Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials.

BACKGROUND: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. METHODS: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). RESULTS: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. CONCLUSIONS: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.

Safety and activity of anti-mesothelin antibody-drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study.

OBJECTIVES: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer. METHODS: Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m2) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing. RESULTS: In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months. CONCLUSIONS: Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02751918.

Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial.

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed. FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. FUNDING: Bayer Healthcare Pharmaceuticals.

The influence of self-reported noise exposure on 2ƒ1-ƒ2 distortion product otoacoustic emission level, fine structure, and components in a normal-hearing population.

Distortion product otoacoustic emissions (DPOAEs) offer an outcome measure to consider for clinical detection and monitoring outer hair cell dysfunction as a result of noise exposure. This investigation detailed DPOAE characteristics and behavioral hearing thresholds up to 20 kHz to identify promising metrics for early detection of cochlear dysfunction. In a sample of normal-hearing individuals with and without self-reported noise exposure, the DPOAE and hearing threshold measures, as assessed by two questions, were examined. The effects on various auditory measures in individuals aged 10-65 years old with clinically normal/near-normal hearing through 4 kHz were evaluated. Individuals reporting occupational noise exposures (n = 84) and recreational noise exposures (n = 46) were compared to age-matched nonexposed individuals. The hearing thresholds and DPOAE level, fine structure, and component characteristics for the full frequency bandwidth were examined. The data suggest that the DPOAE levels measured using a range of stimulus levels hold clinical utility while fine structure characteristics offer limited use. Under carefully calibrated conditions, the extension to frequencies beyond 8 kHz in combination with various stimulus levels holds clinical utility. Moreover, this work supports the potential utility of the distortion product place component level for revealing differences in cochlear function due to self-reported, casual noise exposure that are not observable in behavioral hearing thresholds.

The Association Between Physiological Noise Levels and Speech Understanding in Noise.

OBJECTIVES: Traditionally, elevated hearing thresholds have been considered to be the main contributors to difficulty understanding speech in noise; yet, patients will often report difficulties with speech understanding in noise despite having audiometrically normal hearing. The purpose of this cross-sectional study was to critically evaluate the relationship of various metrics of auditory function (behavioral thresholds and otoacoustic emissions) on speech understanding in noise in a large sample of audiometrically normal-hearing individuals. DESIGN: Behavioral hearing thresholds, distortion product otoacoustic emission (DPOAE) levels, stimulus-frequency otoacoustic emission levels, and physiological noise (quantified using OAE noise floors) were measured from 921 individuals between 10 and 68 years of age with normal pure-tone averages. The quick speech-in-noise (QuickSIN) test outcome, quantified as the signal-to-noise ratio (SNR) loss, was used as the metric of speech understanding in noise. Principle component analysis (PCA) and linear regression modeling were used to evaluate the relationship between the measures of auditory function and speech in noise performance. RESULTS: Over 25% of participants exhibited mild or worse degree of SNR loss. PCA revealed DPOAE levels at 12.5 to 16 kHz to be significantly correlated with the variation in QuickSIN scores, although correlations were weak (R = 0.017). Out of all the metrics evaluated, higher levels of self-generated physiological noise accounted for the most variance in QuickSIN performance (R = 0.077). CONCLUSIONS: Higher levels of physiological noise were associated with worse QuickSIN performance in listeners with normal hearing sensitivity. We propose that elevated physiological noise levels in poorer speech in noise performers could diminish the effective SNR, thereby negatively impacting performance as seen by poorer QuickSIN scores.

A randomized, double-blind, comparison of radium-223 and placebo, in combination with abiraterone acetate and prednisolone, in castration-resistant metastatic prostate cancer: subgroup analysis of Japanese patients in the ERA 223 study.

BACKGROUND: ERA 223 compared concurrent abiraterone acetate/prednisolone (AAP) plus radium-223 with AAP plus placebo in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. We report data from a subgroup of Japanese patients in ERA 223. METHODS: Patients were randomized to radium-223 (55 kBq/kg) or placebo once every 4 weeks (max. 6 cycles), and also received oral abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily during and after radium-223/placebo treatment, until a symptomatic skeletal event (SSE). The primary endpoint was SSE-free survival (SSE-FS); overall survival (OS) was a secondary endpoint. RESULTS: Of 806 patients randomized in ERA 223, 114 patients (57 per arm) were enrolled in Japan. SSE-FS was not improved significantly in the radium-223 arm [25.5 months, 95% CI 20.6-not estimated (NE)] compared with the placebo arm (28.7 months, 95% CI 19.7-NE) (HR = 0.907, 95% CI 0.501-1.642). OS and other secondary endpoints were not improved significantly in the radium-223 arm. The incidence of fracture was 23% and 11% in the radium-223 and placebo arms, respectively. The incidence of death was 32% and 36%, respectively. CONCLUSIONS: In the Japanese ERA 223 subgroup, concurrent treatment with AAP and radium-223 did not significantly improve SSE-FS and increased the incidence of fracture, similar to outcomes achieved in the overall population, while an increased incidence of death was not evident. The combination of radium-223 with AAP is not recommended in Japanese patients with asymptomatic or mildly symptomatic mCRPC and bone metastases. CLINICAL TRIAL REGISTRATION: Clinical trial registration no: NCT02043678.

Evanescent waves in simulated ear canals: Experimental demonstration and method for compensation.

Evanescent waves emerge from a small sound source that radiates into a waveguide with a larger cross-sectional area, but unlike planar waves, do not propagate far from the source. Evanescent waves thus contaminate in-ear calibration of acoustic stimuli. Measurements with an otoacoustic-emission (OAE) probe inserted at the entrance of long tubes of various diameters show a decline in the evanescent wave with distance from the source when advancing a probe tube through the OAE probe and into the long tube. The amplitude of the evanescent pressure increases with frequency and depends strongly on the diameter of the long tube. Modifying the shape of the aperture of the probe's sound source, thus effectively enlarging its diameter and redirecting acoustic flow, greatly reduced evanescent waves. The reduction in evanescent-wave pressure was observed in calibration cavities used to determine the Thévenin-equivalent source pressure and impedance of the probe. Errors in source calibrations were considerably larger in the unmodified configuration. An alternative method is proposed for calculation of acoustic source parameters that models the evanescent-wave pressure and reduces its influence on the calculation. This reduction greatly improves the quality of source calibrations, which should improve the accuracy of ear-canal impedance measurements and related quantities.

Loss of the tectorial membrane protein CEACAM16 enhances spontaneous, stimulus-frequency, and transiently evoked otoacoustic emissions.

α-Tectorin (TECTA), ß-tectorin (TECTB), and carcinoembryonic antigen-related cell adhesion molecule 16 (CEACAM) are secreted glycoproteins that are present in the tectorial membrane (TM), an extracellular structure overlying the hearing organ of the inner ear, the organ of Corti. Previous studies have shown that TECTA and TECTB are both required for formation of the striated-sheet matrix within which collagen fibrils of the TM are imbedded and that CEACAM16 interacts with TECTA. To learn more about the structural and functional significance of CEACAM16, we created a Ceacam16-null mutant mouse. In the absence of CEACAM16, TECTB levels are reduced, a clearly defined striated-sheet matrix does not develop, and Hensen's stripe, a prominent feature in the basal two-thirds of the TM in WT mice, is absent. CEACAM16 is also shown to interact with TECTB, indicating that it may stabilize interactions between TECTA and TECTB. Although brain-stem evoked responses and distortion product otoacoustic emissions are, for most frequencies, normal in young mice lacking CEACAM16, stimulus-frequency and transiently evoked emissions are larger. We also observed spontaneous otoacoustic emissions (SOAEs) in 70% of the homozygous mice. This incidence is remarkable considering that <3% of WT controls have SOAEs. The predominance of SOAEs >15 kHz correlates with the loss of Hensen's stripe. Results from mice lacking CEACAM16 are consistent with the idea that the organ of Corti evolved to maximize the gain of the cochlear amplifier while preventing large oscillations. Changes in TM structure appear to influence the balance between energy generation and dissipation such that the system becomes unstable.

Exploration of stimulus-frequency otoacoustic emission suppression tuning in hearing-impaired listeners.

OBJECTIVE: Otoacoustic emissions (OAEs) can provide useful measures of tuning of auditory filters. We previously established that stimulus-frequency (SF) OAE suppression tuning curves (STCs) reflect major features of behavioral tuning (psychophysical tuning curves, PTCs) in normally-hearing listeners. Here, we aim to evaluate whether SFOAE STCs reflect changes in PTC tuning in cases of abnormal hearing. DESIGN: PTCs and SFOAE STCs were obtained at 1 kHz and/or 4 kHz probe frequencies. For exploratory purposes, we collected SFOAEs measured across a wide frequency range and contrasted them to commonly measured distortion product (DP) OAEs. STUDY SAMPLE: Thirteen listeners with varying degrees of sensorineural hearing loss. RESULTS: Except for a few listeners with the most hearing loss, the listeners had normal/nearly normal PTCs. However, attempts to record SFOAE STCs in hearing-impaired listeners were challenging and sometimes unsuccessful due to the high level of noise at the SFOAE frequency, which is not a factor for DPOAEs. In cases of successful measurements of SFOAE STCs there was a large variability in agreement between SFOAE STC and PTC tuning. CONCLUSIONS: These results indicate that SFOAE STCs cannot substitute for PTCs in cases of abnormal hearing, at least with the paradigm adopted in this study.

Characteristics of the 2f(1)-f(2) distortion product otoacoustic emission in a normal hearing population.

Distortion-product otoacoustic emission (DPOAE) fine structure and component characteristics are reported between 0.75 and 16 kHz in 356 clinically normal hearing human subjects ages 10 to 65 yr. Stimulus tones at 55/40, 65/55, and 75/75 dB SPL were delivered using custom designed drivers and a calibration method that compensated for the depth of insertion of the otoacoustic emission (OAE) probe in the ear canal. DPOAE fine structure depth and spacing were found to be consistent with previous reports with depth varying between 3 and 7 dB and average spacing ratios (f/Δf) between 15 and 25 depending on stimulus level and frequency. In general, fine structure depth increased with increasing frequency, likely due to a diminishing difference between DPOAE component levels. Fine structure spacing became wider with increasing age above 8 kHz. DPOAE components were extracted using the inverse fast Fourier transform method, adhering to a strict signal to noise ratio criterion for clearer interpretation. Component data from four age groups between 18 and 55 yr old were available for the stimulus levels of 75/75 dB SPL. The age groups could be differentiated with greater than 90% accuracy when using the level of the component presumed to originate from the DPOAE characteristic frequency place. This accuracy held even for frequencies at and below 4 kHz where the age groups exhibited similar average hearing thresholds.

Comparison of nine methods to estimate ear-canal stimulus levels.

The reliability of nine measures of the stimulus level in the human ear canal was compared by measuring the sensitivity of behavioral hearing thresholds to changes in the depth of insertion of an otoacoustic emission probe. Four measures were the ear-canal pressure, the eardrum pressure estimated from it and the pressure measured in an ear simulator with and without compensation for insertion depth. The remaining five quantities were derived from the ear-canal pressure and the Thévenin-equivalent source characteristics of the probe: Forward pressure, initial forward pressure, the pressure transmitted into the middle ear, eardrum sound pressure estimated by summing the magnitudes of the forward and reverse pressure (integrated pressure) and absorbed power. Two sets of behavioral thresholds were measured in 26 subjects from 0.125 to 20 kHz, with the probe inserted at relatively deep and shallow positions in the ear canal. The greatest dependence on insertion depth was for transmitted pressure and absorbed power. The measures with the least dependence on insertion depth throughout the frequency range (best performance) included the depth-compensated simulator, eardrum, forward, and integrated pressures. Among these, forward pressure is advantageous because it quantifies stimulus phase.

Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma.

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79-0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Behavioral hearing thresholds between 0.125 and 20 kHz using depth-compensated ear simulator calibration.

OBJECTIVES: The purpose of this study was to obtain behavioral hearing thresholds for frequencies between 0.125 and 20 kHz from a large population between 10 and 65 yr old using a clinically feasible calibration method expected to compensate well for variations in the distance between the eardrum and an insert-type sound source. Previous reports of hearing thresholds in the extended high frequencies (>8 kHz) have either used calibration techniques known to be inaccurate or specialized equipment not suitable for clinical use. DESIGN: Hearing thresholds were measured from 352 human subjects between 10 and 65 yr old having clinically normal-hearing thresholds (<20 dB HL) up to 4 kHz. An otoacoustic emission probe fitted with custom sound sources was used, and the stimulus levels individually tailored on the basis of an estimate of the insertion depth of the measurement probe. The calibrated stimulus levels were determined on the basis of measurements made at various depths of insertion in a standard ear simulator. Threshold values were obtained for 21 frequencies between 0.125 and 20 kHz using a modified Békésy technique. Forty-six of the subjects returned for a second measurement months later from the initial evaluation. RESULTS: In agreement with previous reports, hearing thresholds at extended high frequencies were found to be sensitive to age-related changes in auditory function. In contrast with previous reports, no gender differences were found in average hearing thresholds at most evaluated frequencies. Two aging processes, one faster than the other in time scale, seem to influence hearing thresholds in different frequency ranges. The standard deviation (SD) of test-retest threshold difference for all evaluated frequencies was 5 to 10 dB, comparable to that reported in the literature for similar measurement techniques but smaller than that observed for data obtained using the standard clinical procedure. CONCLUSIONS: The depth-compensated ear simulator-based calibration method and the modified Békésy technique allow reliable measurement of hearing thresholds over the entire frequency range of human hearing. Hearing thresholds at the extended high frequencies are sensitive to aging and reveal subtle differences, which are not evident in the frequency range evaluated regularly (≤8 kHz). Previously reported gender-related differences in hearing thresholds may be related to ear-canal acoustics and the calibration procedure and not because of differences in hearing sensitivity.

Time-efficient measures of auditory frequency selectivity.

OBJECTIVE: The objective of this study was to compare two recently proposed methods for fast measurements of psychophysical tuning curves (fast-PTCs) in terms of resulting tuning curve features and training effects. DESIGN: Fast-PTCs with swept-noise (SN) and gated-noise (GN) maskers were measured at signal frequencies of 500, 1000, 2000, and 4000 Hz. The effect of amplitude modulating the signal in the GN condition was evaluated. Two PTC runs were obtained for each condition to assess training effects. STUDY SAMPLE: Eight normally-hearing young adults participated in the study. RESULTS: The SN and GN methods resulted in similar estimates of frequency selectivity when training effects were considered. Amplitude modulating the tone in the GN method reduced the effect of training. On average, SN-PTCs were most repeatable compared to the two other methods and they were not affected by training. Estimation of the shift in the PTC tip frequency was not affected by the measurement method or training effects. Fast-PTC methods resulted in similar estimates of tuning as compared to published notched-noise data. CONCLUSIONS: The SN method and the GN procedure with amplitude modulated signals allowed for time-efficient estimation of frequency selectivity that was unaffected by training.

Impact of Electronic Cigarette Vaping on Cerebral Ischemia: What We Know So Far.

Electronic cigarettes (ECs) are battery-powered nicotine delivery devices that have rapidly gained popularity and attention globally. ECs work by heating a liquid to produce an aerosol that usually contains nicotine, flavoring compounds, and other chemicals, which are inhaled during vaping. EC aerosols are depicted to contain a lower number and overall quantity of harmful toxicants than conventional cigarettes (CCs). However, emerging research indicates that EC aerosols contain harmful ingredients including ultrafine particles, volatile organic compounds, and heavy metals. One common ingredient found in both CCs and ECs is nicotine, which has been shown to be both highly addictive and toxic. Particularly relevant to our current review, there is an enormous amount of literature that shows that smoking-derived nicotine exacerbates ischemic brain damage. Therefore, the question arises: will EC use impact the outcome of stroke? ECs are highly popular and relatively new in the market; thus, our understanding about the long-term effects of EC use on brain are lacking. The current review strives to extrapolate the existing understanding of the nicotine-induced effects of conventional smoking on the brain to the possible effects that ECs may have on the brain, which may ultimately have a potential for adverse stroke risk or severity.

Auditory filter shapes and high-frequency hearing in adults who have impaired speech in noise performance despite clinically normal audiograms.

Some individuals complain of hearing difficulties in the presence of background noise even in the absence of clinically significant hearing loss (obscure auditory dysfunction). Previous evidence suggests that these listeners have impaired frequency resolution, but there has been no thorough characterization of auditory filter shapes in this population. Here, the filter shapes of adults (n = 14) who self-reported speech recognition problems in noise and performed poorly on a sentence-in-noise perception test despite having clinically normal audiograms were compared to those of controls (n = 10). The filter shapes were evaluated using a 2-kHz probe with a fixed level of 30, 40, or 50 dB sound pressure level (SPL) and notched-noise simultaneous maskers that were varied in level to determine the masker level necessary to just mask the probe. The filters of the impaired group were significantly wider than those of controls at all probe levels owing to an unusual broadening of the upper slope of the filter. In addition, absolute thresholds were statistically indistinguishable between the groups at the standard audiometric frequencies, but were elevated in the impaired listeners at higher frequencies. These results strengthen the idea that this population has a variety of hearing deficits that go undetected by standard audiometry.

The importance of loss functions: A note on the evolution of the Toxicity Probability Interval design.

The Toxicity Probability Interval Design by Ji et al. (2007), which was subsequently modified by the mTPI (Ji et al., 2010), proposed a more efficient approach to early-phase dose-finding than conventional designs like 3 + 3. Subsequent authors reported issues with the method, finding that it tends to stay at a dose level when clinical intuition would suggest the toxicity level warrants decrease. Several iterations of refinement proceeded in an effort to address these issues, including the mTPI-2 and the keyboard method, as well as alternative approaches such as the BOIN. This author suggests the reason for these safety issues involves the underlying loss function. The TPI and mTPI used the identify function defined over wide intervals. As explained in this paper, this function and its domain can be problematic as a model of patients' loss experience. Later refinements moved the loss function closer to one more consistent with clinical intuition, and this explains their improved safety performance. Greater attention to quality as defined by fitness for use, including early evaluation of patient-experience and clinical-intuition implications of proposed loss functions, may improve future design efforts.

Distortion Product Otoacoustic Emission (DPOAE) Growth in Aging Ears with Clinically Normal Behavioral Thresholds.

Age-related hearing loss (ARHL) is a devastating public health issue. To successfully address ARHL using existing and future treatments, it is imperative to detect the earliest signs of age-related auditory decline and understand the mechanisms driving it. Here, we explore early signs of age-related auditory decline by characterizing cochlear function in 199 ears aged 10-65 years, all of which had clinically defined normal hearing (i.e., behavioral thresholds ≤ 25 dB HL from .25 to 8 kHz bilaterally) and no history of noise exposure. We characterized cochlear function by measuring behavioral thresholds in two paradigms (traditional audiometric thresholds from .25 to 8 kHz and Békésy tracking thresholds from .125 to 20 kHz) and distortion product otoacoustic emission (DPOAE) growth functions at f2 = 2, 4, and 8 kHz. Behavioral thresholds through a standard clinical frequency range (up to 8 kHz) showed statistically, but not clinically, significant declines across increasing decades of life. In contrast, DPOAE growth measured in the same frequency range showed clear declines as early 30 years of age, particularly across moderate stimulus levels (L2 = 25-45 dB SPL). These substantial declines in DPOAE growth were not fully explained by differences in behavioral thresholds measured in the same frequency region. Additionally, high-frequency Békésy tracking thresholds above ~11.2 kHz showed frank declines with increasing age. Collectively, these results suggest that early age-related cochlear decline (1) begins as early as the third or fourth decade of life, (2) is greatest in the cochlear base but apparent through the length of the cochlear partition, (3) cannot be detected fully by traditional clinical measures, and (4) is likely due to a complex mix of etiologies.

Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma.

Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by ipilimumab leads to immune-mediated tumor regression and immune-related adverse events (irAEs), including diarrhea and colitis. The current analyses were undertaken to promote an understanding of the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of ipilimumab-induced gastrointestinal irAEs. Treatment-naïve or previously treated patients with unresectable stage III/IV melanoma (n = 115) received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) and were randomized to receive concomitant blinded prophylactic oral budesonide (9 mg/d with gradual taper through week 16) or placebo. Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease (IBD), fecal calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora, inflammatory cell infiltration into gastrointestinal mucosa, and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis. The pattern of ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD. Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation. Despite an observed association between colonic inflammation and grade 2 or higher diarrhea, no baseline biomarkers could reliably predict development of gastrointestinal toxicity. Although classic IBD and ipilimumab-related gastrointestinal toxicity are both immune mediated, the observed pattern of biomarkers suggests ipilimumab-related gastrointestinal toxicity may be a distinct clinicopathologic entity.