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 < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction 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.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Measurement reliability for acupoint activity determined with the prognos ohmmeter.

The concepts of meridians and acupoints are critical to traditional Chinese medicine but are met with skepticism in Western medicine. Empirical validation of these concepts is in its beginning stages and still hampered by problems with measurement. A promising avenue and foundation for validity testing is the demonstration that acupoint activity can be reliably measured via determination of electrical resistance at well-defined body surface points. In this article, efforts are described to maximize measurement reliability; we tested a variety of protocols to determine which method of data aggregation is associated with maximal reliability. Twenty-one healthy individuals were subjected to 5 repeated measurement cycles to test the predicted increase in reliability with increasing number of aggregated measurements. Reliability, defined as internal consistency, was indeed highest for 5 measurements (mean alpha = .88). Even the aggregate of only three measures was quite reliable (alpha = .84). Reliability for measuring acupoints on the left side of the body was roughly .05 higher than on the right side. Consistent with previous literature, we conclude that with repeated measures the reliability of electrical resistance measurements at acupoints is high and that a strong foundation for validation research is now laid.

Binaural summation of amplitude modulation involves weak interaural suppression.

The brain combines sounds from the two ears, but what is the algorithm used to achieve this summation of signals? Here we combine psychophysical amplitude modulation discrimination and steady-state electroencephalography (EEG) data to investigate the architecture of binaural combination for amplitude-modulated tones. Discrimination thresholds followed a 'dipper' shaped function of pedestal modulation depth, and were consistently lower for binaural than monaural presentation of modulated tones. The EEG responses were greater for binaural than monaural presentation of modulated tones, and when a masker was presented to one ear, it produced only weak suppression of the response to a signal presented to the other ear. Both data sets were well-fit by a computational model originally derived for visual signal combination, but with suppression between the two channels (ears) being much weaker than in binocular vision. We suggest that the distinct ecological constraints on vision and hearing can explain this difference, if it is assumed that the brain avoids over-representing sensory signals originating from a single object. These findings position our understanding of binaural summation in a broader context of work on sensory signal combination in the brain, and delineate the similarities and differences between vision and hearing.

The role of inflammation in the association between gestational diabetes and obstructive sleep apnea: A pilot study.

BACKGROUND: Obstructive sleep apnea is associated with pregnancy complications including gestational diabetes. Mechanisms underlying the association between obstructive sleep apnea and gestational diabetes remain to be elucidated. METHODS: Twenty-three participants with gestational diabetes underwent home sleep apnea testing. Obstructive sleep apnea was defined as an apnea hypopnea index > 5. Fasting morning blood samples were measured using multianalyte profiling (xMAP) multiplexed bead array immunoassay for Interleukin 6, tumor necrosis factor-alpha, and Interleukin 8. RESULTS: Age, body mass index, and gestational age at enrollment were 31 + 4.4 years, 35.7 + 7.4 kg/m2, and 28 ± 4 weeks, respectively. Participants were 52% Caucasian and 16% had obstructive sleep apnea. We observed positive correlations between apnea hypopnea index and Interleukin 6 (r = 0.62, p = 0.005), Interleukin 8 (r = 0.56, p = .56), and tumor necrosis factor-alpha (r = .58, p = .009). Women with obstructive sleep apnea had higher levels of Interleukin 6 (F = 5.01, p = .037) and Interleukin 8 (F = 6.33, p = .021) vs. women without obstructive sleep apnea. CONCLUSION: These preliminary results indicate that in women with gestational diabetes, apnea hypopnea index is associated with an elevated inflammatory profile.

Causes and consequences of blood pressure alterations in obstructive sleep apnea.

The obstructive sleep apnea (OSA) syndrome has been considered to be a cause of both transient blood pressure elevations during sleep and sustained hypertension during the awake state. The purpose of this review was to examine critically the existing literature regarding (1) the blood pressure alterations associated with OSA, (2) causal mechanisms relating specific blood pressure alterations to OSA, and (3) potential consequences of the systemic circulatory abnormalities associated with OSA. Particular attention was directed at studies that assessed the prevalence of OSA in patients with hypertension and that examined the effects on blood pressure of treatment of OSA. We conclude that patients with OSA have abnormal sleep blood pressure patterns, manifested most frequently by apnea-associated blood pressure elevations. Confounding factors such as obesity and antihypertensive drug therapy, and conflicting evidence regarding changes in daytime blood pressure after therapy for OSA, make it premature to conclude that OSA and daytime hypertension are directly associated. Circumstantial evidence suggests that the blood pressure alterations that occur during sleep could contribute to the high cardiovascular morbidity in patients with OSA. Further research into the relationship between OSA and hypertension should improve the future care of patients with these conditions and enhance our understanding of cardiopulmonary pathophysiology.

The role of the primary care physician in recognizing obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a common disorder among middle-aged adults. However, OSA is a recently described disorder for which most primary care physicians do not have formal training. The primary objectives of this article are to evaluate what percentage of patients referred by primary care physicians for sleep studies had OSA; to characterize the clinical features of these patients and compare them with our known OSA population; and to determine whether primary care physicians asked key questions contained in a work sheet to make the diagnosis of OSA. METHODS: A retrospective chart review at a hospital-based sleep center that is accredited to evaluate all sleep disorders, not just OSA. The health maintenance organization is a staff model one. PATIENTS: Sixty-nine patients who were referred for a sleep study by a health maintenance organization internist or family practitioner between June 1, 1994, and May 30, 1995. RESULTS: Ninety-six percent of the 68 patients referred for polysomnography had OSA. Most were very symptomatic and obese. These 68 patients represent 0.13% of the primary care patient panel. In addition, most of the patients were referred by a few physicians; 6 (11%) of the 55 physicians ordered 33% of the 68 studies. CONCLUSIONS: Primary care physicians did recognize obese patients with prominent symptoms of sleep apnea. However, only a small percentage of their patient panel was referred, suggesting that this condition is still underdiagnosed. This seems particularly true as most of the sleep studies were ordered by a small group of physicians. Future work incorporating educational interventions is necessary to improve detection and treatment of OSA.

Effect of methadone plus neuroleptics on treatment-resistant chronic paranoid schizophrenia.

In a placebo-controlled single-crossover study, seven patients with treatment-resistant chronic paranoid schizophrenia who received methadone plus neuroleptic showed significant improvement. Methadone may be a useful adjunctive treatment in a subpopulation of patients with chronic paranoid schizophrenia.

Outcomes for cocaine abusers after once-a-week psychosocial therapy.

OBJECTIVE: The authors studied the efficacy of once-weekly psychotherapy, family therapy, or group therapy led by paraprofessionals among patients with cocaine use disorders. METHOD: Of subjects who sought outpatient treatment, 168 consented to participate in the study and were each randomly assigned to one of the three forms of therapy; 122 patients were interviewed 6-12 months later. Their pre- and posttreatment scores on the Addiction Severity Index were compared. RESULTS: Significant improvements were observed for the cohort as a whole, but virtually all of the improvement was restricted to the 23 subjects (19%) who were not using cocaine at follow-up. There was a strong relationship between abstinence from cocaine use and absence of addiction-related problems, especially psychiatric symptoms and family problems. CONCLUSIONS: The results of the study indicate that outpatient therapy once a week is ineffective for cocaine use disorder. The 19% abstinence rate probably represents spontaneous remission among patients with enough motivation to seek treatment, as the number of therapy sessions attended was not related to improvement. Either an intense level of outpatient contact or residential treatment followed by aftercare is probably needed, at least initially, while the patient is attempting to initiate and sustain abstinence.

Unusual complication of nasal CPAP: subcutaneous emphysema following facial trauma.

Subcutaneous emphysema is an unusual complication of nasal continuous positive airway pressure (CPAP). We report a case of a 58-year-old man who fell and sustained mild facial trauma to the left side of his head. After using CPAP the following night, he developed diffuse subcutaneous emphysema of his face and left neck. He discontinued CPAP, and his symptoms improved. The potential mechanisms of this patient's subcutaneous emphysema and the prior reports of this complication following facial trauma or dental procedure without use of CPAP are reviewed. Although there are case reports of bacterial meningitis and pneumocephalus following use of nasal CPAP, we are not aware of any prior reports of subcutaneous emphysema following use of CPAP. In light of our experience and the above related case reports, we would suggest nasal CPAP be withheld temporarily in the setting of acute facial trauma.

The Taskforce 2000 survey on medical education in sleep and sleep disorders.

Previous research has shown evidence of a widening gap between scientific research and clinical teaching in sleep and sleep disorders. To address the deficiencies in current medical education in sleep, the Taskforce 2000 was established by the American Sleep Disorders Association. The present study was undertaken to assess the teaching activities, needs and interests of the membership of the two largest professional sleep societies (American Sleep Disorders Association and Sleep Research Society). Survey instruments included a brief, 5-item postcard survey, which was mailed to all members, followed by an in-depth, 34-item questionnaire, which was completed by 158 respondents from the intitial postcard survey (N = 808). Results indicated that the majority of respondents (65.2%) are currently involved in teaching sleep to medical students or postgraduate trainees, although the average amount of teaching time was only 2.1 hours for undergraduate and 4.8 hours for graduate education in sleep. Teaching of sleep laboratory procedures and clinical evaluation of sleep-disordered patients is limited at either an undergraduate or postgraduate level. The major deficiencies noted were the lack of time in the medical curriculum and the need for better resources and teaching facilities. A large majority of respondents indicated their willingness to be involved in sleep education for physicians, and rated this a high priority for the professional organization.

Portable recording in the assessment of obstructive sleep apnea. ASDA standards of practice.

The objective assessment of patients with a presumptive diagnosis of obstructive sleep apnea (OSA) has primarily used attended polysomnographic study. Recent technologic advances and issues of availability, convenience and cost have led to a rapid increase in the use of portable recording devices. However, limited scientific information has been published regarding the evaluation of the efficacy, accuracy, validity, utility, cost effectiveness and limitations of this portable equipment. Attaining a clear assessment of the role of portable devices is complicated by the multiplicity of recording systems and the variability of clinical settings in which they have been analyzed. This paper reviews the current knowledge base regarding portable recording in the assessment of OSA, including technical considerations, validation studies, potential advantages and disadvantages, issues of safety, current clinical usage and areas most in need of further study.

Environmental noise as a cause of sleep disruption in an intermediate respiratory care unit.

Our laboratory previously reported continuously monitored peak sound levels in several areas at Rhode Island Hospital. The number of sound peaks greater than 80 A-weighted decibels (dBA) was found to be high in the intensive and intermediate respiratory care unit (IRCU) areas, even at night. Environmental noise of this magnitude is potentially sleep-disruptive. Therefore, we hypothesized that nocturnal peak sound levels of > or = 80 dBA would be associated with an increase in EEG arousals from sleep in patients in the IRCU. Six patients underwent sleep monitoring while environmental peak sound levels were continuously recorded. Each 8-hour period (2200 to 0600 hours) was broken down into 30-minute segments. If there were 10 minutes or more of wakefulness in a segment, that segment was dropped from further analysis. Of the remaining 61 segments, there was a very strong correlation (r = 0.57, p = 0.0001) between the number of sound peaks of > or = 80 dBA and arousals from sleep. These 61 periods were then classified as quiet, moderately loud, and very loud based on the number of sound peaks (< or = 5, 6-15, and > 15, respectively). Analysis of variance revealed a significant difference between the number of arousals (p = 0.001) in quiet periods and that in very loud periods. We conclude that environmental noise may be an important cause of sleep disruption in the IRCU.

Air leaking through the mouth during nocturnal nasal ventilation: effect on sleep quality.

Air leaking through the mouth has been reported in kyphoscoliotic patients receiving nasal ventilation via volume-limited ventilators. This study accessed the frequency of occurrence and effect on sleep quality of air leaking through the mouth during nocturnal nasal ventilation in patients with chest wall and neuromuscular disease using pressure-limited ventilation. Overnight and daytime polysomnography was performed in six stable experienced users of nocturnal nasal noninvasive positive-pressure ventilation (NPPV) who had chronic respiratory failure due to neuromuscular disease or chest wall deformity. All patients used the BiPAP S/T-D ventilatory support system (Respironics, Inc., Murrysville, PA). Measures included sleep scoring, leak quantitation, diaphragm and submental electromyograms (EMGs), and tidal and leak volumes. All patients had air leaking through the mouth for the majority of sleep. Sleep quality was diminished because of poor sleep efficiency and reduced percentages of slow-wave and rapid eye movement (REM) sleep. Air leaking through the mouth was associated with frequent arousals during stages 1 and 2 and REM sleep that contributed to sleep fragmentation, but arousals were infrequent during slow-wave sleep. Despite prevalent leaking, oxygenation was well maintained in all but one patient. Patients used a-combination of passive and active mechanisms to control air leaking. Although nasal ventilation improves nocturnal hypoventilation and symptoms in patients with restrictive thoracic disorders, air leaking through the mouth is very common during use. The leaking is associated with frequent arousals during lighter stages of sleep that interfere with progression to deeper stages, compromising sleep quality. Portable pressure-limited ventilators compensate for leaks, maintaining ventilation and oxygenation, but further studies are needed to determine which interfaces and ventilator techniques best control air leaking and optimize sleep quality.

Evaluation and clinical management of cocaine abusers.

The development of an individualized treatment program for cocaine abusers requires a comprehensive assessment of the psychobiological, social, and pharmacological elements that determined the drug abuse behavior as well as those elements that resulted from the behavior. A working knowledge of the "disease model" of chemical dependency, as well as other relevant models, is mandatory. Although the existing outcome data are insufficient, there is a large array of possible treatment options and facilities; the clinician should attempt to match the patient with the program based on relevant clinical and anecdotal information. Clinicians should be familiar with the ethos and procedures of the "12-Step programs"; they are often a critical element in treatment.

Depression as a manifestation of obstructive sleep apnea: reversal with nasal continuous positive airway pressure.

Fifty-five patients with obstructive sleep apnea each completed a Zung Self-Rating Depression Scale (SDS), Twenty-five patients (45%) had SDS scores greater than or equal to 50, consistent with depression. The SDS scores did not correlate with age, the number of respiratory events per hour sleep, antihypertensive medication, or the oxygen saturation baseline or nadir. The group with SDS scores of 50 or greater, however, had 68.0 +/- 8.8 respiratory events per hour compared with 47.9 +/- 4.7 in the group with SDS scores under 50 (p less than .05). Nineteen patients who were treated with nasal continuous positive airway pressure completed a follow-up SDS Inventory. After treatment, the SDS scores fell from 60.5 +/- 1.9 to 44.4 +/- 2.6 (p less than .001) in the 11 patients with baseline elevated scores. The authors conclude that obstructive sleep apnea can produce prominent symptoms of depression that appear to be related to the severity of the underlying apnea; furthermore, treatment of obstructive sleep apnea may result in alleviation of these symptoms in certain patients.

Sleep-related eating disorder as a cause of obstructive sleep apnea.

A patient with obesity resulting from sleep-related eating disorder demonstrated signs and symptoms of obstructive sleep apnea (OSA). Incarceration restricted access to food during the night, leading to weight loss and clinical improvement. Release from prison allowed recurrence of unrestricted sleep-eating, recurrent obesity, and documented OSA. Successful treatment of sleep-related eating disorder can result in improvement in coexisting OSA.

Massive epistaxis from nasal CPAP therapy.

A 75-year-old man with obstructive sleep apnea and secondary right heart failure was started on nasal CPAP therapy. Shortly thereafter he experienced massive life-threatening epistaxis requiring nasal packing and hospitalization. The epistaxis was thought to be due to the drying effect of nasal CPAP.

Importance of breath size in calibrating the respiratory inductive plethysmograph.

The usual method of calibrating the respiratory inductive plethysmograph (RIP) is to have the subject breathe over a rather narrow volume range, either resting tidal volume or into a bag containing a fixed larger volume, in both the standing and supine positions. During a previous study in our laboratory using the RIP to quantify ventilation during sleep in young and elderly adults, we began to observe that the accuracy of the RIP measurements could be improved if we calibrated using a wider range of tidal volumes which encompassed the smaller breath sizes we were measuring during sleep. We therefore decided to investigate whether the size of the breaths used for calibrating the RIP was indeed important in improving the accuracy of the device. Eight healthy, nonsmoking young adult men participated in the study. Three sets of calibration factors for the RIP were determined based on low (300 to 500 ml), normal (500 to 800 ml) and high tidal volume (over 800 ml) breaths. Each of these sets of calibration factors were then used to validate three different sets of supine tidal volumes (low, normal, high). For all volumes tested, the RIP values most closely approximated the spirometric volumes when the calibration breaths and validation breaths were of the same size.