Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer.

BackgroundThe importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options.MethodsBreast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2-negative were retested centrally with both US Food and Drug Administration (FDA)-approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA-approved assay cutoffs; results were compared.ResultsOf the 552 unique patient samples centrally retested with local HER2-negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2-positive (95% confidence interval [CI] = 2.5%-5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2-positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2-negative tumors, the 22 patients with centrally determined HER2-positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR-negative tumors (27.3% versus 22.3%). These patients also had shorter median progression-free survival (6.4 months [95% CI = 3.8-15.9 months] versus 9.1 months [95% CI = 8.3-10.3 months]) and overall survival (25.9 months [95% CI = 13.8-not estimable] versus 27.9 months [95% CI = 25.0-32.9 months]).ConclusionsThis study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2-positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2-targeted therapy

Infused Therapy and Survival in Older Patients Diagnosed with Metastatic Breast Cancer who Received Trastuzumab

We used Surveillance, Epidemiology, and End Results-Medicare data (2000-2006) to describe treatment and survival in women diagnosed with metastatic breast cancer (MBC) who received trastuzumab. There were 610 patients with a mean age of 74 years. Overall, 32% received trastuzumab alone and 47% received trastuzumab plus a taxane. In multivariate analysis, trastuzumab plus chemotherapy was associated with a lower adjusted cancer mortality rate (Hazard Ratio [HR] 0.54; 95% Confidence Interval [CI] 0.39-0.74; p < .001) than trastuzumab alone among patients who received trastuzumab as part of first-line therapy. Adding chemotherapy to first-line trastuzumab for metastatic breast cancer is associated with improved cancer survival

Response inhibition and serotonin in autism:a functional MRI study using acute tryptophan depletion

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target

Multiple Images of a Highly Magnified Supernova Formed by an Early-Type Cluster Galaxy Lens

In 1964, Refsdal hypothesized that a supernova whose light traversed multiple paths around a strong gravitational lens could be used to measure the rate of cosmic expansion. We report the discovery of such a system. In Hubble Space Telescope imaging, we have found four images of a single supernova forming an Einstein cross configuration around a redshift z=0.54 elliptical galaxy in the MACS J1149.6+2223 cluster. The cluster's gravitational potential also creates multiple images of the z=1.49 spiral supernova host galaxy, and a future appearance of the supernova elsewhere in the cluster field is expected. The magnifications and staggered arrivals of the supernova images probe the cosmic expansion rate, as well as the distribution of matter in the galaxy and cluster lenses.Comment: Published in the 6 March 2015 issue of Science; 17 pages, 7 figures, and 3 tables including Supplementary Material

Effects of acute tryptophan depletion on neural processing of facial expressions of emotion in humans

Introduction Acute tryptophan depletion (ATD) temporarily lowers brain serotonin (5-HT) synthesis, and behavioral studies have shown that this alters the processing of facial expressions of emotion. Materials and methods The neural basis for these alterations is not known. Therefore, we employed ATD and event-related functional magnetic resonance imaging (fMRI) to examine neural responses during incidental processing of fearful, happy, sad, and disgusted facial expressions. Fourteen healthy male controls (age, 28 ± 10) were scanned under both placebo (SHAM) and depletion (ATD) conditions. Results and discussion We predicted that ATD would be associated with changes in neural activity within facial emotion-processing networks. We found that serotonergic modulation did not affect performance on the fMRI tasks, but was associated with widespread effects on neural response to components of face processing networks for fearful, disgusted, and happy but not sad expressions across differing intensities. Conclusion Hence, the 5-HT system affects brain function (in ‘limbic’ and ‘face processing’ regions) during incidental processing of emotional facial expressions; but this varies with emotion type and intensities

Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2‐negative breast cancer

BACKGROUND: The importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options. METHODS: Breast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2-negative were retested centrally with both US Food and Drug Administration (FDA)-approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA-approved assay cutoffs; results were compared. RESULTS: Of the 552 unique patient samples centrally retested with local HER2-negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2-positive (95% confidence interval [CI] = 2.5%-5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2-positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2-negative tumors, the 22 patients with centrally determined HER2-positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR-negative tumors (27.3% versus 22.3%). These patients also had shorter median progression-free survival (6.4 months [95% CI = 3.8-15.9 months] versus 9.1 months [95% CI = 8.3-10.3 months]) and overall survival (25.9 months [95% CI = 13.8-not estimable] versus 27.9 months [95% CI = 25.0-32.9 months]). CONCLUSIONS: This study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2-positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2-targeted therapy. Cancer 2014;120:2657–2664

Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2‐negative breast cancer

BACKGROUND The importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options. METHODS Breast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2‐negative were retested centrally with both US Food and Drug Administration (FDA)‐approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA‐approved assay cutoffs; results were compared. RESULTS Of the 552 unique patient samples centrally retested with local HER2‐negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2‐positive (95% confidence interval [CI] = 2.5%‐5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2‐positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2‐negative tumors, the 22 patients with centrally determined HER2‐positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR‐negative tumors (27.3% versus 22.3%). These patients also had shorter median progression‐free survival (6.4 months [95% CI = 3.8‐15.9 months] versus 9.1 months [95% CI = 8.3‐10.3 months]) and overall survival (25.9 months [95% CI = 13.8‐not estimable] versus 27.9 months [95% CI = 25.0‐32.9 months]). CONCLUSIONS This study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2‐positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2‐targeted therapy. Cancer 2014;120:2657–2664. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Breast tumor samples from patients in the VIRGO observational cohort study originally determined to be negative for HER2 (human epidermal growth factor receptor 2) were retested using both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) (n = 552); of these, 22 (4%) were found to be HER2‐positive. Eighteen samples were initially assessed with a single test, and 15 of these were determined to be HER2‐positive with the testing methodology (IHC or FISH) not performed initially. These results highlight the value of using multiple tests to assess HER2 status to ensure patients do not forgo potentially efficacious therapy

Serotonin and the Neural Processing of Facial Emotions in Adults With Autism:An fMRI Study Using Acute Tryptophan Depletion

Context: People with autism spectrum disorders (ASDs) have lifelong deficits in social behavior and differences in behavioral as well as neural responses to facial expressions of emotion. The biological basis to this is incompletely understood, but it may include differences in the role of neurotransmitters such as serotonin, which modulate facial emotion processing in health. While some individuals with ASD have significant differences in the serotonin system, to our knowledge, no one has investigated its role during facial emotion processing in adults with ASD and control subjects using acute tryptophan depletion (ATD) and functional magnetic resonance imaging. Objective: To compare the effects of ATD on brain responses to primary facial expressions of emotion in men with ASD and healthy control subjects. Design: Double-blind, placebo-controlled, crossover trial of ATD and functional magnetic resonance imaging to measure brain activity during incidental processing of disgust, fearful, happy, and sad facial expressions. Setting: Institute of Psychiatry, King's College London, and South London and Maudsley National Health Service Foundation Trust, England. Participants: Fourteen men of normal intelligence with autism and 14 control subjects who did not significantly differ in sex, age, or overall intelligence. Main Outcome Measures: Blood oxygenation level-dependent response to facial expressions of emotion. Results: Brain activation was differentially modulated by ATD depending on diagnostic group and emotion type within regions of the social brain network. For example, processing of disgust faces was associated with interactions in medial frontal and lingual gyri, whereas processing of happy faces was associated with interactions in middle frontal gyrus and putamen. Conclusions: Modulation of the processing of facial expressions of emotion by serotonin significantly differs in people with ASD compared with control subjects. The differences vary with emotion type and occur in social brain regions that have been shown to be associated with group differences in serotonin synthesis/receptor or transporter density. Arch Gen Psychiatry. 2012; 69(10): 1003-1013. Published online June 4, 2012. doi: 10.1001/archgenpsychiatry.2012.51

Serotonin and the neural processing of facial emotions in adults with autism

Context: People with autism spectrum disorders (ASDs) have lifelong deficits in social behavior and differences in behavioral as well as neural responses to facial expressions of emotion. The biological basis to this is incompletely understood, but it may include differences in the role of neurotransmitters such as serotonin, which modulate facial emotion processing in health. While some individuals with ASD have significant differences in the serotonin system, to our knowledge, no one has investigated its role during facial emotion processing in adults with ASD and control subjects using acute tryptophan depletion (ATD) and functional magnetic resonance imaging. Objective: To compare the effects of ATD on brain responses to primary facial expressions of emotion in men with ASD and healthy control subjects. Design: Double-blind, placebo-controlled, crossover trial of ATD and functional magnetic resonance imaging to measure brain activity during incidental processing of disgust, fearful, happy, and sad facial expressions. Setting: Institute of Psychiatry, King\u27s College London, and South London and Maudsley National Health Service Foundation Trust, England. Participants: Fourteen men of normal intelligence with autism and 14 control subjects who did not significantly differ in sex, age, or overall intelligence. Main Outcome Measures: Blood oxygenation level-dependent response to facial expressions of emotion. Results: Brain activation was differentially modulated by ATD depending on diagnostic group and emotion type within regions of the social brain network. For example, processing of disgust faces was associated with interactions in medial frontal and lingual gyri, whereas processing of happy faces was associated with interactions in middle frontal gyrus and putamen. Conclusions: Modulation of the processing of facial expressions of emotion by serotonin significantly differs in people with ASD compared with control subjects. The differences vary with emotion type and occur in social brain regions that have been shown to be associated with group differences in serotonin synthesis/receptor or transporter density. Arch Gen Psychiatry. 2012; 69(10): 1003-1013. Published online June 4, 2012. doi: 10.1001/archgenpsychiatry.2012.51