Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer : long-term survival results from the STAMPEDE trial

Background STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. Methods We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. Results Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P  0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial

Background STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Methods and findings Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Conclusions Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. Trial registration ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544

Effect of a noise modulation masker on the detection of second-order amplitude modulation

Amplitude modulation waveforms can contain complex patterns of modulation frequency and depth that are characteristic of many biologically relevant sounds. To investigate the mechanisms involved in the processing of such patterns, we measured detection thresholds for second-order amplitude modulation (AM), a sinusoidal AM in which AM depth varies with time at frequency fm′. Second-order AM generates sidebands in the modulation spectrum on either side of the frequency components introduced by the first-order AM. Previous masking studies suggested that a distortion product located at fm′ contributes to the detection of second-order AM. This hypothesis was tested by masking the putative distortion product using a noise modulation masker centred on (1) the second-order modulation frequency (fm′=2 Hz) and (2) the first-order modulation frequency (fm=16 Hz). The second-order AM was applied to a 5-kHz pure-tone carrier. Increasing the depth of a 2-Hz-wide noise modulator masker centred on 2 Hz had little effect on detection thresholds for second-order AM, but increased detection thresholds for 2-Hz first-order AM six-fold. Increasing the depth of an 8-Hz-wide noise modulator masker centred on 16 Hz increased detection thresholds for both first- and second-order AM three-fold. These results show that the detection of the second-order AM, when fm′ is 2 Hz, is not dependent on the detection of modulation at fm′ but is dependent on the detection of modulation components centred on fm

Early activity in Broca's area during reading reflects fast access to articulatory codes from print

Prior evidence for early activity in Broca's area during reading may reflect fast access to articulatory codes in left inferior frontal gyrus pars opercularis (LIFGpo). We put this hypothesis to test using a benchmark for articulatory involvement in reading known as the masked onset priming effect (MOPE). In masked onset priming, briefly presented pronounceable strings of letters that share an initial phoneme with subsequently presented target words (e.g., gilp-GAME) facilitate word naming responses compared with unrelated primes (dilp-GAME). Crucially, these priming effects only occur when the task requires articulation (naming), and not when it requires lexical decisions. A standard explanation of masked onset priming is that it reflects fast computation of articulatory output codes from letter representations. We therefore predicted 1) that activity in left IFG pars opercularis would be modulated by masked onset priming, 2) that priming-related modulation in LIFGpo would immediately follow activity in occipital cortex, and 3) that this modulation would be greater for naming than for lexical decision. These predictions were confirmed in a magnetoencephalography (MEG) priming study. MOPEs emerged in left IFG at similar to 100 ms posttarget onset, and the priming effects were more sustained when the task involved articulation

Second-order modulation detection thresholds for pure-tone and narrow-band noise carriers

Modulation perception has typically been characterized by measuring detection thresholds for sinusoidally amplitude-modulated (SAM) signals. This study uses multicomponent modulations. "Second-order" temporal modulation transfer functions (TMTFs) measure detection thresholds for a sinusoidal modulation of the modulation waveform of a SAM signal [Lorenzi et al., J. Acoust. Soc. Am. 110, 1030-2038 (2001)]. The SAM signal therefore acts as a "carrier" stimulus of frequency f(m), and sinusoidal modulation of the SAM signal's modulation depth (at rate f(m)') generates two additional components in the modulation spectrum at f(m)-f(m)' and f(m)+f(m)'. There is no spectral energy at the envelope beat frequency f(m)' in the modulation spectrum of the "physical" stimulus. In the present study, second-order TMTFs were measured for three listeners when f(m) was 16, 64, and 256 Hz. The carrier was either a 5-kHz pure tone or a narrow-band noise with center frequency and bandwidth of 5 kHz and 2 Hz, respectively. The narrow-band noise carrier was used to prevent listeners from detecting spectral energy at the beat frequency f(m)' in the "internal" stimuli's modulation spectrum. The results show that, for the 5-kHz pure-tone carrier, second-order TMTFs are nearly low pass in shape; the overall sensitivity and cutoff frequency measured on these second-order TMTFs increase when f(m) increases from 16 to 256 Hz. For the 2-Hz-wide narrow-band noise carrier, second-order TMTFs are nearly flat in shape for f(m) = 16 and 64 Hz, and they show a high-pass segment for f(m) = 256 Hz. These results suggest that detection of spectral energy at the envelope beat frequency contributes in part to the detection of second-order modulation. This is consistent with the idea that nonlinear mechanisms in the auditory pathway produce an audible distortion component at the envelope beat frequency in the internal modulation spectrum of the sounds. (C) 2001 Acoustical Society of America

Time-lapse imaging of primary preneoplastic mammary epithelial cells derived from genetically engineered mouse models of breast cancer.

Time-lapse imaging can be used to compare behavior of cultured primary preneoplastic mammary epithelial cells derived from different genetically engineered mouse models of breast cancer. For example, time between cell divisions (cell lifetimes), apoptotic cell numbers, evolution of morphological changes, and mechanism of colony formation can be quantified and compared in cells carrying specific genetic lesions. Primary mammary epithelial cell cultures are generated from mammary glands without palpable tumor. Glands are carefully resected with clear separation from adjacent muscle, lymph nodes are removed, and single-cell suspensions of enriched mammary epithelial cells are generated by mincing mammary tissue followed by enzymatic dissociation and filtration. Single-cell suspensions are plated and placed directly under a microscope within an incubator chamber for live-cell imaging. Sixteen 650 &mu;m x 700 &mu;m fields in a 4x4 configuration from each well of a 6-well plate are imaged every 15 min for 5 days. Time-lapse images are examined directly to measure cellular behaviors that can include mechanism and frequency of cell colony formation within the first 24 hr of plating the cells (aggregation versus cell proliferation), incidence of apoptosis, and phasing of morphological changes. Single-cell tracking is used to generate cell fate maps for measurement of individual cell lifetimes and investigation of cell division patterns. Quantitative data are statistically analyzed to assess for significant differences in behavior correlated with specific genetic lesions

No Effect of Interstimulus Interval on Acoustic Reflex Thresholds

The acoustic reflex (AR), a longstanding component of the audiological test battery, has received renewed attention in the context of noise-induced cochlear synaptopathy-the destruction of synapses between inner hair cells and auditory nerve fibers. Noninvasive proxy measures of synaptopathy are widely sought, and AR thresholds (ARTs) correlate closely with synaptic survival in rodents. However, measurement in humans at high stimulus frequencies-likely important when testing for noise-induced pathology-can be challenging; reflexes at 4 kHz are frequently absent or occur only at high stimulus levels, even in young people with clinically normal audiograms. This phenomenon may partly reflect differences across stimulus frequency in the temporal characteristics of the response; later onset of the response, earlier onset of adaptation, and higher rate of adaptation have been observed at 4 kHz than at 1 kHz. One temporal aspect of the response that has received little attention is the interstimulus interval (ISI); inadequate duration of ISI might lead to incomplete recovery of the response between successive presentations and consequent response fatigue. This research aimed to test for effects of ISI on ARTs in normally hearing young humans, measured at 1 and 4 kHz. Contrary to our hypotheses, increasing ISIs from 2.5 to 8.5 s did not reduce ART level, nor raise ART reliability. Results confirm that clinically measured ARTs-including those at 4 kHz-can exhibit excellent reliability and that relatively short (2.5 s) ISIs are adequate for the measurement of sensitive and reliable ARTs