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Biomedical subjects

Stephen Chan

Publications and source records attributed to Stephen Chan.

At least 19 recordsLinked to original sources
PubMed2006

Lapatinib plus capecitabine for HER2-positive advanced breast cancer.

BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. RESULTS: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. CONCLUSIONS: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).

Adult↗
PubMed2006

5'-Adenosinephosphosulphate reductase (CysH) protects Mycobacterium tuberculosis against free radicals during chronic infection phase in mice.

A major obstacle to tuberculosis (TB) control is the problem of chronic TB infection (CTBI). Here we report that 5'-adenosinephosphosulphate reductase (CysH), an enzyme essential for the production of reduced-sulphur-containing metabolites, is critical for Mycobacterium tuberculosis (Mtb) survival in chronic infection phase in mice. Disruption of cysH rendered Mtb auxotrophic for cysteine and methionine, and attenuated virulence in BALB/c and C57BL/6 immunocompetent mice. The mutant and wild-type Mtb replicated similarly during the acute phase of infection, but the mutant showed reduced viability during the persistent phase of the infection. The cysH mutant caused disease and death after 4-7 weeks of infection in four different groups of mice - Rag1(-/-), NOS2(-/-), gp91phox(-/-) NOS2(-/-) and gp91phox(-/-) mice given aminoguanidine [to suppress the effects of nitric oxide synthase 2 (NOS2)]- indicating minimal metabolic effect on the cysH mutant survival in these mice. The cysH mutant was also susceptible to peroxynitrite and hydrogen peroxide in vitro. These results show that CysH is important for Mtb protection during the chronic infection phase, and that resistance to nitrosative and oxidative stress may be the mechanism of this protection. Thus, this metabolic gene of an intracellular pathogen could have a secondary role in protection against the host immune response. Finally the lack of an endogenous human orthologue of cysH and its possible role in defence against adaptive immunity renders CysH an attractive enzyme for further studies as a target for therapeutics active against CTBI.

Animals↗
PubMed2006

Impaired long-term depression in P2X3 deficient mice is not associated with a spatial learning deficit.

The hippocampus is a brain region critical for learning and memory processes believed to result from long-lasting changes in the function and structure of synapses. Recent findings suggest that ATP functions as a neurotransmitter or neuromodulator in the mammalian brain, where it activates several different types of ionotropic and G protein-coupled ATP receptors that transduce calcium signals. However, the roles of specific ATP receptors in synaptic plasticity have not been established. Here we show that mice lacking the P2X3 ATP receptor (P2X3KO mice) exhibit abnormalities in hippocampal synaptic plasticity that can be restored by pharmacological modification of calcium-sensitive kinase and phosphatase activities. Calcium imaging studies revealed an attenuated calcium response to ATP in hippocampal neurons from P2X3KO mice. Basal synaptic transmission, paired-pulse facilitation and long-term potentiation are normal at synapses in hippocampal slices from P2X3KO. However, long-term depression is severely impaired at CA1, CA3 and dentate gyrus synapses. Long-term depression can be partially rescued in slices treated with a protein phosphatase 1-2 A activator or by postsynaptic inhibition of calcium/calmodulin-dependent protein kinase II. Despite the deficit in hippocampal long-term depression, P2X3KO mice performed normally in water maze tests of spatial learning, suggesting that long-term depression is not critical for this type of hippocampus-dependent learning and memory.

Adenosine Triphosphate↗
PubMed2006

Risk of intracranial pathologic conditions requiring emergency intervention after a first complex febrile seizure episode among children.

OBJECTIVE: To determine the likelihood of intracranial pathologic conditions requiring emergency neurosurgical or medical intervention among children without meningitis who presented to the pediatric emergency department after a first complex febrile seizure. METHODS: We performed a retrospective review of prospectively collected data for children in neurologically normal condition who presented to a single pediatric emergency department after a first complex febrile seizure (focal, multiple, or prolonged). The complex febrile seizure classification was determined independently by 2 epileptologists. The presence of intracranial pathologic conditions was determined through review of neuroimaging results, telephone interviews, or medical record review. RESULTS: Data for 71 children with first complex febrile seizures were analyzed. Fifty-one (72%) had a single complex feature (20 focal, 22 multiple, and 9 prolonged), and 20 (28%) had multiple complex features. None of the 71 patients (1-sided 95% confidence interval: 4%) had intracranial pathologic conditions that required emergency neurosurgical or medical intervention. CONCLUSIONS: For children with first complex febrile seizures, the risk of intracranial pathologic conditions that require emergency neurosurgical or medical intervention is low, which suggests that routine emergency neuroimaging for this population is unnecessary.

Brain↗
PubMed2006

Blunt microdissection and rotational atherectomy: an effective combination for the resistant chronic total occlusion.

Percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) has a lower success rate than nontotal occlusions. Like nontotal coronary occlusions, successful procedural outcomes of CTOs confers improvement in clinical outcomes. Reasons for unsuccessful PCI of CTOs may stem from various steps of the procedure including failure to cross the occlusion with a guidewire or a balloon, or failure to adequately dilate or modify the lesion. The Frontrunner blunt microdissection device is designed to improve the odds of guidewire passage through coronary occlusions, whereas the Rotablator rotational atherectomy device is intended for plaque modification, especially in resistant, elastic or calcific lesions. The Frontrunner and Rotablator can each facilitate the procedure at their respective junctures; the combined use of these technologies can enhance the overall PCI success rates, especially regarding difficult CTOs. This case presentation encounters two technical challenges: the inability of the balloon catheter to cross the CTO, and the inability to recross the occlusion with the less favorable RotaWire. In this case, the combined use of the Frontrunner and Rotablator devices was necessary to achieve overall procedural success. When tackling difficult CTOs, a comprehensive strategy that encompasses multiple devices and technologies can enable ultimate procedural success.

Aged↗
PubMed2005

Emerging strategic themes for guiding change in academic radiology departments.

Academic radiologists are faced with increasing demands on their time and energy, particularly in the clinical arena, where larger examination volumes and higher service expectations are the norm for most medical centers. These demands are intensified by the continuing shortage of academic radiologists. If academic radiology departments continue to devote most of their resources to the clinical mission at the expense of research and educational missions, then there are potentially serious adverse consequences for long-term viability of the profession of radiology. This dilemma represents a critical strategic problem, not just for academic radiology but also for the entire profession of radiology. In this article, the success and growth of academic radiology during the 20th century are framed as the result of the dogged pursuit of certain key strategic themes. With the concept of paradigm shift, introduced by Kuhn, several new strategic themes are identified that are just emerging from changes in work practices, organizational structure, and mind-sets in radiology departments at academic medical centers. One benefit of this approach is that it facilitates the ability of radiologists to articulate and focus on those strategic themes that will help academic radiology departments to adapt more rapidly and successfully to environmental changes during the 21st century.

Clinical Competence↗
PubMed2005

Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer.

PURPOSE: In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. PATIENTS AND METHODS: Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. RESULTS: Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). CONCLUSION: In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

Adult↗
PubMed2005

Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.

PURPOSE: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients were randomly assigned to six cycles of docetaxel 100 mg/m2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. RESULTS: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. CONCLUSION: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity.

Adolescent↗
PubMed2005

Unusual findings in brain biopsies of two patients with acute magnetic resonance imaging lesions associated with focal seizures.

PURPOSE: Patients with focal seizures often have magnetic resonance imaging (MRI) abnormalities in the brain region of their presumed seizure focus. Neoplasms, ischemic infarctions, inflammatory processes, and other specific pathologic entities have been diagnosed by biopsies of such MRI abnormalities. Two patients with this presentation had brain lesion biopsies with a leading presumptive diagnosis of glial neoplasm but were found to have indistinct histopathology. METHODS: Each patient was initially seen with focal seizures (right parietal region, right hippocampus) corresponding with focally increased T2 signal on MRI. In both patients, the preoperative clinical suspicion was for neoplastic or inflammatory processes. RESULTS: Several weeks after seizure onset, craniotomy in patient 1 and stereotactic needle biopsy in patient 2 revealed mild gliosis with reactive vascular changes and perivascular hemosiderin deposition, not diagnostic of but compatible with venous congestion (or possibly venous thrombosis). Postoperatively, patient 1 had brief sensory seizures that stopped 5 months after surgery, whereas subsequent seizures did not develop in patient 2. Both patients had normalization of their MRI (except for postoperative changes) and have remained seizure free. CONCLUSIONS: We describe two patients who had brain biopsies of striking focal increased T2 signal MRI abnormalities associated with seizures. Pathologic findings contradicted our preoperative suspicions (neoplasm or inflammatory process), compatible with (but not conclusive for) subacute venous congestion/thrombosis. These findings indicate that patients with seizures may have an associated discrete intraaxial MRI lesion that is not neoplastic. To our knowledge, this is the first report of focal seizure-associated MRI lesions with biopsy findings compatible with venous congestion/thrombosis.

Adult↗
PubMed2004

Management education during radiology residency: development of an educational practice.

The practice of radiology has dramatically increased in complexity, largely due to three broad influences. These include the proliferation of imaging technologies, the economic pressures to limit healthcare costs, and the increasingly intrusive role of third parties (whether payors, regulators, or government) in everyday healthcare transactions. Practicing radiologists have been adapting to these technologic and socioeconomic changes and will continue to do so by managing the quality and scope of their professional services, the workflow of radiology operations, and the economic viability of their practices. It is likely that radiology practices would benefit from the presence of one or more radiologists with managerial training and skills. In this article, it is proposed that management education for radiologists may actually be initiated during residency; the value and the experiences with such an educational practice are described.

Curriculum↗
PubMed2004

Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel.

PURPOSE: The predictive value of topoisomerase-II alpha (topo-II) has been evaluated in advanced breast cancer patients randomly treated with single-agent doxorubicin or docetaxel. EXPERIMENTAL DESIGN: Primary tumor samples from patients enrolled in a randomized, phase III clinical trial comparing single-agent doxorubicin (75 mg/m(2) q3wks) with docetaxel (100 mg/m(2) q3wks) were collected and topo-II status was evaluated by immunohistochemistry (clone KiS1). RESULTS: Topo-II status was evaluated in 108 samples, 55 (51%) in the doxorubicin arm and 53 (49%) in the docetaxel arm. An increment of 10% in cells expressing topo-II is associated with a statistically significant odds ratio (OR; 95% confidence interval) of 1.09 (1.03-1.15; P = 0.002) for overall response to doxorubicin versus 1.002 (0.94-1.07; P = 0.95) in the docetaxel arm. With increasing topo-II, the favorable OR for overall response to docetaxel compared with doxorubicin decreases to become not significant in patients with topo-II tumor content >10%. In a multivariate analysis, (a) HER-2 status seems positively correlated with overall response to chemotherapy (OR, 2.34; 95% confidence interval, 0.87-6.27; P = 0.09). (b) Overall response to doxorubicin is significantly lower than overall response to docetaxel (OR, 0.17; 95% confidence interval, 0.04-0.64; P = 0.009) but with a significant interaction term for doxorubicin-treated patients with topo-II tumor content >10% (OR, 8.31; 95% confidence interval, 1.86-37.03; P = 0.05). CONCLUSIONS: (a) Topo-II overexpression confers a higher probability of response in the doxorubicin arm only. (b) Despite being a small retrospective study, this study is in line with previously reported studies and the hypotheses raised are now being tested in a prospective neoadjuvant trial.

Adult↗
PubMed2003

Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial.

PURPOSE: This randomized, multicenter, phase III study compared doxorubicin and docetaxel (AT) with doxorubicin and cyclophosphamide (AC) as first-line chemotherapy (CT) in metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients (n = 429) were randomly assigned to receive doxorubicin 50 mg/m(2) plus docetaxel 75 mg/m(2) (n = 214) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (n = 215) on day 1, every 3 weeks for up to eight cycles. RESULTS: Time to progression (TTP; primary end point) and time to treatment failure (TTF) were significantly longer with AT than AC (median TTP, 37.3 v 31.9 weeks; log-rank P =.014; median TTF, 25.6 v 23.7 weeks; log-rank P =.048). The overall response rate (ORR) was significantly greater for patients taking AT (59%, with 10% complete response [CR], 49% partial response [PR]) than for those taking AC (47%, with 7% CR, 39% PR) (P =.009). The ORR was also higher with AT in patients with visceral involvement (58% v 41%; liver, 62% v 42%; lung, 58% v 35%), three or more organs involved (59% v 40%), or prior adjuvant CT (53% v 41%). Overall survival (OS) was comparable in both arms. Grade 3/4 neutropenia was frequent in both groups, although febrile neutropenia and infections were more frequent for patients taking AT (respectively, 33% v 10%, P <.001; 8% v 2%, P =.01). Severe nonhematologic toxicity was infrequent in both groups, including grade 3/4 cardiac events (AT, 3%; AC, 4%). CONCLUSION: AT significantly improves TTP and ORR compared with AC in patients with MBC, but there is no difference in OS. AT represents a valid option for the treatment of MBC.

Adult↗
PubMed2003

Amyotrophic lateral sclerosis and primary lateral sclerosis: evidence-based diagnostic evaluation of the upper motor neuron.

Magnetic resonance imaging and MR spectroscopy are important tools in the diagnostic evaluation of patients with suspected motor neuron disease. Further investigation is needed to determine and to compare the utility of various neuroimaging markers for diagnosis and disease progression [112]. Newer MR tools, such as diffusion tensor imaging, magnetization transfer imaging, and functional MR imaging, have substantial promise as scientific and clinical tools in this ongoing endeavor.

Amyotrophic Lateral Sclerosis↗
PubMed2002

A review of selective estrogen receptor modulators in the treatment of breast and endometrial cancer.

The understanding of how estrogen affects different body tissues by selective actions on the two subtypes of estrogen receptors (alpha and beta) has created the possibility of targeted therapy by the manufacturing of a group of compounds known as selective estrogen receptor modulators. The goal of an ideal selective estrogen receptor modulator that has all the beneficial effects of estrogen receptor modulation without adverse side effects seems increasingly achievable with improving drug design. The clinical findings for the new selective estrogen receptor modulator, arzoxifene, which has been shown to be highly active in the treatment of advanced breast cancer as well as advanced endometrial cancer, has confirmed the value of selective targeting of the estrogen receptors, and may herald a new era in endocrine therapy in clinical oncology.

Antineoplastic Agents, Hormonal↗
PubMed2002

The importance of strategy for the evolving field of radiology.

During the 20th century, the field of radiology experienced extraordinary growth and became an essential component of the practice of clinical medicine. In the 21st century, it is likely that radiology will continue to grow by interfacing with new and important domains such as information technology and molecular biology and by playing a more central role in general medical education, biomedical research, and noninvasive therapeutic interventions. To sustain such wide-ranging growth and yet remain intact as a medical specialty, the profession will require many radiologists who can provide leadership to bridge the many gaps between the various frontiers and the traditional core of radiology. These radiologists will need skills and background in two critical management areas: leadership and strategy. This article approaches the broad topic of strategy in several ways. First, it provides the radiologist with a basic framework for strategy development. Second, it summarizes central ideas from the evolving field of strategic thinking. Finally, it outlines a strategy-based method for dealing with uncertainty about the future and identifies situations where specific strategic tools and techniques are likely to be helpful.

Forecasting↗