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Richard Bell

Publications and source records attributed to Richard Bell.

At least 19 recordsLinked to original sources
PubMed2007

2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.

BACKGROUND: Trastuzumab--a humanised monoclonal antibody against HER2--has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drug's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study. METHODS: HERA is an international multicentre randomised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer. 5102 women participated in the trial; we analysed data from 1703 women who had been randomised for treatment with trastuzumab for 1 year and 1698 women from the control group, with median follow-up of 23.5 months (range 0-48 months). The primary endpoint of the trial was disease-free survival. Here, we assess overall survival, a secondary endpoint. Analyses were done on an intent-to-treat basis. This trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS: 97 (5.7%) patients randomised to observation alone and 58 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up. 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47-0.91; p=0.0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54-0.76; p<0.0001). INTERPRETATION: Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years. The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer.

Adult↗
PubMed2006

Structural and functional modifications in glutamateric synapses following prolonged ethanol exposure.

This article summarizes the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism in Santa Barbara, California, USA. The organizer and chair was L. Judson Chandler. The presentations were (1) Chronic Ethanol Exposure, N-Methyl-D-Aspartate (NMDA) Receptor Dynamics, and Withdrawal Hyperexcitability, by Adam Hendricson, Regina Maldve, and Richard Morrisett; (2) Ethanol-Induced Synaptic Targeting of NMDA Receptors Is Associated With Enhanced Postsynaptic Density-95 Clustering and Spine Size, by Judson Chandler and Ezekiel Carpenter-Hyland; (3) Presynaptic and Postsynaptic Alterations in the Nucleus Accumbens Following Chronic Alcohol Exposure, by Feng Zhou, Youssef Sari, and Richard Bell; and (4) An Active Role for Accumbens Homer2 Expression in Alcohol-Induced Neural Plasticity, by Karen Szumlinski.

Alcohol Withdrawal Delirium↗
PubMed2006

Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part I: adult brain growth.

BACKGROUND: The alcohol-preferring (P) rat, a Wistar strain selectively bred to consume large amounts of alcohol voluntarily, has been used as an animal model of human alcoholism for 3 decades. Heretofore, knowledge about brain morphology has been confined to postmortem examination. Quantitative neuroimaging procedures make it feasible to examine the potential longitudinal effects of alcohol exposure in vivo, while controlling modifying factors, such as age, nutrition, and exercise. To date, few imaging studies have considered what morphological changes occur with age in the rodent brain, and none has systematically applied quantitative neuroimaging approaches to measure volume changes in regional brain structures over extended periods in the adult rat. METHODS: We used structural magnetic resonance imaging (MRI) in a longitudinal design to examine 2 cohorts of adult P rats, never exposed to alcohol: Cohort A included 8 rats, 7 of which survived the entire study (578 days) and 4 MRI sessions; Cohort B included 9 rats, all of which survived the study (452 days) and 5 MRI sessions. RESULTS: Growth in whole-brain volume reached maximal levels by about 450 days of age, whereas body weight continued its gain without asymptote. Growth was not uniform across the brain structures measured. Over the initial 12 months of the study, the corpus callosum area expanded 36%, cerebellum 17%, and hippocampus 10%, whereas ventricle size was unchanged. Factors affecting growth rate estimates included litter effects, MR image signal-to-noise ratio, and measurement error. CONCLUSION: Unlike longitudinal human reports of regional volume declines in aging brain tissue, several brain structures in adult rats continued growing, and some growth patterns were litter-dependent. Determining normal regional growth patterns of brain and of the substantial variance exerted by litter differences, even in selectively bred rats, is essential for establishing baselines against which normal and aberrant dynamic changes can be detected in animal models of aging and disease.

Aging↗
PubMed2006

Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part II: effects of voluntary chronic alcohol consumption.

BACKGROUND: Tracking the dynamic course of human alcoholism brain pathology can be accomplished only through naturalistic study and without opportunity for experimental manipulation. Development of an animal model of alcohol-induced brain damage, in which animals consume large amounts of alcohol following cycles of alcohol access and deprivation and are examined regularly with neuroimaging methods, would enable hypothesis testing focused on the degree, nature, and factors resulting in alcohol-induced brain damage and the prospects for recovery or relapse. METHODS: We report the results of longitudinal magnetic resonance imaging (MRI) studies of the effects of free-choice chronic alcohol intake on the brains of 2 cohorts of selectively bred alcohol-preferring (P) rats. In the companion paper, we described the MRI acquisition and analysis methods, delineation of brain regions, and growth patterns in total brain and selective structures of the control rats in the present study. Both cohorts were studied as adults for about 1 year and consumed high doses of alcohol for most of the study duration. The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark. RESULTS: Brain structures of the adult P rats in both the alcohol-exposed and the water control conditions showed significant growth, which was attenuated in a few measures in the alcohol-exposed groups. The region with the greatest demonstrable effect was the corpus callosum, measured on midsagittal images. CONCLUSION: The P rats showed an age-alcohol interaction different from humans, in that normal growth in selective brain regions that continues in adult rats was retarded.

Animals↗
PubMed2006

Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer.

Up to one fourth of women diagnosed with early breast cancer (EBC) have tumors that are human epidermal growth factor receptor 2 (HER-2) positive. This is associated with a high risk of relapse and death from meta-static disease. Trastuzumab, a monoclonal antibody directed against the extracellular domain of HER-2, improves survival and quality of life in women with HER-2-positive metastatic breast cancer receiving chemotherapy. Four major adjuvant trials-Herceptin Adjuvant (HERA), National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) N9831, and Breast Cancer International Research Group (BCIRG) 006-including between them >13,000 women with HER-2-positive EBC, have investigated different adjuvant treatment approaches with trastuzumab. These trials have shown that trastuzumab reduces the 3-year risk of recurrence by about half in this population. The benefit was similar across the trials despite differences in patient populations, chemotherapy regimens, and sequencing of treatment. At a 2-year follow-up, interim results from the combined analysis of the NSABP B-31 and NCCTG N9831 trials showed a one third lower mortality for trastuzumab, and there was a trend toward an overall survival benefit in the HERA and BCIRG trials. A small Finnish trial, FinHer, investigating another regimen of trastuzumab, has also shown similarly positive results. Further follow-up of the major adjuvant trials will clarify the survival benefit for women receiving trastuzumab, as well as the optimal treatment duration (1 or 2 years). Notably, cardiac events in the trastuzumab-containing arms of these trials have remained within acceptable levels, with a slightly higher (0.6%-3.3%) incidence of congestive heart failure that mostly responded to treatment. Further follow-up will provide information on long-term cardiac safety. Overall, results from clinical trials are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk:benefit ratio demonstrated in these studies.

Antibodies, Monoclonal↗
PubMed2005

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.

BACKGROUND: Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. METHODS: This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. RESULTS: Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. CONCLUSIONS: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)

Adult↗
PubMed2005

A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma.

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta(2)-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.

Adult↗
PubMed2005

Preoperative evaluation of pancreatic cystic lesions: cost-benefit analysis and proposed management algorithm.

BACKGROUND: This study was performed to develop a management algorithm that accurately predicts the necessity of operative intervention and results in significant cost savings for patients with cystic pancreatic tumors. METHODS: We reviewed 60 patients treated between 1992 and 2003. Accuracy rates of tests used to differentiate benign from premalignant and malignant cysts were calculated. A management algorithm was generated that incorporated clinical presentation, radiologic findings, and selective use of endoscopic procedures. This algorithm was tested for predictive accuracy, and savings between actual management and proposed management were compared. RESULTS: There was an average of 3 preoperative tests performed per patient. Endoscopic procedures included endoscopic retrograde cholangiopancreatography in 21 patients and endoscopic ultrasound in 25 patients. A cyst fluid carcinoembryonic antigen (CEA) level of 158 ng/mL or greater had an accuracy rate of 87.5% that was significantly higher than endoscopic retrograde cholangiopancreatography (72%), endoscopic ultrasound morphology (45%), or endoscopic ultrasound cytology (66.7%). There was no combination of tests that provided greater accuracy than cyst fluid CEA level alone (P < .05). The management algorithm had a positive predictive value of 81%. The average actual cost of radiographic and endoscopic procedures was dollar 8,080 per patient. The proposed cost based on the algorithm was dollar 6,677 with a savings of dollar 1,403 per patient (P = .009). CONCLUSIONS: In patients with clinical symptoms or radiographic findings of mucinous or malignant tumors, further testing is excessive. Of endoscopic tests available, the cystic fluid CEA level most accurately predicts the presence of a mucinous neoplasm. A management algorithm based on presenting symptoms, radiographic findings, and cyst fluid CEA level provides a guideline for the evaluation of cystic lesions in the most cost-efficient manner while ensuring proper care.

Adult↗
PubMed2005

Efficacy of ibandronate in metastatic bone disease: review of clinical data.

Metastatic bone disease affects many cancer patients and has a significant disease burden because of complications such as pathologic fractures and severe pain, which affect patient mobility and quality of life. Bisphosphonates are the current standard of care for treating metastatic bone disease. Available agents have shown varying degrees of efficacy in clinical trials, and treatment potential can be limited by efficacy, tolerance, or toxicity issues. Ibandronate (Bondronat); F. Hoffman-La Roche Ltd., Basel, Switzerland, http://www.roche.com) is a highly potent, single-nitrogen bisphosphonate that is available in i.v. and oral formulations. In phase III trials in breast cancer patients, both formulations reduced the incidence of skeletal complications associated with metastatic bone disease and had significant and sustained effects on bone pain and patient quality of life. Open-label studies of loading-dose ibandronate administered over consecutive days suggest it also may be useful for relieving severe or opioid-resistant metastatic bone pain. New trials have been designed or are in progress that may extend the clinical indications of ibandronate for patients with metastatic bone disease.

Bone Density Conservation Agents↗
PubMed2004

The nucleophilic addition of alpha-metallated 1,3-dioxanes to planar chiral cationic eta3-allylmolybdenum complexes. Synthesis of (2E,5S,6R,7E)-6-methyl-8-phenylocta-2,7-dienoic acid methyl ester, a key component of the Cryptophycins.

Two adjacent stereogenic centres and a pendant alkene were constructed via nucleophilic addition of a 1,3-dioxan-4-ylcopper(I) reagent to a cationic eta3-allylmolybdenum complex as part of a synthesis of (2E,5S,6R,7E)-6-methyl-8-phenylocta-2,7-dienoic acid, a key component of the Cryptophycins. Oxidative addition of Mo(CO)(4)(THF)(2) to allyl benzoates provides an efficient synthesis of eta3-allylmolybdenum(dicarbonyl) complexes.

Allyl Compounds↗
PubMed2004

Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer.

The objective of this study is to assess the effect of oral ibandronate on bone pain and quality of life in women with metastatic bone disease from breast cancer. In two double-blind, placebo-controlled studies, 564 patients were randomised to receive oral ibandronate, 50mg once daily, or placebo for up to 96 weeks. Throughout the studies, we assessed bone pain (on a 5-point scale from 0=none to 4=intolerable), analgesic use (7-point scale) and quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 [EORTC QLQ-C30], 100-point scale). Oral ibandronate significantly reduced and maintained bone-pain scores below baseline throughout the 96-week study period (at endpoint, -0.1 vs +0.2, P=0.001 vs placebo). Analgesic use increased in both groups; however, the increase was significantly less in the ibandronate group (0.60 vs 0.85, P=0.019). Although quality of life deteriorated during the study, the decrease in quality of life was significantly lower with ibandronate therapy (-8.3 vs -26.8, P=0.032). Drug-related adverse events were generally minor and as expected with oral bisphosphonates. Oral ibandronate had beneficial effects on bone pain and quality of life and was well tolerated. These results suggest that this treatment is of considerable clinical value as a co-analgesic to patients with painful bone metastases.

Administration, Oral↗
PubMed2004

Maximizing clinical benefit with trastuzumab.

To optimize patient management in breast cancer a number of factors are considered, including hormone receptor and HER2 status. A feasible approach for women with less aggressive, estrogen receptor/HER2-positive metastatic breast cancer is to consider trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) combined with endocrine therapy. Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors. In patients with aggressive HER2-positive metastatic breast cancer, trastuzumab/chemotherapy combination regimens are warranted. When administered first line in combination with a taxane, trastuzumab improves all clinical outcome parameters, including survival, in such patients. Trastuzumab adds little to the toxicity profile of taxanes, and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone. There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single-agent activity in breast cancer, including capecitabine (Xeloda; F. Hoffmann-La Roche), gemcitabine, and vinorelbine. Trastuzumab is also being investigated as part of triplet drug regimens. Trastuzumab has good single-agent activity in first-line therapy. This is of relevance to women with HER2-positive disease who are not suitable for, or do not wish to receive, cytotoxic chemotherapy. The benefits noted with trastuzumab-containing regimens were documented in clinical trials where trastuzumab was given until disease progression. A further rationale exists to continue trastuzumab beyond progression. Data from retrospective reviews indicate that this strategy is feasible.

Antibodies, Monoclonal↗
PubMed2004

Managing metastatic bone disease: three case studies.

Metastatic bone disease constitutes a major clinical problem. Skeletal complications are common and lead to significant morbidity, and patients live with metastatic bone disease for several years, increasing the prevalence of this problem. Effective management aims to reduce the incidence of skeletal complications and relieve symptoms, such as severe bone pain, which adversely affect patient mobility and quality of life. This article describes and discusses strategies for managing metastatic bone disease, with particularly emphasis on the role of the bisphosphonate ibandronate. Two case histories show the long-term efficacy and tolerability of oral ibandronate in the treatment of metastatic breast cancer. The third case history illustrates the benefits of rapid pain relief from an intensive, high-dose regimen of intravenous ibandronate in metastatic prostate cancer.

Administration, Oral↗
PubMed2004

Profiling the safety and tolerability of bisphosphonates.

Because patients with metastatic bone disease suffer a significant burden from their illness and from anticancer treatments, it is therefore important to minimize the side effects of bisphosphonates. The intravenous bisphosphonates, zoledronic acid and pamidronate, have tolerability issues that include a flu-like syndrome, injection-site reactions, and occasional renal toxicity. Because of the potentially severe nature of the renal toxicity, renal monitoring is required before each dose, with drug withdrawal if the patients' renal function deteriorates. Oral clodronate often causes gastrointestinal disturbances, particularly diarrhea; compliance is often poor because of the large tablet size and multiple daily dosing. Long-term data have shown that the bisphosphonate ibandronate is well tolerated either intravenously or orally, with a renal safety profile similar to placebo and no evidence of cumulative renal damage. Studies investigating the effects of 15-minute infusions and intensive dosing indicate that intravenous ibandronate given rapidly or at high doses is also well tolerated with no renal safety concerns. Taken together, these results suggest that the favorable safety profile of ibandronate provides an important alternative to existing bisphosphonate options for metastatic bone disease. Using ibandronate could improve patient acceptability and simplify management, with reductions in the need for safety monitoring and management of adverse events.

Administration, Oral↗
PubMed2004

Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories.

HER2 overexpression is associated with poor breast cancer prognosis and is the target for the humanized monoclonal antibody trastuzumab. This novel agent, when administered until disease progression in combination with chemotherapy, extends the survival of women with HER2-positive metastatic breast cancer (MBC). However, the optimal duration of trastuzumab therapy remains to be confirmed. We conducted a retrospective case review study of women with HER2-positive MBC who continued to receive trastuzumab beyond disease progression. Objectives were to assess whether treatment beyond disease progression shows any evidence of efficacy and to evaluate the feasibility of this approach. One hundred five patients (median age, 47 years; range, 24-77 years) were identified in 13 centers. Women had received </=6 chemotherapy regimens (median, 1) before trastuzumab therapy. Median survival from first trastuzumab dose was 29 months. The overall response rate to trastuzumab alone or with a taxane as the first regimen was 39%; a further 30% of patients had stable disease as the best response. These rates were 36% and 38% after a second regimen of trastuzumab alone or with paclitaxel or vinorelbine was administered. Some patients responded to both the first and second regimens; others responded to the second regimen after the first had failed. Twenty-two patients experienced cardiac events, of whom 18 received >/=1 more trastuzumab regimen. Trastuzumab treatment beyond progression appears to be of value, producing responses and clinical benefit, and is well tolerated without significant cardiac toxicity. The feasibility of this approach warrants examination in prospective trials.

Adult↗
PubMed2003

Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age.

Relapsed or refractory multiple myeloma has a poor outlook. Some patients respond to thalidomide; however, criteria for predicting response have not been conclusively identified. We initiated a prospective multicenter phase 2 trial in patients with relapsed/refractory myeloma using thalidomide up to the maximum dose, 800 mg/d. Interferon-alpha-2B (1.5-3.0 x 10(6) U, subcutaneously, 3 times per week) was added at week 12 if disease was responsive or stable. Patients intolerant of interferon continued thalidomide alone. Thalidomide with or without interferon was continued until disease progression. Objectives were to determine toxicity, response rate (RR), progression-free survival (PFS), and overall survival (OS) and to elucidate relevant prognostic factors. We enrolled 75 patients, with median age 64 years (range, 36-83 years). Median individual maximum-tolerated dose of thalidomide was 600 mg/d; 41% reached 800 mg/d. Overall RR was 28%, and 55% stable disease (SD). The only predictor for response was age 65 years or younger (38% versus 17%; P =.043). At 18 months median follow-up, the actuarial median PFS and OS were 5.5 and 14.6 months, respectively. Multivariate analysis for OS demonstrated age exceeding 65 years (median, 9.2 months versus longer than 26 months; P =.011), raised serum lactate dehydrogenase (P =.002), and raised serum creatinine (P =.007) predicted inferior outcomes. Nineteen patients received interferon. Ten discontinued owing to toxicity. Four of 12 patients who received interferon for longer than 4 weeks were converted from SD to partial response. Our findings confirm substantial activity of thalidomide in relapsed/refractory myeloma. Interferon may improve response in selected patients, but is often not tolerated. The inferior outcome demonstrated in those with the identified prognostic factors is important in planning management for such patients.

Adult↗
PubMed2003

Psychometric properties of the Impact of Event Scale - Revised.

This study investigated the psychometric properties of the Impact of Event Scale -- Revised (IES-R) in two samples of male Vietnam veterans: a treatment-seeking sample with a confirmed posttraumatic stress disorder (PTSD) diagnosis (N = 120) and a community sample with varying levels of traumatic stress symptomatolgy (N = 154). The scale showed high internal consistency (alpha = 0.96). Confirmatory factor analysis did not provide support for a three-factor solution corresponding to the three subscales of intrusion, avoidance, and hyperarousal. Exploratory factor analysis suggested that either a single, or a two-factor solution (intrusion/hyperarousal and avoidance), provide the best account of date. However, correlations among the subscales were higher in the community sample than in the treatment sample, suggesting that the IES-R may be sensitive to a more general construct of traumatic stress in those with lower symptom levels. The correlation between the IES-R and the PTSD Checklist was high (0.84) and a cutoff of 1.5 (equivalent to a total score of 33) was found to provide the best diagnostic accuracy.

Adult↗