patients and in the long term in 25 patients. Median survival was 2.5 years (interquartile range, 0.7 to 4.6 years). One-year, 2-year, and 5-year survival rates were 68%, 54%, and 25%, respectively. Long-term survival was inversely associated with age and LOS in the ICU and the RSSC. The provision of maintenance NIV after weaning was associated with better long-term survival, independent of age and LOS (hazard rate, 0.48; p = 0.03). CONCLUSIONS: These results demonstrate that a specialist multidisciplinary approach, including the use of NIV, can be successful in weaning most COPD patients from prolonged invasive ventilation. The data also suggest that long-term NIV may improve survival in selected patients.

Aged↗
PubMed2005

Proliferation marker Ki-67 in early breast cancer.

Molecular markers have been extensively investigated with a view to providing early and accurate information on long-term outcome and prediction of response to treatment of early breast cancer. Proliferation is a key feature of the progression of tumors and is now widely estimated by the immunohistochemical assessment of the nuclear antigen Ki-67. The expression of Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake. High Ki-67 is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy, but its independent significance is modest and does not merit measurements in most routine clinical scenarios. However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs.

Antineoplastic Agents↗
PubMed2005

Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial.

PURPOSE: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) trial was designed to test the hypothesis that the clinical and/or biologic effects of neoadjuvant tamoxifen compared with anastrozole and with the combination of tamoxifen and anastrozole before surgery in postmenopausal women with estrogen receptor (ER) -positive, invasive, nonmetastatic breast cancer might predict for outcome in the Arimidex, Tamoxifen Alone or in Combination (ATAC) adjuvant therapy trial. PATIENTS AND METHODS: Postmenopausal women with ER-positive, invasive, nonmetastatic, and operable or locally advanced potentially operable breast cancer were randomly assigned to neoadjuvant tamoxifen (20 mg daily), anastrozole (1 mg daily), or a combination of tamoxifen and anastrozole for 3 months. The tumor objective response (OR) was assessed by both caliper and ultrasound. Comparisons were also made of clinical response with ultrasound response, actual and feasible surgery with feasible surgery at baseline, OR in human epidermal growth factor receptor 2 (HER2)-positive cancers, and tolerability. RESULTS: There were no significant differences in OR in the intent-to-treat population between patients receiving tamoxifen, anastrozole, or the combination. In patients who were assessed as requiring mastectomy at baseline (n = 124), 44% of patients received breast-conserving surgery (BCS) after anastrozole compared with 31% of patients after tamoxifen (P = .23); this difference became significant for patients who were deemed feasible for BCS by their surgeon (46% v 22%, respectively; P = .03). The OR for patients with HER2-positive cancer (n = 34) was 58% for anastrozole compared with 22% for tamoxifen (P = .18). All treatments were well tolerated. CONCLUSION: Neoadjuvant anastrozole is as effective and well tolerated as tamoxifen in ER-positive operable breast cancer in postmenopausal women, but the hypothesis that clinical outcome might predict for long-term outcome in adjuvant therapy was not fulfilled.

Aged↗
PubMed2005

Chemotherapy for breast cancer during pregnancy: an 18-year experience from five London teaching hospitals.

PURPOSE: The rare association between breast cancer and pregnancy means that few oncologists gain an expertise in this area. In particular, there are few published data concerning the use of chemotherapy for breast cancer during pregnancy. In this retrospective case series, we describe the experiences of five hospitals in London, United Kingdom, and how they manage this condition. PATIENTS AND METHODS: Retrospective searches were performed at five London hospitals in order to identify women who received chemotherapy for breast cancer while pregnant. RESULTS: Twenty-eight women were identified who had received chemotherapy for breast cancer during pregnancy. Twenty-four women received adjuvant or neoadjuvant chemotherapy for early breast cancer, and four women received palliative chemotherapy for metastatic disease. A total of 116 cycles of chemotherapy were administered during pregnancy. Sixteen women were treated with anthracycline-based chemotherapy and 12 received cyclophosphamide, methotrexate, and fluorouracil. All but one of the women were treated after the first trimester. One spontaneous abortion occurred in the woman treated during her first trimester; otherwise, there were no serious adverse consequences for the mothers or neonates. CONCLUSION: These data provide evidence that in terms of peripartum complications and immediate fetal outcome, chemotherapy can be safely administered to women during the second and third trimesters of pregnancy.

Adult↗
PubMed2005

The validation of a new actigraphy system for the measurement of periodic leg movements in sleep.

BACKGROUND AND PURPOSE: To determine the accuracy of a new actigraphy system for the measurement of periodic leg movements (PLMs). Continuous measurements of leg movements, made overnight, are essential to diagnose and monitor treatment for PLMs. We have developed the Actiwatch with Cambridge Neuro-Technology Ltd (Cambridge, UK) to detect leg movements consistent with PLMs, to record these movements from both feet over three consecutive nights and to report standard indices of PLMs. We describe three studies designed to validate this device. PATIENTS AND METHODS: The Actiwatch was assessed on a bench model across a range of movement amplitudes. The level of agreement on individual movements between the Actiwatch and bilateral anterior tibialis electromyography (BATEMG) measures was assessed in 199 epochs from five patients with known PLMs. The ability of the Actiwatch to correctly identify patients with PLMs was assessed in a comparison with polysomnography (PSG) in 50 consecutive patients investigated in the sleep laboratory. RESULTS: The Actiwatch detected all mechanically generated movements (100% sensitivity and 100% specificity) on the bench test. On individual movements BATEMG measurement and the Actiwatch agreed on 94% of epochs. The sensitivity and specificity of the Actiwatch to detect leg movements in severe PLMs as defined by BATEMG (PLMI>or=25) are high (100% sensitive and 97% specific). Our bilateral system gave better agreement with BATEMG than previous systems but the two measures are still not interchangeable. CONCLUSIONS: EMG is only a surrogate measure of limb movement and indices measured in this way correlate poorly with symptoms. We have demonstrated that the Actiwatch faithfully records movement, which offers the potential to reassess the relationships between limb movement indices and symptoms. This which offers a convenient and economical alternative to PSG in the study of large populations to increase our understanding of the epidemiology and clinical significance of PLMs.

Adolescent↗
PubMed2005

Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists.

PURPOSE: To investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy. PATIENTS AND METHODS: The IMPACT trial compared the preoperative use of tamoxifen with anastrozole alone or in combination in postmenopausal women (n = 330) with primary breast cancer. Biomarkers were measured in tumor biopsy specimens taken at baseline, and after 2 and 12 weeks of treatment. RESULTS: 52 (93%) of 56, 46 (85%) of 54, and 37 (84%) of 44 patients in the anastrozole, tamoxifen, and combination groups, respectively. There was a significantly greater suppression of Ki67 in the anastrozole-treated group than in the tamoxifen- or combination-treated groups, which is parallel to the greater efficacy seen for anastrozole over these two treatments in the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial. A positive relationship was noted between estrogen-receptor level and Ki67 suppression in all patients. Ki67 was reduced to a greater extent in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors. HER-2-negative tumors tended to show a greater reduction in Ki67 compared with HER-2-positive tumors, but the difference was only significant in the tamoxifen group after 2 weeks, and in the anastrozole group after 12 weeks. CONCLUSION: These results confirm the value of Ki67 as a molecular marker, and provide information regarding the relationships between treatment-induced changes in Ki67 and other important biomarkers. Studies such as this should help integrate agents targeted at growth factor signaling with endocrine agents in breast cancer.

Aged↗
PubMed2005

Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival.

PURPOSE: Neoadjuvant (preoperative) therapy for breast cancer may allow for the development of intermediate markers of treatment benefit, thereby circumventing the need for efficacy trials of adjuvant therapy, which require much larger patient numbers and longer follow-up. The aim of this study--as part of the Immediate Preoperative "Arimidex" (anastrozole), Tamoxifen, or Arimidex Combined with Tamoxifen (IMPACT) trial (n = 330)--was to test the hypotheses that changes in Ki-67 after 2 weeks and/or 12 weeks: (i) differed between treatments, (ii) predicted clinical tumor response, and/or (iii) may predict long-term outcome differences between treatments in adjuvant therapy. EXPERIMENTAL DESIGN: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared these same agents in the adjuvant setting. Biomarkers were measured in biopsy specimens taken before and after 2 and 12 weeks of treatment. RESULTS: Suppression of the proliferation marker Ki-67 after 2 and 12 weeks was significantly greater with anastrozole than with tamoxifen (P = 0.004 and P < 0.001) but was similar between tamoxifen and the combination (P = 0.600 and P = 0.912). This result closely parallels that seen for the relative recurrence-free survival with the treatments after a median follow-up of 31 months in the ATAC trial in 9,366 patients. Against expectations, apoptosis was not increased in any of the treatment arms. CONCLUSIONS: The data indicate that short-term changes in proliferation in the neoadjuvant setting may be able to predict outcome during adjuvant use of the same treatments. If this can be confirmed, these findings could lead to a profound change in approaches to drug development in breast cancer. The data indicate that estrogen is not an important survival factor for human breast cancer cells.

Aged↗