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Biomedical subjects

I E Smith

Publications and source records attributed to I E Smith.

At least 91 records · Page 5Linked to original sources
PubMed1998

Randomized phase II trial of infusional fluorouracil, epirubicin, and cyclophosphamide versus infusional fluorouracil, epirubicin, and cisplatin in patients with advanced breast cancer.

PURPOSE: We previously developed an inpatient regimen that consisted of infusional fluorouracil (5-FU), epirubicin, and cisplatin (ECisF), with a response rate of 86% in advanced breast cancer. The current phase II 2:1 randomized study investigated whether cyclophosphamide can be substituted for cisplatin (ECycloF) to reduce toxicity and allow the regimen to be administered on an outpatient basis without loss of efficacy. PATIENTS AND METHODS: Ninety-six women (median age, 49 years; range, 28 to 73) with breast cancer (59 metastatic, 37 locally advanced) received continuous infusional 5-FU (200 mg/m2/d via Hickman line) and six cycles of epirubicin (60 mg/m2 every 21 days) with either cyclophosphamide 600 mg/m2 every 21 days (38 metastatic, 24 locally advanced) or cisplatin 60 mg/m2 every 21 days (21 metastatic, 13 locally advanced). There were no significant differences in patient characteristics between these groups. RESULTS: ECycloF was better tolerated than ECisF in terms of lethargy (P = .005), stomatitis (P = .008), plantar palmar erythema (P = .02), constipation (P < .001), thrombosis (P = .0014), and nausea and vomiting (P = .05). Although there was a trend toward more anemia and leukopenia with ECisF (P =. 1), there was no significant difference in the rates of infection. Efficacy was comparable in terms of overall response (69% v 68%), complete response (CR; 13% v 15%), and median progression-free survival (9 v 8 months). CONCLUSION: ECycloF is an outpatient regimen with a lower incidence of severe nonhematologic toxicity than inpatient ECisF; it has comparable efficacy and is considerably more economical.

Adult↗
PubMed1998

Pivotal trials of letrozole: a new aromatase inhibitor.

Letrozole (Femara) is a nonsteroidal aromatase inhibitor that is approximately 10,000 times as potent as aminoglutethimide in vivo. Two pivotal multinational phase III trials have compared letrozole (0.5 and 2.5 mg/d) against megestrol acetate and aminoglutethimide, respectively, in patients with locally advanced or metastatic breast cancer. The letrozole vs megestrol acetate trial showed the superiority of letrozole (2.5 mg/d) over megestrol acetate with respect to response rate, response duration, duration of overall clinical benefit (complete response plus partial response plus stable disease > or = 6 months), time to progression, and time to treatment failure. The letrozole-treated patients also showed a nonsignificant trend toward better survival. In the letrozole vs aminoglutethimide trial, letrozole (2.5 mg/d) was significantly superior in terms of duration of overall clinical benefit and survival. There were also strong trends favoring letrozole with regard to objective response rate and duration of response. Unexpectedly, both trials demonstrated a dose-response effect for 2.5 mg of letrozole over 0.5 mg in terms of response and overall survival. This finding raises the possibility that intratumoral aromatase suppression may be more relevant in breast cancer therapy than are plasma estrogen levels.

Aminoglutethimide↗
PubMed1997

Induction of apoptosis by tamoxifen and ICI 182780 in primary breast cancer.

Hormonal breast cancer therapies have traditionally been considered cytostatic, but recent pre-clinical data suggest that anti-oestrogens can induce apoptosis. The aim of this study was to assess whether tamoxifen (TAM) and ICI 182780 (ICI) could induce apoptosis in human breast cancer, and whether this was related to oestrogen receptor status. We measured apoptosis in primary breast cancer patients before and after pre-surgical treatment with 20 mg/day TAM (study 1) or 6 or 18 mg/day ICI (study 2). In each study there was a randomised non-treatment (NT) control group. TAM significantly increased apoptotic index (AI) in ER+ but not in ER- tumours. There was a significant increase in AI following treatment with ICI. Insufficient pairs of samples were available to determine whether this change was confined to ER+ tumours, but in a cross-sectional analysis AI was significantly higher in excision biopsies for ICI-treated than NT patients for ER+ but not ER- tumours. Our results provide clinical evidence that apoptosis may be induced in ER+ primary breast cancer by both non-steroidal and steroidal anti-oestrogens.

Adult↗
PubMed1997

Role of recombinant interferon-gamma maintenance in responding patients with small cell lung cancer. A randomised phase III study of the EORTC Lung Cancer Cooperative Group.

This study was undertaken to determine if recombinant interferon-gamma (rIFN-gamma) given every other day as maintenance therapy could prolong the survival of patients with small cell lung cancer (SCLC) who achieved a complete or nearly-complete response to induction therapy. A secondary endpoint was to assess the toxicity of alternate day doses of this treatment. One hundred and seventy seven patients in complete or nearly-complete response following chemotherapy with or without thoracic radiotherapy were studied. Patients were randomised to receive either rIFN-gamma 4 million units (0.2 mg) subcutaneously every other day for 4 months or observation. One hundred and twenty of the 127 registered patients were eligible; 59 patients received IFN and 61 patients without maintenance therapy were followed. Alternate day IFN was reasonably well tolerated by the majority of patients, but in 12% substantial non-haematological toxicity (including flu-like syndrome) occurred. One of 3 patients with pneumonitis died after having received 3.6 mg IFN. The median survival time from the date of randomisation was 8.9 months for the IFN arm and 9.9 months for the observation arm. rIFN-gamma at the dose and schedule used in this study failed to prolong response duration and survival in SCLC patients in complete or nearly-complete response. The toxicity seen with every other day doses of IFN was less than that reported with daily dosing. The hypothesis that this agent may increase the deleterious effects of radiation on normal lung tissue was supported by the development of pneumonitis in 3 cases of whom 1 had a fatal outcome. The results do not warrant further studies with rIFN-gamma on maintaining response in SCLC.

Antineoplastic Agents↗
PubMed1997

The novel anti-oestrogen idoxifene inhibits the growth of human MCF-7 breast cancer xenografts and reduces the frequency of acquired anti-oestrogen resistance.

The effect of idoxifene, a novel anti-oestrogen with less agonist activity than tamoxifen, was compared with that of tamoxifen on the growth of hormone-dependent MCF-7 breast cancer xenografts. Forty tumours were established with oestradiol support in ovariectomized athymic mice, allowed to grow to a median volume of 420 mm3 and then continued with oestradiol, no support, tamoxifen or idoxifene delivered by 1.5-cm silastic capsule. Tumour regression occurred with both anti-oestrogens, although maximum regression was observed following oestradiol withdrawal alone. While prolonged anti-oestrogen therapy was associated with static growth, tumour volumes were significantly lower with idoxifene (P=0.01). After 6 months, 0/10 idoxifene-treated tumours developed acquired resistance compared with 3/10 tumours treated with tamoxifen. In separate experiments, 94 animals were treated initially with oestradiol, tamoxifen, idoxifene or placebo following implantation with 1-mm3 pieces of either wild-type (WT) or tamoxifen-resistant (TR) MCF-7 tumour. After 4 months, only 1/11 WT tumours became established with idoxifene compared with 4/11 with tamoxifen, 8/12 with oestradiol and 0/12 with placebo. Likewise, fewer TR tumours were supported by idoxifene (3/12) than by tamoxifen (8/12) or oestrogen (11/12). These data indicate that, compared with tamoxifen, idoxifene shows reduced growth support of MCF-7 xenografts and may share only partial cross-resistance. Furthermore, the development of acquired anti-oestrogen resistance may be reduced during long-term idoxifene therapy. The drug's reduced agonist activity may, in part, explain these observations and indicate a preferable biochemical profile for breast cancer treatment.

Animals↗
PubMed1997

Ultrasound assessment of residual abnormalities following primary chemotherapy for breast cancer.

The purpose of this study was to assess the usefulness of ultrasonography (US) in the assessment of the breast following primary medical therapy (PMT) of large operable breast cancer. A total of 52 patients were studied; all had invasive breast cancer, confirmed by core biopsy, with initial size > 4 cm by palpation, T2-3, N0-1, M0. PMT was with epirubicin, cisplatin and continuous infusional 5-fluorouracil, as previously described (Jones et al, 1994, J Clin Oncol 12: 1259-1265). Independent clinical and US assessments were made during PMT before surgery or biopsy. A total of 31 (60%) patients achieved complete clinical response (cCR), but in only five of these was the post-treatment ultrasound normal. Post-treatment sonographic findings of diffuse parenchymal distortion or a mass lesion without Doppler signal were associated with more favourable histology (pathological CR, non-invasive or microinvasive carcinoma), whereas a mass with Doppler positivity was more often associated with residual macroscopic invasive carcinoma. Patients who did not achieve cCR had a high incidence of residual macroscopic carcinoma (71%) regardless of the sonographic characteristics. With median follow-up of 27 months (range 12-43), ten (19%) patients have relapsed and six (12%) have died, but only one relapse has occurred within treated breast. Ultrasonography is a sensitive technique for assessing the response to PMT, particularly in patients who achieve cCR. It may be helpful in selecting those patients who do not require post-PMT surgery and in localizing abnormalities in those who do, particularly in those with cCR. However, clinicians should be aware that a residual US abnormality is by no means pathognomonic of residual cancer.

Adult↗
PubMed1997

Absence of p21 expression is associated with abnormal p53 in human breast carcinomas.

The p53 tumour-suppressor gene is important in the regulation of cell growth and apoptosis, and loss of functional wild-type activity may be associated with tumour formation and resistance to therapy. Differentiation of functionally normal wild-type protein from mutant or abnormal protein remains difficult using either immunohistochemical assays or mutational DNA sequencing. p21(WAF1/CIP1) (p21) is induced by wild type p53 and plays an important role in promoting cell cycle arrest. To test the hypothesis that p21 protein expression may act as a downstream marker of tumours from patients with locally advanced breast cancer before treatment with doxorubicin, pretreatment p53 status had been characterized in 63 tumours by p53 protein immunostaining and DNA mutational analysis. There was a significant association between immunostaining for p53 and the presence of p53 mutations (P = 0.01). Of 56 patients available for determination of p21, 31 (55%) expressed p21 protein. Twenty-eight out of 31 patients (90%) positive for p21 had low negative p53 protein expression, whereas only 3 of 13 patients (23%) with high p53 expressed p21 (P = 0.009). No association was seen between p21 protein expression and p53 mutations (P = 0.24). The combination of p53 and p21 immunostaining results improved the specificity of the immunostaining but at a cost of significant reduction in sensitivity. Immunohistochemical assessment of p21 protein expression is inversely associated with abnormal p53 protein in human breast cancer. The detection of p21 protein expression in combination with p53 protein expression did not improve the ability of immunohistochemistry (IHC) to differentiate between normal and mutant p53 protein.

Adult↗
PubMed1997

Continuous infusional topotecan in advanced breast and non-small-cell lung cancer: no evidence of increased efficacy.

Two open, phase II studies were performed to evaluate the activity and toxicity of infusional topotecan in patients with advanced non-small-cell lung carcinoma (NSCLC) and advanced breast cancer who had not received previous chemotherapy for metastatic disease. Twenty-five patients with an ECOG performance score < 2 were treated with infusional topotecan administered as a daily, continuous intravenous infusion starting at 0.6 mg m(-2) day(-1) (NSCLC) and 0.5 mg m(-2) day(-1) (breast cancer) for 21 days every 4 weeks. Three patients achieved a partial response as defined by WHO criteria: one with NSCLC (8%; 95% CI 0-39%) and two with advanced breast cancer (15%; 95% CI 2-45%). The major toxicities were neutropenia and thrombocytopenia, with one episode of neutropenic sepsis. These data suggest that topotecan delivered as a continuous intravenous infusion over 21 days as single-agent therapy does not appear to offer a clinical advantage over conventional 5-day schedules against advanced NSCLC and advanced breast cancer.

Adult↗
PubMed1997

Secondary failure of nasal intermittent positive pressure ventilation using the Monnal D: effects of changing ventilator.

BACKGROUND: Some patients started on nasal intermittent positive pressure ventilation (NIPPV) with the Monnal D ventilator deteriorate after a period. The effects of changing them to the Nippy ventilator were investigated. METHODS: The records of such patients were examined retrospectively. Comparisons were made between blood gas tensions and overnight oximetry records before NIPPV, 12 weeks after the initiation of NIPPV with the Monnal D, at the time of deterioration, and 12 weeks after initiation of treatment with the Nippy ventilator. RESULTS: Ten patients (seven women) were identified. Prior to starting NIPPV their mean (SD) age was 59.6 (8.39) years and their mean arterial oxygen and carbon dioxide tensions (PaO2 and PaCO2) while breathing air were 6.1 (1.79) and 9.6 (3.28) kPa, respectively. All were started on NIPPV with the Monnal D with improvements in symptoms, PaO2, PaCO2, and overnight oximetry after 12 weeks of treatment. After a mean interval of 118 (69.0) weeks all measures of ventilation had deteriorated and the patients were converted to the Nippy ventilator. Twelve weeks after initiation of treatment with the Nippy ventilator symptoms and overnight oximetry were improved again and the mean PaO2 and PaCO2 were 8.9 (1.27) and 6.9 (0.45) kPa, respectively. After a total mean period of 59 (26.9) weeks on the Nippy all but one of the patients have maintained this improvement. CONCLUSIONS: Support with NIPPV using the Monnal D ventilator may fail after an interval and changing to the Nippy ventilator can reverse this deterioration, probably because of its superior responsiveness to leaks and patient effort. The regular follow up of patients on long term NIPPV is necessary if secondary treatment failure is to be identified and effectively treated.

Aged↗
PubMed1997

A comparison of children affected by prenatal alcohol exposure and attention deficit, hyperactivity disorder.

Behavioral deficits are often noted in children with fetal alcohol syndrome (FAS) and other individuals with prenatal alcohol exposure, including mental retardation, learning problems, social problems, and deficits in attention. Because attention deficit, hyperactivity disorder (ADHD) has been diagnosed so frequently in children with FAS and other alcohol related birth defects, there has been speculation that alcohol is an etiological factor in ADHD. To examine the relationship between behavior characteristics of children with fetal alcohol exposure and those seen in children with a diagnosis of ADHD, 149 low socioeconomic status (SES), African-American children (mean age = 7.63 years) were given a battery of neuropsychological and behavioral tests. One hundred and twenty-two were a sub-sample from a longitudinal study of prenatal alcohol exposure, whereas twenty-seven were identified in an ADHD Clinic. Children were given two sets of tests: (1) "traditional model" of conventional behavioral and psychiatric measures of ADHD and externalizing behavior; and (2) measures of neurocognitive functioning reflecting a four-factor model of the neurological basis of the components of attention (Mirsky AF, in Integrated Theory and Practice in Clinical Neuropsychology, Hillsdale, NJ, Lawrence Erlbaum Associates, 1989). Results indicated that children with the physical characteristics associated with prenatal alcohol exposure and those with a diagnosis of ADHD had equivalent intellectual abilities with both clinical groups performing more poorly than contrast children from the same SES and ethnic groups. However, there were clear distinctions on behavioral and neurocognitive measures between the two clinical groups with those with ADHD performing more poorly on conventional tests sensitive to attentional problems and conduct disorder. When these two groups were compared on measures designed to measure the model of the four factors of attention by Mirsky, they were noted to have distinct patterns of deficits. These results suggested that the alcohol-affected children did not have the same neurocognitive and behavioral characteristics as children with a primary diagnosis of ADHD.

Black or African American↗
PubMed1997

Patient benefits from new treatment options and schedules for breast cancer.

Adjuvant chemotherapy is of proven survival benefit for patients with early breast cancer, but trials of new adjuvant therapies take many years to conduct and evaluate. In addition, adjuvant chemotherapy is given "blind," with no prior knowledge of the sensitivity of a patient's tumor to the agents being used. Primary chemotherapy is an innovative approach in which chemotherapy is given as first-line treatment, before surgery. This approach was developed for tumor reduction in inoperable locally advanced breast cancer, and the results obtained in several studies suggested that primary chemotherapy with adjuvant surgery could be an effective alternative to the conventional approach of primary surgery with adjuvant chemotherapy. Several combination regimens have proved successful as primary chemotherapy, with response rates of 69% to 78%, including 12% to 30% complete remissions. The use of infusional 5-fluorouracil, in combination with bolus injections of epirubicin and cisplatin (infusional ECF), as primary chemotherapy in women with metastatic or locally advanced breast cancer has been pioneered by The Royal Marsden NHS Trust in the United Kingdom. Infusional ECF has shown a response rate of 98%, with 66% complete remissions, in a trial involving 50 women with large operable breast tumors. Infusional ECF is now being compared with conventional doxorubicin/cyclophosphamide chemotherapy in a multicenter trial. Administering chemotherapy before surgery also allows the drug sensitivity of the tumor to be assessed at the time of treatment. Techniques for testing the chemosensitivity of tumors in vivo and adjusting the chemotherapy in line with initial results are being investigated. In this way, primary chemotherapy may offer an effective approach to testing new therapies as front-line treatments.

Antineoplastic Agents↗
PubMed1997

Expression of epidermal growth factor receptor and c-erbB2 during the development of tamoxifen resistance in human breast cancer.

Expression of epidermal growth factor receptor (EGFR) or of c-erbB2 in primary breast cancer has been shown to predict for a poor chance of subsequent response of recurrent/metastatic disease to endocrine therapy. To assess the role of these receptors in the development of tamoxifen resistance, we examined their expression immunohistochemically on paraffin-embedded sections from breast cancers from 155 patients whose disease was progressing on tamoxifen therapy. Patients were categorized into those who initially responded to therapy (n = 56), those who never responded (n = 39), and those who relapsed while on adjuvant therapy and may or may not have "responded" (n = 60). In 61 cases, pretreatment specimens were also obtained for direct comparison with the resistance specimen for each patient. None of the 18 pretreatment samples from patients who responded to therapy expressed c-erbB2, and 1 of 18 expressed EGFR. Of the nonresponders, 7 of 18 expressed EGFR pretreatment, and 4 of 18 expressed c-erbB2 (1 patient expressed both receptors). Results confirmed previous findings that when considered independently, expression of either receptor pretreatment tended to predict for a poor chance of response (EGFR, P = 0.046; c-erbB2, P = 0.11). Importantly, patients who were either EGFR positive and/or c-erbB2 positive had a much poorer chance of response than "double negatives" (response rates of 1 of 11 and 17 of 25, respectively; P = 0.0039). At the time of disease progression compared to pretreatment, there was no significant change in expression of either receptor, irrespective of initial response. The inverse relationship between EGFR and estrogen receptor was maintained at relapse on tamoxifen. These data argue strongly against the acquired expression of these receptors during treatment playing a major role in the development of tamoxifen resistance in human breast cancer.

Adult↗
PubMed1996

Primary chemotherapy for early breast cancer.

The use of primary chemotherapy represents a novel approach being used with increasing frequency in the management of early breast cancer. Many studies now testify to the usefulness of this modality in increasing the frequency of breast conservation. The acceptance of high-risk breast cancer as a systemic, and therefore predominantly medical rather than a surgical, disease suggests, however, that its role is likely to be far more reaching. While some trials have so far suggested the possibility of a survival benefit for this approach, definitive conclusions are not yet possible and await the final mature results from several large randomized studies. Even if such studies do not show a large extra benefit for primary chemotherapy over existing adjuvant treatment, the use of the primary tumour as an in vivo model of individual chemosensitivity and the identification of molecular markers as early predictors of response, suggest that this approach will become an integral part of the modern multidisciplinary management of early breast cancer.

Antineoplastic Agents↗