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Biomedical subjects

Stephen E Jones

Publications and source records attributed to Stephen E Jones.

At least 19 recordsLinked to original sources
PubMed2006

Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer.

PURPOSE: The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant chemotherapy regimen. Studies of docetaxel and cyclophosphamide (TC) in metastatic breast cancer (MBC) showed promise in MBC. In 1997, we initiated a randomized adjuvant trial of TC compared with standard-dose AC with a primary end point of disease-free survival (DFS). PATIENTS AND METHODS: Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1997 and December 1999, 1,016 patients were randomly assigned to four cycles of either standard-dose AC (60 and 600 mg/m2, respectively; n = 510) or TC (75 and 600 mg/m2, respectively; n = 506), administered intravenously every 3 weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor-positive disease, were administered after completion of chemotherapy. RESULTS: Both treatment groups (TC and AC) were well balanced with respect to major prognostic factors. Patients were observed through 2005 for a median of 5.5 years. At 5 years, DFS rate was significantly superior for TC compared with AC (86% v 80%, respectively; hazard ratio [HR] = 0.67; 95% CI, 0.50 to 0.94; P = .015). Overall survival rates for TC and AC were 90% and 87%, respectively (HR = 0.76; 95% CI, 0.52 to 1.1; P = .13). More myalgia, arthralgia, edema, and febrile neutropenia occurred on the TC arm; more nausea and vomiting occurred on the AC arm as well as one incident of congestive heart failure. CONCLUSION: At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.

Adult↗
PubMed2006

Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer.

PURPOSE: To compare and describe the quality of life (QOL) of women allocated to tamoxifen or exemestane within the Intergroup Exemestane Study (IES). PATIENTS AND METHODS: Postmenopausal women with primary breast cancer who were disease free after 2 to 3 years were randomly assigned to switch from tamoxifen to exemestane or continue with tamoxifen until 5 years of treatment were completed. A subset of IES centers participated in a QOL substudy. The Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine subscale (ES) were administered before random assignment and at predefined follow-up times. The primary end point was the FACT-B composite Trial Outcome Index (TOI). Secondary end points included total FACT-B+ES score, total ES score, and severity of individual endocrine symptoms. This analysis reports QOL up to 24 months. RESULTS: Five hundred eighty-two patients from eight countries were enrolled onto the substudy. Completion and return of questionnaires was excellent, with 85% available for analysis. QOL was generally good and stable over 2 years, with no clinically meaningful differences found between groups in TOI or ES. Prevalence of severe endocrine symptoms at trial entry was high for vasomotor complaints and sexual problems, which persisted for both groups during the study. No significant differences between groups were seen for any endocrine symptoms apart from vaginal discharge, which was more pronounced with tamoxifen (P < .001). CONCLUSION: The switch from tamoxifen to exemestane neither increased nor decreased endocrine symptoms present after 2 to 3 years of tamoxifen; the switch also did not initiate significant reports of new symptoms. Results indicate that the clinical benefits of exemestane over tamoxifen are achieved without significant detrimental effect on QOL.

Adult↗
PubMed2006

Computed tomographic angiography in stroke imaging: fundamental principles, pathologic findings, and common pitfalls.

The development of multidetector row computed tomography (MDCT) now permits visualization of the entire vascular tree that is relevant for the management of stroke within 15 seconds. Advances in MDCT have brought computed tomography angiography (CTA) to the frontline in evaluation of stroke. CTA is a rapid and noninvasive modality for evaluating the neurovasculature. This article describes the role of CTA in the management of stroke. Fundamentals of contrast delivery, common pathologic findings, artifacts, and pitfalls in CTA interpretation are discussed.

Angiography↗
PubMed2006

Inactivation of the Akt survival pathway during photoreceptor apoptosis in the retinal degeneration mouse.

PURPOSE: Previous work has indicated that the serine-threonine protein kinase Akt is a general mediator of cellular survival signals and that loss of Akt-mediated signaling can lead to the activation of apoptosis. This study was conducted to establish whether regulation of the Akt survival pathway mechanisms is implicated in the induction of apoptosis during photoreceptor cell death in the rd mouse model of retinal degeneration. METHODS: Quantitative Western blot analysis and immunocytochemistry were used to examine the activation status and localization of key components of the Akt signaling cascade (Akt, BAD, Forkhead [FKHR], HSP27, mitogen-activated protein (MAP) kinase kinase-3 and -6 (MKK3/6), the tumor-suppressor phosphatase PTEN, and the cytoplasmic protein-tyrosine kinase cSrc-p60), in the retina of the rd mouse in comparison with the control. The time points examined spanned the period of photoreceptor degeneration. RESULTS: In the period up to the peak of photoreceptor apoptosis at postnatal day 15, dysregulation of the survival pathway was identified at several levels, including deactivation of both Akt itself and its downstream transcription factor target Forkhead (FKHR) and activation of the upstream negative regulator PTEN. CONCLUSIONS: Taken in conjunction with previous studies, the data support a model in which photoreceptor cell death in the rd mouse is the result of combined inactivation of the Akt survival pathway and the activation of the two major apoptotic pathways.

Animals↗
PubMed2006

Exemestane as adjuvant treatment of early breast cancer: intergroup exemestane study/tamoxifen exemestane adjuvant multicenter trials.

This review summarizes the status of 2 major clinical trials involving exemestane, a nonsteroidal inactivator of aromatase. The first trial, Intergroup Exemestane Study (IES), has been previously reported. More than 4700 postmenopausal women were randomized to receive exemestane versus continued tamoxifen at 2-3 years into 5 years of adjuvant tamoxifen. In the hormone receptor-positive group, there was a one-third improvement in disease-free survival and a near survival advantage (P = 0.08) for the crossover strategy. The second trial is the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) study. Recently, the design was modified to take into account the information from the IES. In the initial phase of TEAM, 7000 patients were randomized to receive 5 years of exemestane versus 5 years of tamoxifen. With the IES results, TEAM was modified so that 5 years of exemestane would be compared with 5 years of tamoxifen crossed over to exemestane. An additional 2500 patients have now been accrued. Updates of the IES and the first report of the TEAM might be available in 2006. The implications of these studies are discussed in this article.

Aged↗
PubMed2005

Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials.

BACKGROUND: Fulvestrant is an estrogen receptor antagonist with no agonist effects. In the second-line treatment of advanced breast carcinoma, fulvestrant was shown previously to be as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to disease progression and objective response rates. The authors reported the overall survival results from these studies. METHODS: A prospectively planned, combined, overall survival analysis was performed, including data from two Phase III trials that compared the efficacy and tolerability of fulvestrant (250 mg monthly; n = 428) with anastrozole (1 mg daily; n = 423) in the treatment of postmenopausal women with advanced breast carcinoma who had disease progression after receipt of previous endocrine treatment. RESULTS: At an extended median follow-up of 27.0 months (range, 0-66.9 months), 319 (74.5%) patients in the fulvestrant group and 322 (76.1%) patients in the anastrozole group had died. Prolonged survival was observed with both drugs, with 10-20% of patients still alive > 5 years after randomization. The median overall survival was similar between treatments, being 27.4 months and 27.7 months in fulvestrant and anastrozole-treated patients, respectively (hazards ratio, 0.98; 95% confidence interval, 0.84-1.15; P = 0.809). Fulvestrant continued to be well tolerated, and was associated with a significantly lower incidence of joint disorders compared with anastrozole (P = 0.0234). CONCLUSIONS: The current analysis showed that fulvestrant was similar to anastrozole with respect to overall survival in the second-line treatment of postmenopausal women with advanced breast carcinoma.

Anastrozole↗
PubMed2005

The indeterminate CT pulmonary angiogram: imaging characteristics and patient clinical outcome.

PURPOSE: To retrospectively review imaging characteristics of indeterminate computed tomographic (CT) pulmonary angiograms for pulmonary embolism (PE) and patient outcome. MATERIALS AND METHODS: Investigational review board approval was obtained, informed consent was waived, and the study was HIPAA compliant. Retrospective review of 3612 CT pulmonary angiography reports created between July 1, 2001, and July 1, 2003, was performed with a keyword search for "indeterminate," "nondiagnostic," or "inadequate" (thereafter, all defined as "indeterminate") and yielded studies from 237 patients (mean age, 57 years; 117 men, 120 women). Randomly selected diagnostic studies were used to form a control group of 25 subjects (mean age, 64 years; eight men, 17 women). Electronic medical records were reviewed for follow-up imaging (repeat CT pulmonary angiography, conventional pulmonary angiography, ventilation-perfusion scintigraphy, or lower-extremity ultrasonography [US]), use of anticoagulation, placement of inferior vena cava (IVC) filters, clinical outcomes, and comments regarding indeterminate reading of CT angiograms. Studies (in patients and control subjects) were reviewed for PE, contrast attenuation in the main pulmonary artery (MPA), motion artifacts, image noise, and flow artifacts. Findings were compared with two-sample t tests assuming unequal variance. RESULTS: The cause cited for indeterminism was most often motion (74%), followed by poor contrast enhancement (40%). Contrast attenuation in the MPA was 245 HU +/- 80 (standard deviation) in patients and 339 HU +/- 88 in control subjects (P < .001). Only 46% of indeterminate studies met institutional criteria for adequate contrast attenuation in the MPA. Rereview of studies demonstrated five missed PEs. A total of 81 patients (33%) underwent follow-up imaging within 5 days, with one positive pulmonary angiogram and four positive lower-limb US scans. Reread or follow-up images depicted thromboembolic disease in 4.2% of patients. Nineteen patients (8%) with indeterminate final result were treated for thromboembolic disease with either anticoagulation or IVC filters. Reports on 22% of indeterminate studies contained recommendations for follow-up imaging, and those recommendations nonsignificantly increased the rate for those examinations from 13% to 19%. Review of discharge summaries showed 22% of studies are clinically interpreted as negative. CONCLUSION: The two major causes of indeterminism are motion artifacts and poor contrast enhancement.

Artifacts↗
PubMed2005

Effectiveness and tolerability of fulvestrant in postmenopausal women with hormone receptor-positive breast cancer.

Fulvestrant, an estrogen receptor antagonist that downregulates the estrogen receptor but has no known agonist effects, has been evaluated in 2 randomized trials involving postmenopausal women with hormone receptor-positive, progressive advanced-stage breast cancer after disease progression with antiestrogen therapy. These phase III studies, from which data were reported separately and in a planned combined analysis, showed that fulvestrant 250 mg per month intramuscularly was at least as effective as anastrozole 1 mg per day orally with respect to the primary endpoint of time to progression as well as secondary efficacy endpoints, which included objective response, clinical benefit, and survival. Both trials showed that patients treated with fulvestrant had a significantly longer duration of response, and a retrospective analysis found that pretreatment with fulvestrant did not preclude response to third-line hormonal therapy. More recently, fulvestrant was shown to be active as first-line hormonal therapy for advanced-stage breast cancer, with overall efficacy similar to that of tamoxifen in patients with hormone receptor-positive disease. Fulvestrant has been well tolerated in comparative trials published to date, translating into low study withdrawal rates and maintenance of quality of life. The incidence of adverse events was similar between the treatment arms in both trials of fulvestrant versus anastrozole, but it was notably lower for fulvestrant relative to tamoxifen in the first-line setting. In light of the results of comparative phase III trials, fulvestrant is effective and well tolerated in the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer.

Anastrozole↗
PubMed2004

A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.

BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. METHODS: We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. RESULTS: Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04). CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.

Administration, Oral↗
PubMed2004

Expression of neurturin, glial cell line-derived neurotrophic factor, and their receptor components in light-induced retinal degeneration.

PURPOSE: Dysregulation of neurturin (NTN) expression has been linked to photoreceptor apoptosis in a mouse model of inherited retinal degeneration. To investigate the extent to which any such dysregulation depends on the nature of the apoptotic trigger, the expression of NTN, glial cell line-derived neurotrophic factor (GDNF), and their corresponding receptor components were compared in a rat model of light-induced retinal degeneration. METHODS: Retinal expression of NTN, GDNF, their corresponding receptors GFRalpha-2 and -1, the transmembrane receptor tyrosine kinase (Ret), and cSrc-p60, a member of the cytoplasmic protein-tyrosine kinases family, were analyzed by Western blot analysis and immunocytochemistry in cyclic light- and dark-reared rats in the presence and absence of intense light exposure. RESULTS: All components for NTN-mediated signaling activation are present in rat photoreceptors and retinal pigment epithelium, the cells primarily affected by light-induced damage. The expression levels of GDNF, its receptor components, and NTN, were not affected by light-induced stress. However, GFRalpha-2 expression strikingly increased with the extent of retinal damage, especially at the photoreceptors, in contrast to decreased levels that were observed previously in an inherited degeneration model. CONCLUSIONS: The present study indicates that the expression of receptors of the GDNF family is independently regulated in normal and light-damaged rat retina, and in conjunction with previous work, suggests that the pattern of modulation of these genes during photoreceptor degeneration is determined by the nature of the apoptotic trigger. Such differential responses to different modes of retinal degeneration may reflect influences of the neurotrophic system on photoreceptor survival or in the regulation of neuronal plasticity.

Animals↗
PubMed2003

Block of cardiac delayed-rectifier and inward-rectifier K+ currents by nisoldipine.

The objective of this study was to determine the concentration-dependent effects of nisoldipine, a dihydropyridine Ca2+ channel blocker, on K+ currents in guinea-pig ventricular myocytes. Myocytes in the conventional whole-cell configuration were bathed in normal Tyrode's solution or K+-free Tyrode's solution for the measurement of the effects of 0.01-100 microM nisoldipine on rapidly activating delayed-rectifier K+ current (I(Kr)), slowly activating delayed-rectifier K+ current (I(Ks)), inwardly rectifying K+ current (I(K1)), and reference L-type Ca2+ current (I(Ca,L)). Nisoldipine inhibited I(Kr) with an IC(50) of 23 microM, and I(Ks) with an IC(50) of 40 microM. The drug also had weak inhibitory effects on inward- and outward-directed I(K1); the IC(50) determined for outward-directed current was 80 microM. Investigation of nisoldipine action on I(Ks) showed that inhibition occurred in the absence of previous pulsing, and with little change in the time courses of activation and deactivation. However, the drug-induced inhibition was significantly weaker at >or =+30 mV than at +10 mV.5 We estimate that nisoldipine is about 30 times less selective for delayed-rectifier K+ channels than for L-type Ca2+ channels in fully polarised guinea-pig ventricular myocytes, and several orders less selective in partially depolarised myocytes.

Animals↗
PubMed2003

Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials.

BACKGROUND: Fulvestrant (ICI 182,780) is a new type of estrogen receptor (ER) antagonist that down-regulates the ER and has no known agonist effects. The authors report the prospectively planned combined analysis of data from 2 Phase III trials comparing fulvestrant 250 mg monthly (n=428) and anastrozole 1 mg daily (n=423) in postmenopausal women with advanced breast carcinoma (ABC) who previously had progressed after receiving endocrine treatment. METHODS: The primary endpoint was time to progression (TTP). Secondary endpoints included objective response (OR), duration of response (DOR), and tolerability. The trials were designed to demonstrate superiority of fulvestrant over anastrozole. Noninferiority of fulvestrant versus anastrozole was determined using a retrospectively applied statistical test. RESULTS: At a median follow-up of 15.1 months, approximately 83% of patients in each treatment arm had progressed. The median TTP was 5.5 months in the fulvestrant group and 4.1 months in the anastrozole group, and the OR rates were 19.2% and 16.5% for fulvestrant and anastrozole, respectively (although the difference between treatments was not statistically significant). In patients who responded, further follow-up (median, 22.1 months) was performed to obtain more complete information on DOR; the median DOR (from randomization to disease progression) in patients who responded to treatment was 16.7 months in the fulvestrant group and 13.7 months in the anastrozole group. In a statistical analysis of DOR (using all randomized patients; from the start of response to disease progression), DOR was significantly longer for patients in the fulvestrant group compared with patients in the anastrozole group. Both drugs were tolerated well; withdrawals due to drug-related adverse events were 0.9% and 1.2% in the fulvestrant group and the anastrozole group, respectively. The incidence of joint disorders was significantly lower in the fulvestrant group (P=0.0036). CONCLUSIONS: Fulvestrant was tolerated well and was at least as effective as anastrozole in the second-line treatment of patients with ABC. This new hormonaltherapy may provide a valuable treatment option for ABC in postmenopausal women.

Adult↗
PubMed2003

Phase II, randomized, double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer.

PURPOSE: To select a daily dose of arzoxifene (LY353381), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR). PATIENTS AND METHODS: This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity. RESULTS: Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P >.05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P >.05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study. CONCLUSION: Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.

Adult↗
PubMed2003

Fulvestrant: an estrogen receptor antagonist that downregulates the estrogen receptor.

Fulvestrant, a novel antiestrogen classified as an estrogen receptor antagonist without known agonist effects, was recently approved in the United States for the treatment of postmenopausal, hormone receptor-positive women with progressive metastatic breast cancer after antiestrogen therapy. In a phase II trial, monthly administration of fulvestrant, 250 mg intramuscularly, conferred clinical benefit (partial response or stable disease for >or= 24 weeks) in 69% of patients with tamoxifen-resistant advanced breast cancer. Furthermore, the median duration of response and survival for this population (26 and 54 months, respectively) was twice as high as those documented for a megestrol acetate-treated historical cohort (14 months and 30 months, respectively). Comparative phase III trials conducted in North America and internationally, which used time to progression as the primary endpoint, demonstrated fulvestrant's tolerability and equivalence to anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer, which led to its approval in this setting. Vasodilation and nausea were the principal treatment-related adverse events in the fulvestrant arms, and mild injection-site reactions occurred in 4.6% and 1.1% of monthly fulvestrant courses given in the North American and international trials, respectively. Recent subanalyses of the pivotal phase III data have found that fulvestrant produces a 30% longer mean duration of response compared with anastrozole and that fulvestrant-induced estrogen receptor downregulation does not preclude response to subsequent hormonal therapy. Ongoing trials in patients with advanced breast cancer will provide further insight into the relative merits of fulvestrant versus tamoxifen as first-line therapy for metastatic disease, the use of fulvestrant within combination and sequential regimens, and the efficacy of fulvestrant specifically in premenopausal women. Research efforts focusing on alternate administration schedules for fulvestrant and its potential as an adjuvant hormonal therapy are also anticipated.

Antineoplastic Agents, Hormonal↗
PubMed2002

A new estrogen receptor antagonist--an overview of available data.

Fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist with no known agonist effects that downregulates the ER, is the first in a new class of antiestrogen. Consequently, fulvestrant is not cross-resistant with other endocrine therapies. In previously untreated postmenopausal women, fulvestrant brought about dose-dependent reductions in ER and progesterone receptor (PgR) protein concentrations and produced no demonstrable estrogen agonist effect. Fulvestrant has demonstrated clinical benefit rates of 69% in postmenopausal women with advanced tamoxifen-resistant breast cancer. In two global phase III trials, fulvestrant was shown to be at least as effective as the aromatase inhibitor anastrozole with similar efficacy for time to progression, objective response and clinical benefit in patients progressing on prior endocrine therapy. Fulvestrant was also well tolerated and, similar to anastrozole, maintained a good quality of life. As a once-monthly intramuscular injection, administered during clinic visits, fulvestrant offers patient compliance advantages, making this new hormonal agent a viable therapeutic option for the palliative treatment of postmenopausal women with endocrine-responsive advanced breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed2002

Antiaromatase agents: evolving role in adjuvant therapy.

The goal of adjuvant hormonal therapy is to prevent breast cancer recurrence. Standard therapy with tamoxifen has shown great value in the adjuvant setting; however, its tolerability profile can render it unsuitable for some patients. The aromatase inactivator, exemestane, and the 2 aromatase inhibitors, letrozole and anastrozole, have been shown to be equivalent or superior to tamoxifen with respect to multiple endpoints in patients with metastatic breast cancer. With tolerability profiles that are similar to, and in many cases, more acceptable than that of tamoxifen, and efficacy potentially superior to tamoxifen, studies using the antiaromatase agents as adjuvant therapy are currently ongoing. These trials will answer some important questions, such as the order in which adjuvant hormonal therapies are selected to maximize efficacy, whether the antiaromatase agents show improved tolerability, and whether combination therapy is more effective than monotherapy.

Anastrozole↗