Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.

Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674.

The efficacy of computer-tailored smoking cessation material as a supplement to nicotine polacrilex gum therapy.

BACKGROUND: Standard, generic self-help materials have been largely ineffective as behavioral treatments for smoking cessation. In contrast, self-help programs tailored to the needs of specific smokers have shown promise in facilitating quitting. OBJECTIVE: To evaluate the incremental efficacy of the Committed Quitters Program (CQP), a set of computer-tailored materials offered to purchasers of nicotine polacrilex gum, compared with a briefuntailored user's guide and audiotape, both as supplements to nicotine replacement therapy. METHODS: We conducted a randomized, open-label trial with 3 parallel arms. Subjects were smokers who purchased 2- or 4-mg nicotine polacrilex gum and called the CQP toll-free enrollment line. Three thousand six hundred twenty-seven subjects consented to participate in 1 of 3 study arms: (1) those receiving the CQP materials (CQP group, n= 1,217), (2) those receiving CQP materials and an outbound telephone call (CQP + C group, n= 1,207); and (3) those receiving no supplemental intervention beyond the user's guide and audiotape that were prepackaged with the nicotine polacrilex gum (UG group, n= 1,203). Twenty-eight-day continuous abstinence rates were assessed by telephone interviews at 6 weeks and 10-week continuous rates at 12 weeks into treatment. RESULTS: Abstinence rates among respondents at the 6- and 12-week assessments were significantly higher for the CQP (36.2% and 27.6%) and CQP + C (35.5% and 27.3%) groups compared with the UG group (24.7% and 17.7%) at both intervals. The quit rates for the CQP and CQP + C groups were almost identical. CONCLUSIONS: The CQP proved to be an effective behavioral treatment, enhancing quit rates over and above nicotine replacement therapy and a brief untailored written guide and audiotape.

Psychophysiological and clinical value of event-related potentials in obsessive-compulsive disorder.

To investigate brain correlates of cognitive function in obsessive-compulsive disorder (OCD), event-related potentials (ERPs) were recorded in a group of thirteen unmedicated OCD patients and thirteen normal controls for verbal auditory stimuli in an oddball paradigm. The patients showed longer latencies of the N1 and P2, shorter latency of the P3, and reduced amplitude of the N2. These results suggest that OCDs stress the speed of task-dependent processes (i.e., by showing shorter N2 and P3 latencies) and have impairment of task-independent ones (i.e., by showing longer N1 and P2 latencies and reduced N2 amplitude). The components were more positive in the left hemisphere in OCDs and in the right hemisphere in normal controls. Future responders to treatment had significantly reduced N2 and enhanced P3 amplitudes relative to future nonresponders. So ERPs might provide psychophysiological profiles in OCDs with clinical and pharmacological implications.

Impaired cell-mediated immunity in systemic lupus erythematosus (SLE). A controlled study of 23 untreated patients.

Cell-mediated immunity was evaluated in 23 patients with systemic lupus erythematosus (SLE) prior to therapy and in 23 control subjects. The patients with SLE who had moderate to severe disease activity had significantly fewer positive delayed skin tests to streptokinase-streptodornase (SK-SD) and Candida than the control subjects, and a higher frequency of anergy than either the control subjects or the patients with mild SLE. Significant impairment of lymphocyte transformation to all common antigens tested was found in patients with SLE as compared to both normal subjects and control subjects with disease. Phytohemagglutinin response was reduced in patients with SLE as compared to normal subjects but not to the control subjects with disease. Lymphocyte transformation responses to SK-SD and Candida were also significantly lower in patients with moderate to severe SLE as compared to patients with mildly active SLE. Primary immune response to keyhole limpet hemocyanin (KLH) was impaired in patients with SLE as measured by lymphocyte transformation and total KLH antibody, but not 2-mercaptoethanol resistant antibody. The data indicate defective T-cell function in SLE, and suggest that the impairment relates in part to disease activity.

Diagnosis and treatment of musculoskeletal running injuries.

In summary, musculoskeletal injuries occur in at least 60% of runners. Selfinduced training error accounts for the majority of running injuries. A review of the runner's mileage, training techniques, biomechanical examination, and shoes will provide clues to the accurate diagnosis and treatment. In most cases it is not correct to categorically advise the runner to stop running, since a modification of running techniques will usually get him or her painlessly "back on the road." The result will be a grateful patient.

Nicotine elimination and tolerance in non-dependent cigarette smokers.

Although most smokers are nicotine-dependent, recent studies suggest that some very light smokers ("chippers", who smoke fewer than five cigarettes per day) may smoke for decades without developing dependence. It was considered that slowed nicotine elimination and/or reduced nicotine tolerance might underlie chippers' ability to maintain smoking at such low levels. To evaluate this hypothesis, we studied the elimination kinetics and pharmacodynamics of nicotine in chippers and matched regular smokers. Plasma nicotine levels and cardiovascular responses were observed for several hours after subjects were administered uniform doses of tobacco smoke. Chippers did show less chronic nicotine tolerance, but only on some response measures. Their rates of nicotine elimination equaled those of regular smokers. This finding, when coupled with other data about chippers' smoking patterns and nicotine absorption, establish that chippers cannot maintain substantial plasma nicotine levels between cigarettes, and thus suggest that attempts to maintain minimal trough levels of nicotine do not underlie chippers' smoking.

The effect of bupropion on nicotine craving and withdrawal.

RATIONALE AND OBJECTIVES: Bupropion has demonstrated efficacy for smoking cessation. Given the importance of nicotine craving and withdrawal in the smoking cessation process, the current study examined the effects of bupropion on these parameters during smoking abstinence. METHODS: During a 2-day Baseline phase with ad lib smoking, 91 non-depressed smokers (who were not trying to quit permanently) were administered measures of nicotine craving, withdrawal symptoms, and timed measures of cognitive performance five times daily. Participants were then assigned randomly to a 14-day treatment regimen with bupropion 300 mg/day, bupropion 150 mg/day, or placebo. Thereafter, the above measures were re-administered during 3 days of abstinence on a closed research ward. RESULTS: Relative to placebo, 300 mg bupropion significantly reduced abstinence-associated increases in rated depression, difficulty concentrating, and irritability, and attenuated a decrease in positive affect. The results also suggested that bupropion might have a positive effect on performance measures during the withdrawal period. No effects were observed on craving, anxiety, restlessness, or hunger. The lack of findings on craving measures may be explained by a floor effect; except on the first day of abstinence, neither drug nor placebo groups showed much craving elevation during abstinence. CONCLUSIONS: Study results indicate that bupropion ameliorates some nicotine withdrawal symptoms.

Nicotine withdrawal in chippers and regular smokers: subjective and cognitive effects.

From previous studies, chippers (very light, long-time cigarette smokers) seem not to be nicotine dependent, despite decades of smoking. The effect of tobacco deprivation on chippers' withdrawal reactions was examined. Matched groups of 26 chippers and 25 regular smokers were studied while abstaining or smoking for 2-day blocks, with assessments administered 5 times daily by palm-top computers. As hypothesized, chippers showed no changes as a result of nicotine deprivation. In contrast, regular smokers demonstrated distinct changes in craving, mood, arousal, and sleep disturbance. The computers also tested participants' cognitive performance. Unlike chippers, regular smokers' performance on complex tasks was slower under deprivation; the effect could not be explained by changes in motor performance or simple reaction time. Results suggest performance may have been improved by nicotine rather than by worsened by withdrawal.

Temptations to smoke after quitting: a comparison of lapsers and maintainers.

This study addresses whether characteristics of temptations to smoke differ for participants who quit smoking and maintain abstinence compared to those who quit and then lapse. Participants used hand-held computers to record temptations and were beeped at random for base-rate assessments. We used generalized estimating equations to compare 1,851 temptation episodes and 5,192 random assessments recorded by 151 participants (116 lapsers, 35 maintainers) over 1-23 days of abstinence. Compared to randomly sampled occasions, temptations were marked by greater negative affect, restlessness, attention disturbance, and exposure to smoking cues; participants were also more likely to be eating or drinking during temptations. Temptations reported by lapsers and maintainers did not differ in any respect, including their reported coping. The results highlight situational variance over individual differences.

Effects of task strain, social conflict, and emotional activation on ambulatory cardiovascular activity: daily life consequences of recurring stress in a multiethnic adult sample.

Ambulatory blood pressure (ABP) may be an independent predictor of cardiovascular endpoints, but little is known about its psychosocial determinants. The acute effects of psychosocial processes on cardiovascular activity during daily life were examined by random-effects regression. Healthy adults (N = 120) were monitored over a 6-day period with ABP monitors and computer-assisted self-report assessments. Task strain, social conflict, and emotional activation were rated following each ABP measurement, as were activity, posture, and other covariates. Results show that blood pressure (BP) and heart rate (HR) were elevated during periods of emotional activation (high negative affect or high arousal). Diastolic BP was lower during periods involving high decisional control, and HR was lower during high-control, low-demand activities. There were substantial individual differences in the effects of psychosocial influences on ambulatory cardiovascular activity. Psychological factors are reliable determinants of ABP, which may account in part for the unique predictive value of ABP.

Dynamic effects of self-efficacy on smoking lapse and relapse.

Self-efficacy (SE) is thought to be critical to success in smoking cessation both as an individual difference and as a dynamic process after a quit attempt. In this study, 214 smokers used palm-top computers to record day-to-day variations in SE during 4 weeks after quitting. SE remained at high and stable levels prior to a 1st lapse but decreased and became more variable thereafter. The authors used event history models with time-varying covariates to assess the effect of daily SE on lapse and relapse risk. Daily SE measures predicted an initial lapse on the subsequent day. However, this relationship was accounted for by stable baseline differences in SE (assessed by questionnaire), rather than by day-to-day dynamics in SE. Progression from 1st lapse to relapse was also examined. In this instance, daily SE predicted subsequent relapse risk, even when baseline SE and concurrent smoking were accounted for, suggesting the importance of SE dynamics for this stage of the relapse process.

Neurotoxicity of nonionic iodinated water-soluble contrast media in myelography: experimental study.

The neurotoxicity of four contrast media--iotrol, iopamidol, metrizamide, and ioglunide--was studied by subarachnoid injection in 14 rabbits implanted with four cerebral electrodes. Thirty-four recordings and quantitative analyses were carried out of spontaneous electrical brain activity, seizure activity, and visual- and somatosensory-evoked potentials. The quantitative study of the electroencephalograms showed differences among the four products. All four of the contrast media induced a general slowing of the electroencephalographic activity and, 30 min after injection, slow waves and a shift of the spectrum energy toward the slow frequencies (0.5-3.5 Hz). The slowing of the recording was the least marked with iotrol and recovery of a normal recording was also quickest with iotrol. The quantitative study of electrical seizures and paroxysms revealed higher seizure activity with ioglunide and iopamidol. The study of the evoked potentials does not permit any distinction among the four contrast agents. Metrizamide induced the fewest seizures, but, considering the slow waves and the seizures, iotrol appears to be the least neurotoxic.

Comparative efficacy of 24-hour and 16-hour transdermal nicotine patches for relief of morning craving.

AIMS: To compare a transdermal nicotine patch designed for 24-hour wear with one designed for 16-hour wear for relief of craving and withdrawal, particularly in the morning hours. DESIGN: Smokers were randomly assigned to use one of two common patch regimens: NicoDerm/NiQuitin (24-hour wear, 21 mg nicotine) or Nicotrol/Nicorette (16-hour wear, 15 mg). In a double-dummy design, participants wore two patches during the day, one active, one placebo and one patch while sleeping. SETTING: A smoking cessation research clinic. PARTICIPANTS: Two hundred and forty-four smokers who suffered morning cravings. INTERVENTION: Two patch formulations approved and marketed for over-the-counter use in the US--NicoDerm CQ (labeled as 21 mg over 24 hours) and Nicotrol (labeled as 15 mg over 16 hours)--were each used according to its instructions. Smokers also received behavioral counseling. MEASUREMENTS: For a week of baseline and 2 weeks after quitting, smokers used palm-top computers to assess craving and withdrawal symptoms several times each day. FINDINGS: The 21 mg/24-hour patch yielded consistently better control of craving, not only during the morning hours, but throughout the day, and over the 2-week period of abstinence. Additionally, the 21 mg/24-hour patch yielded greater reductions in anxiety, irritability and restlessness. Smokers using the 21 mg/24-hour dosing regimen also experienced longer abstinence than those using the 15 mg/16-hour patch. CONCLUSIONS: These findings demonstrate that 24-hour dosing with a 21 mg patch affords superior relief of craving and withdrawal during the first 2 weeks of abstinence, when symptoms are at their peak, and when relapse is most likely. They confirm the importance of dosing parameters in nicotine replacement products.

Progression from a smoking lapse to relapse: prediction from abstinence violation effects, nicotine dependence, and lapse characteristics.

Determinants of progression from an initial smoking lapse to relapse, using prospective data from 133 participants were examined. Participants used palm-top computers to record their first lapse, and their reaction to it, within minutes of the event, and were followed for 3 months to assess subsequent smoking. Indicators of the Abstinence Violation Effect--self-efficacy, attributions, and affective reactions to the lapse--generally failed to predict progression to relapse, but participants who felt like giving up after the first lapse progressed more rapidly to a second lapse. Participants who attempted restorative coping were less likely to progress to another lapse on the same day. Those whose lapses were triggered by stress progressed more quickly, whereas those triggered by eating and drinking or accompanied by alcohol consumption progressed more slowly. More nicotine-dependent participants progressed more rapidly toward relapse, but neither the amount smoked in the first lapse nor its subjective reinforcement predicted progression.

Remember that? A comparison of real-time versus retrospective recall of smoking lapses.

Research and treatment assessments often rely on retrospective recall of events. The accuracy of recall was tested using accounts of smoking lapse episodes from 127 participants who had quit smoking, and lapses and temptations were recorded in near-real time using a hand-held computer. These computer records were compared with retrospective accounts elicited 12 weeks later, with a focus on recall of lapses in 4 content domains: mood, activity, episode Triggers, and abstinence violation effects. Recall of lapses was quite poor: Average kappas for items ranged from 0.18 to 0.27. Mean profile rs assessing recall for the overall pattern of behavior were .36, .30, .33, and .44 for these domains, respectively. In recall, participants overestimated their negative affect and the number of cigarettes they had smoked during the lapse, and their recall was influenced by current smoking status. The findings suggest caution in the use of recall in research and intervention.

First lapses to smoking: within-subjects analysis of real-time reports.

Studies of smoking relapse and temptation episodes have relied on retrospective recall and confounded between- and within-subject variability. Real-time data on temptations and lapses to smoke were gathered using palm-top computers. We made within-subject comparisons of the initial lapse, a temptation episode, and base rate data obtained through randomly scheduled assessments. Negative affect discriminated all three situations, with lapses worse than temptations, and temptations worse than random situations. Participants attributed lapses to negative mood and smoking cues, whereas temptations were more often attributed to behavioral transitions. Participants were 12 times more likely to report coping in temptations than in lapses. However, only cognitive (vs. behavioral) coping strategies were effective. Lapses (vs. the other situations) were more likely to occur when smoking was permitted, when cigarettes were easily available, and in the presence of other smokers. The results have clinical implications, and the computerized monitoring methods may be applicable to an array of clinical research problems.

Does smoking abstinence self-efficacy vary across situations? Identifying context-specificity within the Relapse Situation Efficacy Questionnaire.

According to self-efficacy and relapse theories. abstinence self-efficacy (ASE) ratings should be context-specific: they should vary across situations. This variability may be important, as it could signal high-risk for relapse situations. In this study, confirmatory factor analysis was used to identify situational variability in a novel ASE assessment (Relapse Situation Efficacy Questionnaire. or RSEQ). Results supported a hierarchical structure, where both context-specific and unidimensional measures of ASE exist within the assessment. Context-specific factors included Negative Affect, Positive Affect, Restrictive Situations (to smoking). Idle Time, Social-Food Situations, Low Arousal, and Craving. Multiple context-specific factors and the aggregate factor predicted cessation outcome, even after controlling for concurrent smoking rate. However, the context rated with the least confidence proved to be the best outcome predictor, suggesting the existence of "Achilles' heel" situations. These data indicate the internal and predictive validity of the RSEQ.

A day at a time: predicting smoking lapse from daily urge.

Smokers who recently quit (N = 214) monitored smoking urges for up to 26 days after quitting. Computers administered 4-5 assessments daily at random times; participants rated urges on waking and when they experienced temptation episodes. Urge intensity after cessation did not generally exceed urges reported during baseline ad lib smoking. Urge intensity and temptation frequency consistently declined over the quit period. Controlling for urge intensity at baseline, all daily urge intensity measures predicted lapse the following day in proportional hazards survival analyses. Average duration of temptation episodes also predicted lapses; frequency of temptation did not. To isolate the effect of day-to-day variations in urges, participants' nicotine dependence and urge intensity on quit day were controlled for. Only urge intensity at waking still predicted lapse risk; this was not because of this measured being closer in time to the day's lapses. Among lapsers, urge intensity at waking and in temptations rose preceding a lapse.

The efficacy of computer-tailored smoking cessation material as a supplement to nicotine patch therapy.

The study evaluated the efficacy of the Committed Quitters Program (CQP), a computer-tailored set of printed behavioral support materials offered free to purchasers of NicoDerm CQ patches, as a supplement to the nicotine patch and the standard brief User's Guide (UG) and audiotape. Callers to the CQP enrollment were randomized to either CQP (n=1854) or just the UG (n=1829). Abstinence and use of program materials were assessed by telephone interview at 6 and 12 weeks (the latter falling 2 weeks after patch use was to be discontinued). Considering all respondents, abstinence rates did not differ significantly between the UG and CQP groups. As expected, among those who reported they used their assigned materials (80.1% of the sample) smokers who received CQP demonstrated higher quit rates at both 6 weeks (38.8% v. 30.7%) and 12 weeks (18.2% v. 11.1%), compared to the UG group. Among those who used it, the Committed Quitters Program proved to be an effective behavioral treatment, improving quit rates over nicotine replacement therapy and a brief untailored written guide and audiotape.

Individual differences in intraperson variability in mood.

The experience sampling method and palm-top computers were used to obtain 75-100 randomly timed in situ assessments of 11 mood-related items from 54 Ss over 12-14 days. The variability in the distribution of an S's responses to each item was used as an estimate of intrasubject mood variability. Mood variability was stable across time (average r > .58) and across situations (average r = .51). The intercorrelations among the individual item variabilities were also substantial (average r = .41); when the items were combined into a mood variability scale, the coefficient alpha was .84. The stability and internal consistency of mood variability could not be reasonably attributed to similarity in item valences, differences among the Ss in the situations they encountered, response biases, or response errors. It was concluded that mood variability is a stable personal characteristic, but additional analyses suggested that it may be independent from other kinds of intraperson variability.