Background:Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points.Methods:Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated.Results:In all, 43 patients (median age 56 years (31–71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1–12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.Conclusion:The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination.
Rats will approach and contact a lever whose insertion into the chamber signals response-independent food delivery. This “autoshaping” or “sign-tracking” phenomenon has recently attracted considerable attention as a platform for studying individual differences in impulsivity, drug sensitization, and other traits associated with vulnerability to drug addiction. Here we examined two basic stimulus selection phenomena, blocking and overshadowing, in the autoshaped lever-pressing of rats. Blocking and overshadowing were decidedly asymmetrical. Previously reinforced lever-extension conditioned stimuli (CSs) completely blocked conditioning to auditory cues (Experiments 1 and 2), and previously nonreinforced lever-extension CSs overshadowed conditioning to auditory cues. By contrast, conditioning to lever-extension CSs was not blocked by either auditory (Experiment 3) or lever insertion (Experiment 4) cues, and was not overshadowed by auditory cues. Conditioning to a lever insertion cue was somewhat overshadowed by the presence of another lever, especially in terms of food cup behavior displayed after lever withdrawal. We discussed several frameworks in which the apparent immunity of autoshaped lever-pressing to blocking might be understood. Given evidence that different brain systems are engaged when different kinds of cues are paired with food delivery, it is worth considering the possibility that interactions among them in learning and performance may follow different rules. In particular, it is intriguing to speculate that the roles of simple cue-reinforcer contiguity as well as of individual and aggregate reinforcer prediction errors may differ across stimulus classes.
Listen to the podcast by Dr Irwin at www.jco.org/podcastsThe International Neuroblastoma Response Criteria (INRC) require serial measurements of primary tumors in three dimensions, whereas the Response Evaluation Criteria in Solid Tumors (RECIST) require measurement in one dimension. This study was conducted to identify the preferred method of primary tumor response assessment for use in revised INRC. Patients and MethodsPatients younger than 20 years with high-risk neuroblastoma were eligible if they were diagnosed between 2000 and 2012 and if three primary tumor measurements (antero-posterior, width, craniocaudal) were recorded at least twice before resection. Responses were defined as $ 30% reduction in longest dimension as per RECIST, $ 50% reduction in volume as per INRC, or $ 65% reduction in volume.Results Three-year event-free survival for all patients (N = 229) was 44% and overall survival was 58%. The sensitivity of both volume response measures (ability to detect responses in patients who survived) exceeded the sensitivity of the single dimension measure, but the specificity of all response measures (ability to identify lack of response in patients who later died) was low. In multivariable analyses, none of the response measures studied was predictive of outcome, and none was predictive of the extent of resection. ConclusionNone of the methods of primary tumor response assessment was predictive of outcome. Measurement of three dimensions followed by calculation of resultant volume is more complex than measurement of a single dimension. Primary tumor response in children with high-risk neuroblastoma should therefore be evaluated in accordance with RECIST criteria, using the single longest dimension.
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