A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer.

The purpose of this study was to determine the safety and maximum tolerated dose (MTD) of BZL101 (FDA IND# 59,521), an orally delivered aqueous extract from the herb Scutellaria barbata, in women with metastatic breast cancer (MBC). The trial was an open-label, phase 1B, multicenter, dose escalation study. Eligible patients had histologically confirmed breast cancer and measurable stage IV disease. The standard phase 1 "3 + 3" study design was used to determine the MTD. Primary endpoints were toxicity and MTD of BZL101. Secondary outcomes included efficacy based on RECIST criteria. A total of 27 women with a median of 2 prior chemotherapy treatments for metastatic disease were treated in four different dose cohorts. Grade 3 and 4 adverse events (AEs) were uncommon. Dose-limiting toxicities included the following: grade 4 AST elevation, grade 3 diarrhea, grade 3 fatigue, and grade 3 rib pain. Fourteen patients were evaluable according to Response Evaluation Criteria in Solid Tumors. Investigator assessment classified three patients with stable disease for >120 days (21%). One patient was on BZL101 for 449 days and remains stable for 700 + days. Independent radiology review identified three patients with objective tumor regression (>0% and <30%). The MTD was not reached, thus per protocol, the MTD was defined as the maximum administered dose of BZL101 40 g/day. In conclusion, oral administration of BZL101 was safe, well tolerated, and showed promising clinical evidence of anticancer activity in this heavily pretreated population of women with MBC.

Contribution of cancer symptoms, dysfunctional sleep related thoughts, and sleep inhibitory behaviors to the insomnia process in breast cancer survivors: a daily process analysis.

STUDY OBJECTIVES: using a comprehensive cognitive-behavioral model of insomnia and a daily process approach, this study was conducted to examine the contribution of cancer symptoms and dysfunctional sleep related thoughts and behaviors to the process of insomnia in breast cancer survivors. DESIGN: within-group longitudinal research design. SETTING: an academic medical center. PARTICIPANTS: 41 women with breast cancer who had completed their primary cancer treatment and met Research Diagnostic Criteria for primary insomnia or insomnia comorbid with breast cancer. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: for 28 days, participants completed morning diaries assessing sleep, nighttime pain and hot flashes, and dysfunctional sleep related thoughts and behaviors during the day and night, and evening diaries assessing daytime pain, fatigue, hot flashes, and mood. All diaries were collected using an automated telephone-based system. Results revealed that poorer sleep was related to nighttime pain and hot flashes in breast cancer patients. Time-lagged effects were also found. The current study identified higher levels of dysfunctional sleep related thoughts and sleep inhibitory behaviors during the day and night as antecedents of insomnia, and higher levels of pain, fatigue, and hot flashes and lower levels of positive mood and dysfunctional sleep related thoughts as consequences of insomnia in this population. CONCLUSIONS: the current study found support for a comprehensive cognitive-behavioral model of insomnia, which has several theoretical, practice, and research implications.

Use of tablet personal computers for sensitive patient-reported information.

Notebook-style computers (e/Tablets) are increasingly replacing paper methods for collecting patient-reported information. Discrepancies in data between these methods have been found in oncology for sexuality-related questions. A study was performed to formulate hypotheses regarding causes for discrepant responses and to analyze whether electronic data collection adds value over paper-based methods when collecting data on sensitive topics. A total of 56 breast cancer patients visiting Duke Breast Clinic (North Carolina) participated by responding to 12 subscales of 5 survey instruments in electronic (e/Tablet) format and to a paper version of 1 of these surveys, at each visit. Twenty-one participants (38%) provided dissimilar responses on paper and electronic surveys to one item of the Functional Assessment of Cancer Therapy-General (FACT-G) Social Well-Being scale that asked patients to rate their satisfaction with their current sex life. Among these 21 patients were 8 patients who answered the question in the electronic environment, and 13 patients who answered both paper and electronic versions but with different responses. Eleven patients (29%) did not respond to the item on either e/Tablet or paper; 45 patients (80%) answered it on e/Tablet; and 37 patients (66%) responded on the paper version. The e/Tablet electronic system may provide a "safer" environment than paper questionnaires for cancer patients to answer private or highly personal questions on sensitive topics such as sexuality.

Mucosal wave: a normophonic study across visualization techniques.

Visualization of vocal fold vibration is essential for accurate diagnoses and optimal treatment of persons with voice disorders. Recently, scientific and anecdotal reports have evidenced an increased amount of variation in the diagnostically relevant features of extent and symmetry of mucosal wave magnitude in normophonic speakers. The objectives of this study were to preliminarily ascertain the variation in mucosal wave magnitude and symmetry for normophonic speakers as assessed via standard and novel techniques, and compare findings across modal and pressed phonations. A correlational design with a multiple baseline across visualization methods approach was used. Mucosal wave presence, magnitude, and symmetry from 52 normophonic speakers were judged via stroboscopy, high-speed videoendoscopy (HSV) playback, mucosal wave playback, and mucosal wave kymography playback. Results demonstrate a prevalence of atypical magnitude and symmetry of mucosal wave during modal and pressed phonations by normophonic persons, differences across techniques, and a relationship between judgments and habitual fundamental frequency. Given the prevalence of mucosal wave magnitude and symmetry variations in the normophonic population, overdiagnosis may be possible without caution. The various visualization techniques provided unique information suggesting that it may be beneficial to use both full view and kymographic visualization techniques in combination. A major restriction of the current commercial HSV systems is the frame rate, typically limited to 2000 frames per second, which appears insufficient for most female habitual phonations.

Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies.

Extracts of milk thistle have been recognized for centuries as "liver tonics" and are well-known to prevent or reverse hepatotoxicity of reactive drug metabolites or naturally occurring toxins. Milk thistle extracts are now under intense study in the experimental therapeutics of cancer for chemoprevention, treatment, and amelioration of chemotherapy side effects. Precision in nomenclature, however, has lagged behind this progress. The crude commercial product of milk thistle is termed silymarin, a complex of at least 7 flavonolignans and 1 flavonoid that comprises 65% to 80% of milk thistle extract. From silymarin is derived silibinin, a semipurified fraction once thought to be a single compound but now recognized as a 1:1 mixture of 2 diastereoisomers, silybin A and silybin B. The distinction between silymarin and silibinin is not only important to understanding the historical literature, but thorough characterization and use of chemically defined mixtures in preclinical and clinical studies are essential to the progress of these botanical compounds as human therapeutics. As a result, we urge clinicians and preclinical investigators alike to exercise rigor in nomenclature and use pure compounds or precisely defined chemical mixtures in subsequent studies. Herein, we provide a guide to the proper nomenclature and composition of milk thistle extracts and discuss the known pharmacokinetic studies of these botanical medicines. The drug-interaction potential of these extracts appears to be quite low, and in fact, silibinin appears to synergize with the antitumor effects of some commonly used chemotherapeutics. However, some precautions are advised as high-dose, phase II studies are conducted.

Adverse effects of environmental noise on acoustic voice quality measurements.

An accurate analysis of voice quality is imperative when using acoustic measurements to diagnose vocal pathologies. It is known that noise has a significant effect on the reliability and validity of acoustic voice measurements, but the precise relationship has not been established. The purpose of this study was to investigate the influence of noise on the accuracy, reliability, and validity of acoustic voice quality measurements while balancing for gender, age, intersubject and intrasubject variability, microphones, computer hardware, analysis software, and type of noise. Level of noise was precisely controlled. The specific focus of interest was to determine the critical levels of noise that can invalidate voice quality measurements and to generate practical recommendations. Results suggest that the recommended, acceptable, and unacceptable levels of noise in the acoustic environment are above 42 dB, above 30 dB, and below 30 dB signal-to-noise ratio, respectively.

Influence of data acquisition environment on accuracy of acoustic voice quality measurements.

Accuracy of acoustic voice analysis is influenced by the quality of recording. Lately, articles have suggested that soundcards perform equivalently to specialized professional-grade data acquisition (DA) systems. The purpose of this study was to investigate the influence of DA environment (DA system and microphone) on acoustic voice quality measurement (VQM) while balancing for gender, age, intersubject and intrasubject variability, and analysis software. More specifically, the relative performance of different hardware environments and the relationship between their technical characteristics and VQM performance was investigated. The discretization error and the effective dynamic range of the different DA environments were measured. We used 3 software systems to record and measure separately 2000 acoustic samples of sustained phonation for fundamental frequency, jitter, and shimmer. Analyses of variance (ANOVA) were performed with these parameters as the dependent variables. The results of the study suggested that professional-grade DA hardware is strongly recommended to provide accurate and valid voice assessment. The fundamental frequency measurement differences across DA environments were highly correlated to the discretization error (r=1.00), whereas jitter and shimmer were highly correlated to the effective dynamic range of the DA environments (r=-0.68 and r=-0.86, respectively).

Influence of sampling rate on accuracy and reliability of acoustic voice analysis.

It is universally recognized that sampling rate (F(S)) influences the reliability and validity of acoustic voice measurements; however, an exact relationship has not been determined. The purpose of this experiment was to investigate the influence of F(S) on acoustic voice quality measurements, while considering the influences of gender, intra-subject variability, microphone, environmental noise, data acquisition hardware, and analysis software as balancing factors. The impact of F(S), from 44.1 kHz to 10 kHz, was explored by analyzing 864,000 measures of fundamental frequency, jitter, and shimmer, using three software analysis systems: MDVP, TF32, and PRAAT. Results suggest that the recommended, acceptable, and critical F(S) for acoustic voice analysis are above 26 kHz, above 19 kHz, and 12 kHz, respectively. Thus, voice samples captured above 26 kHz can be used for data analysis and compared without introducing error due to F(S).

Letrozole in the treatment of breast cancer.

Over the last 30 years the role of tamoxifen in breast cancer treatment has been progressively expanded by clinical investigation to encompass the entire spectrum of disease from cancer chemoprevention to palliation of advanced disease. The primacy of tamoxifen for these indications in postmenopausal women is now under challenge by the selective aromatase inhibitors, a class of endocrine agent that induces oestrogen deprivation rather than oestrogen receptor blockade. This review considers the biochemical, pharmacological and clinical properties of the nonsteroidal aromatase inhibitor letrozole. This agent is superior to tamoxifen for the treatment of metastatic breast cancer, a finding that suggests that letrozole may ultimately eclipse tamoxifen for other indications, including chemoprevention. Further clinical investigation will be necessary to establish the risks and benefits of letrozole versus tamoxifen for each new indication, with adjuvant therapy being the next in line. The object of this review is to provide a reference source on the biochemical, pharmacological and clinical properties of letrozole for clinicians to consider both established and future indications.

Regression tree approach to studying factors influencing acoustic voice analysis.

Multiple factors influence voice quality measurements (VQM) obtained during an acoustic voice assessment including: gender, intrasubject variability, microphone, environmental noise (type and level), data acquisition (DA) system, and analysis software. This study used regression trees to investigate the order and relative importance of these factors on VQM including interaction effects of the factors and how the outcome differs when the acoustic environment is controlled for noise. Twenty normophonic participants provided 20 voice samples each, which were recorded synchronously on five DA systems combined with six different microphones. The samples were mixed with five noise types at eight signal-to-noise ratio (SNR) levels. The resulting 80,000 audio samples were analyzed for fundamental frequency (F(0)), jitter and shimmer using three software analysis systems: MDVP, PRAAT, and TF32 (CSpeech). Fifteen regression trees and their Variable Importance Measures were utilized to analyze the data. The analyses confirmed that all of the factors listed above were influential. The results suggest that gender, intrasubject variability, and microphone were significant influences on F(0). Software systems and gender were highly influential on measurements of jitter and shimmer. Environmental noise was shown to be the prominent factor that affects VQM when SNR levels are below 30 dB.