Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study.

BACKGROUND: Endocrine treatment (ET) with an aromatase inhibitor (AI) is the treatment of choice in post-menopausal patients with hormone receptor-positive early breast cancer (EBC). However, adverse events (AEs) often lead to treatment discontinuation. This analysis aimed to identify side-effects that lead to patients failing to persist with letrozole treatment. PATIENTS AND METHODS: Post-menopausal hormone receptor-positive EBC patients starting ET with letrozole were enroled in EvAluate-TM, a non-interventional study. Information regarding treatment compliance and persistence was gathered in months 6 and 12. Persistence was defined as the time from 30 d after the start to the end of treatment. The influence on persistence of musculoskeletal syndrome, menopausal disorder, sleep disorder and other AEs within the first 30 d was analysed using Cox regression analyses. RESULTS: Among 3887 patients analysed, the persistence rate after 12 months was >85%. In all, 568 patients (14.6%) discontinued the treatment, 358 of whom (63.0%) did so only because of side-effects. The main AEs influencing persistence were musculoskeletal symptoms (hazard ratio [HR] 2.55; 95% confidence interval [CI], 1.90-3.42), sleep disorders (HR 1.95; 95% CI, 1.41-2.70) and other AEs (HR 2.03; 95% CI, 1.51-2.73). Menopausal disorder was not associated with non-persistence (HR 1.17; 95% CI, 0.74-1.84). CONCLUSIONS: These results suggest that side-effects of AIs such as musculoskeletal syndrome and sleep disorder lead to ET discontinuation within the first treatment year in significant numbers of EBC patients. Compliance programmes adapted for subgroups that are at risk for early non-persistence might help to ensure the recommended therapy duration. CLINICAL TRIALS NUMBER: CFEM345DDE19.

Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients.

Background: Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. Patients and methods: The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Results: Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). Conclusion: These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs.

Tactile stimulation and hemispheric asymmetries modulate auditory perception and neural responses in primary auditory cortex.

Although multisensory integration has been an important area of recent research, most studies focused on audiovisual integration. Importantly, however, the combination of audition and touch can guide our behavior as effectively which we studied here using psychophysics and functional magnetic resonance imaging (fMRI). We tested whether task-irrelevant tactile stimuli would enhance auditory detection, and whether hemispheric asymmetries would modulate these audiotactile benefits using lateralized sounds. Spatially aligned task-irrelevant tactile stimuli could occur either synchronously or asynchronously with the sounds. Auditory detection was enhanced by non-informative synchronous and asynchronous tactile stimuli, if presented on the left side. Elevated fMRI-signals to left-sided synchronous bimodal stimulation were found in primary auditory cortex (A1). Adjacent regions (planum temporale, PT) expressed enhanced BOLD-responses for synchronous and asynchronous left-sided bimodal conditions. Additional connectivity analyses seeded in right-hemispheric A1 and PT for both bimodal conditions showed enhanced connectivity with right-hemispheric thalamic, somatosensory and multisensory areas that scaled with subjects' performance. Our results indicate that functional asymmetries interact with audiotactile interplay which can be observed for left-lateralized stimulation in the right hemisphere. There, audiotactile interplay recruits a functional network of unisensory cortices, and the strength of these functional network connections is directly related to subjects' perceptual sensitivity.

Quantile estimation to derive optimized test thresholds for random field statistics.

We present a numerical method to estimate the true threshold values in random fields needed to determine the significance of apparent signals observed in noisy images. To accomplish this, a quantile estimation algorithm is applied to derive the threshold with a predefined confidence interval from a large number of simulated random fields. Also, a computationally efficient method for generating a random field simulation is presented using resampling techniques. Applying these techniques, thresholds have been determined for a large variety of parameter settings (smoothness, voxel size, brain shape, type of statistics). By means of interpolation techniques, thresholds for additional arbitrary settings can be quickly derived without the need to run individual simulations. Compared to the parametric approach of Worsley et al. (1996) (Worsley, K.J., Marrett, S., Neelin P., Vandal, A.C., Friston, K.J., Evans, A.C., 1996. A unified statistical approach for determining significant signals in images of cerebral activation. Hum. Brain Mapp. 4, 58-73) and Friston et al. (1991) (Friston, K.J., Frith, C.D., Liddle, P.F., Frackowiak, R.S. 1991. Comparing functional (PET) images: the assessment of significant change. J. Cereb. Blood Flow Metab. 11(4), 690-699), and to the Bonferroni approach, these optimized thresholds lead to higher levels of significance (i.e., lower p values) with a specific amount of activation especially with fields of moderate smoothness (i.e., with a relative full width half maximum between 2 and 6). Alternatively, the threshold for a specified level of significance can be lowered. This improved statistical sensitivity is illustrated by the analysis of an actual event related functional magnetic resonance data set, and its limitations are tested by determining the false positive rate with experimental MR noise data. The grid of estimated threshold values as well as the interpolation algorithm to derive thresholds for arbitrary parameter settings are made available over the internet (http://neuro2.med.uni-magdeburg.de/quantile_estimation).

Functional magnetic resonance tomography correlates of taste perception in the human primary taste cortex.

The present study investigated the functional magnetic resonance tomography correlates of taste perception in the human primary taste cortex. There is conflicting evidence in the literature about chemotopical organization in this brain region. The topography of hemodynamic activity elicited by five taste stimuli (sweet, sour, salty, bitter and umami) was analyzed on the flattened cortical surfaces of six single subjects. A high inter-individual topographical variability had to be noted. The results showed different patterns of hemodynamic activity for the investigated tastes with some considerable overlap. However, the taste specific patterns were stable over time in each subject. Such an individual taste specific pattern was also found for the umami taste within the primary taste cortex of each subject. These results suggest that input from glutamate receptors on the tongue might be processed in an exclusive way in the primary taste cortex rather than as a combination of inputs from the classical taste receptors.

Three cases of Arcanobacterium haemolyticum associated with abscess formation and cellulitis.

Arcanobacterium haemolyticum has been described as an unusual pathogen causing pharyngotonsillitis and systemic disease in patients with predisposing conditions. A case of soft tissue abscess with no apparent portal of entry is reported in a healthy 31-year-old man who presented with a breast tumor. A second case of abscess formation in a 50-year-old patient with complicated wound healing is presented. In addition, a case of Arcanobacterium haemolyticum cellulitis in a 25-year-old female is reported. Due to its innocuous, coryneform appearance, this pathogen is probably underreported; therefore, the diagnostic evaluation of this organism is emphasized.