IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients

Purpose: Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Experimental design: Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Results: Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). Conclusions: The addition of Irosustat to aromatase inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments

Synthesis, characterization and biological activities of N-heteroaromatic hydrazones and their complexes with Pd(II), Pt(II) and Cd(II)

Condensation derivatives of ethyl hydrazinoacetate with 2-formylpyridine and quinoline-2-carboxaldehyde were synthesized. Pd(II), Pt(II) and Cd(II) complexes with the 2-formylpyridine derivative and a Cd(II) complex with the quinoline-2-carboxaldehyde derivative were synthesized and characterized by spectroscopic techniques. In the complexes, both ligands are coordinated in neutral NN bidentate modes, while the remaining two coordination sites are occupied by chloride. All compounds showed biological activity when tested against Escherichia coli, Bacillus subtilis and Staphylococcus aureus

Oscillatory Dynamics Supporting Semantic Cognition: MEG Evidence for the Contribution of the Anterior Temporal Lobe Hub and Modality-Specific Spokes

The "hub and spoke model" of semantic representation suggests that the multimodal features of objects are drawn together by an anterior temporal lobe (ATL) "hub", while modality-specific "spokes" capture perceptual/action features. However, relatively little is known about how these components are recruited through time to support object identification. We used magnetoencephalography to measure neural oscillations within left ATL, lateral fusiform cortex (FC) and central sulcus (CS) during word-picture matching at different levels of specificity (employing superordinate vs. specific labels) for different categories (manmade vs. animal). This allowed us to determine (i) when each site was sensitive to semantic category and (ii) whether this was modulated by task demands. In ATL, there were two phases of response: from around 100 ms post-stimulus there were phasic bursts of low gamma activity resulting in reductions in oscillatory power, relative to a baseline period, that were modulated by both category and specificity; this was followed by more sustained power decreases across frequency bands from 250 ms onwards. In the spokes, initial power increases were not stronger for specific identification, while later power decreases were stronger for specific-level identification in FC for animals and in CS for manmade objects (from around 150 ms and 200 ms, respectively). These data are inconsistent with a temporal sequence in which early sensory-motor activity is followed by later retrieval in ATL. Instead, knowledge emerges from the rapid recruitment of both hub and spokes, with early specificity and category effects in the ATL hub. The balance between these components depends on semantic category and task, with visual cortex playing a greater role in the fine-grained identification of animals and motor cortex contributing to the identification of tools