Ixabepilone as Monotherapy or in Combination with Capecitabine for the Treatment of Advanced Breast Cancer

Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis.1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis.2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer

The rational formula from the runhydrograph

The rational formula is possibly the simplest flood estimation technique available using rainfall-runoff relationships. In spite of the many criticisms regarding its over-simplification of the processes of rainfall conversion into runoff, it remains possibly the most widely used method for estimating peak flood flows for urban drainage systems and small

Improved radar rainfall estimation at ground level

International audienceA technique has been developed to provide an estimate of the rainfall reaching the earth's surface by extrapolating radar data contained aloft to ground level, simultaneously estimating unknown data in the radar volume scan. The technique has been developed so as to be computationally fast, to work in real time and comprises the following steps. A rainfall classification algorithm is applied to separate the rainfall into two separate types: convective and stratiform rainfall. Climatological semivariograms based on the rainfall type are then defined and justified by testing, which result in a fast and effective means of determining the semivariogram parameters anywhere in the radar volume scan. Then, extrapolations to ground level are computed by utilising 3-D Universal and Ordinary Cascade Kriging; computational efficiency and stability in Kriging are ensured by using a nearest neighbours approach and a Singular Value Decomposition (SVD) matrix rank reduction technique. To validate the proposed technique, a statistical comparison between the temporally accumulated radar estimates and the Block Kriged raingauge estimates is carried out over matching areas, for selected rainfall events, to determine the quality of the rainfall estimates at ground level

Radar rainfall image repair techniques

International audienceThere are various quality problems associated with radar rainfall data viewed in images that include ground clutter, beam blocking and anomalous propagation, to name a few. To obtain the best rainfall estimate possible, techniques for removing ground clutter (non-meteorological echoes that influence radar data quality) on 2-D radar rainfall image data sets are presented here. These techniques concentrate on repairing the images in both a computationally fast and accurate manner, and are nearest neighbour techniques of two sub-types: Individual Target and Border Tracing. The contaminated data is estimated through Kriging, considered the optimal technique for the spatial interpolation of Gaussian data, where the "screening effect" that occurs with the Kriging weighting distribution around target points is exploited to ensure computational efficiency. Matrix rank reduction techniques in combination with Singular Value Decomposition (SVD) are also suggested for finding an efficient solution to the Kriging Equations which can cope with near singular systems. Rainfall estimation at ground level from radar rainfall volume scan data is of interest and importance in earth bound applications such as hydrology and agriculture. As an extension of the above, Ordinary Kriging is applied to three-dimensional radar rainfall data to estimate rainfall rate at ground level. Keywords: ground clutter, data infilling, Ordinary Kriging, nearest neighbours, Singular Value Decomposition, border tracing, computation time, ground level rainfall estimatio

Introduction: Global Governance in the Interregnum

Global governance is in flux. Scholarship on the practice of global governance has reimagined it as a realm of disputes and confrontation, rather than one of interest-alignment within multilateral interstate forums. A profound sense of governance deficit is provoking critical reflection both within the corridors of power and among practitioners and scholars. A call within academic circles for renewed reflection on global governance as a practice-oriented scholarship has elicited varied responses from the international relation (IR) fraternity. In taking stock of the state of the art of ‘global governance theory’, a number of scholars have advocated for its revival to be grounded in the kind of critical reflection often absent from mainstream IR discussion. Others contest any meaningful demarcation between IR and global governance scholarship. This forum responds to a number of converging developments. Situating contributions broadly within the notion of an interregnum, it is a first cut towards a more innovative global governance research and practice-oriented agenda. We focus, in particular, on reframing the problematique of global governance from one dominated by multilateral interstate geopolitics, towards a critical reappraisal of both structure and political economy in light of the evident complexity of global governance systems

Demography and commonly recorded clinical conditions of Chihuahuas under primary veterinary care in the UK in 2016

The Chihuahua, the world’s smallest dog breed, is a popular breed in the UK today. The VetCompass™ Programme collates de-identified clinical records from primary-care veterinary practices in the UK for epidemiological research. This study aimed to characterise the demography, age at death and common disorders of Chihuahuas under primary veterinary care during 2016 in the UK

Stochastic properties of water storage

August 1980.Includes bibliographical references (pages 46-48)

Psychiatric Symptomatology, Mood Regulation, and Resting State Functional Connectivity of the Amygdala: Preliminary Findings in Youth With Mood Disorders and Childhood Trauma

Background: As mood dysregulation and hyperarousal are overlapping and prominent features of posttraumatic stress disorder (PTSD), and mood disorders (MD) including bipolar disorder (BD), we aimed to clarify the role of trauma and MD on the resting state functional connectivity (RSFC) of amygdala in MD youth with or without trauma exposure, and healthy controls (HC). Methods: Of 23 subjects, 21 completed the magnetic resonance imaging (MRI) protocol, 5 were excluded for subject motion, leaving final sample size of 16: nine subjects with MD (5/9 with trauma), and 7 HC. Youth were assessed with Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL), and other behavioral measures including Young Mania Rating Scale (YMRS). Imaging data were acquired using functional MRI in 3-T scanner. Imaging included T1-weighted structural MRI and 6-min resting state acquisition. Results: In between group analysis, the average correlation coefficients between left anterior cingulate cortex (Acc) and left insula cortex with left amygdala regions were significantly larger in HC compared to the patient population. Connectivity between left amygdala and left cingulate cortex shows a significant negative correlation with YMRS severity. Conclusions: In this preliminary study, MD with trauma youth had more manic symptoms and difficulties regulating anger. While MD youth showed reduced RSFC of left amygdala with left acc and left insula, no significant difference between the subgroups of children with MD was observed. However, when looking at both clinical groups together, we observed a significant correlation of RSFC of left amygdala to left acc, and YMRS scores

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