Robert J. Wellman

Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A Retrospective Cohort Study

Background Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM. Methods We conducted a population-based, retrospective cohort study of 12 500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities. Results Among 12 500 women (mean age = 60 years, range = 22–99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35). Conclusions Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety.

Tobacco Promotion and the Initiation of Tobacco Use: Assessing the Evidence for Causality

OBJECTIVE. We sought to determine whether there is evidence of a causal link between exposure to tobacco promotion and the initiation of tobacco use by children. METHODS. We conducted a structured search in Medline, PsycINFO, and ABI/INFORM Global to identify relevant empirical research. The literature was examined against the Hill epidemiologic criteria for determining causality. RESULTS. (1) Children are exposed to tobacco promotion before the initiation of tobacco use; (2) exposure increases the risk for initiation; (3) there is a dose-response relationship, with greater exposure resulting in higher risk; (4) the increased risk is robust; it is observed with various study methods, in multiple populations, and with various forms of promotion and persists after controlling for other factors; (5) scientifically plausible mechanisms whereby promotion could influence initiation exist; and (6) no explanation other than causality can account for the evidence. CONCLUSIONS. Promotions foster positive attitudes, beliefs, and expectations regarding tobacco use. This fosters intentions to use and increases the likelihood of initiation. Greater exposure to promotion leads to higher risk. This is seen in diverse cultures and persists when other risk factors, such as socioeconomic status or parental and peer smoking, are controlled. Causality is the only plausible scientific explanation for the observed data. The evidence satisfies the Hill criteria, indicating that exposure to tobacco promotion causes children to initiate tobacco use.

A Sensitization—Homeostasis Model of Nicotine Craving, Withdrawal, and Tolerance: Integrating the Clinical and Basic Science Literature

Recent reports suggest that nicotine withdrawal symptoms are common among adolescents after a few weeks of intermittent tobacco use. No current model of nicotine dependence had predicted the rapid development of symptoms of dependence and withdrawal before the development of tolerance. We present a model that integrates neuroscience with clinical observations regarding how nicotine dependence develops, progresses, and resolves in humans. The central tenet of this sensitization-homeostasis model is that nicotines dependence liability derives from its ability to stimulate neural pathways responsible for the suppression of craving. As a result of sensitization, the craving suppression produced by nicotine is magnified to superphysiological levels. The overinhibition of neurons responsible for craving initiates compensatory homeostatic measures that stimulate the craving pathways and result in craving when nicotine is absent. Separate homeostatic mechanisms are responsible for craving, withdrawal, and tolerance. The sensitization-homeostasis model is unique in its attribution of dependence to craving suppression, its attention to the temporal relationships among clinical features of nicotine dependence, and its extensive integration of clinical observations and basic science. It provides a framework for theory-based research.

Susceptibility to Nicotine Dependence: The Development and Assessment of Nicotine Dependence in Youth 2 Study

OBJECTIVES. The purpose of this work was to identify characteristics that predict progression from the first inhalation of a cigarette to dependence. We studied a cohort of 1246 public school 6th-graders in 6 Massachusetts communities (mean age at baseline: 12.2 years). METHODS. We conducted a 4-year prospective study using 11 interviews. We assessed 45 risk factors and measured diminished autonomy over tobacco with the Hooked on Nicotine Checklist and evaluated tobacco dependence according to the International Classification of Diseases, 10th Revision. Cox proportional-hazards models were used. RESULTS. Among 217 youths who had inhaled from a cigarette, the loss of autonomy over tobacco was predicted by feeling relaxed the first time inhaling from a cigarette and depressed mood. Tobacco dependence was predicted by feeling relaxed, familiarity with Joe Camel, novelty seeking, and depressed mood. CONCLUSIONS. Once exposure to nicotine had occurred, remarkably few risk factors for smoking consistently contributed to individual differences in susceptibility to the development of dependence or loss of autonomy. An experience of relaxation in response to the first dose of nicotine was the strongest predictor of both dependence and lost autonomy. This association was not explained by trait anxiety or any of the other measured psychosocial factors. These results are discussed in relation to the theory that the process of dependence is initiated by the first dose of nicotine.

Diminished autonomy over tobacco can appear with the first cigarettes

Individuals have lost full autonomy over their smoking when quitting becomes unpleasant or difficult. We examined autonomy in relation to smoking frequency and lifetime cigarette use. A self-administered questionnaire was completed by three convenience samples of Year 10 students (ages 14-15) in New Zealand between 2002 and 2004 (n=96,156). The Hooked On Nicotine Checklist was used to measure diminished autonomy. Diminished autonomy was reported by 46% of subjects who smoked less often than monthly and by 25%-30% of current smokers who had smoked only one cigarette in total. The prevalence of diminished autonomy increased with increasing frequency of current use and with increasing lifetime use. Symptoms developed earlier among girls than boys. The data confirm previous reports that diminished autonomy appears soon after the onset of intermittent tobacco use and extends this literature by providing the first description of how diminished autonomy develops in relation to the total number of cigarettes smoked. These data suggest that smoking one cigarette in total can prompt a loss of autonomy.

A Comparison of the Effects of 2 Types of Massage and Usual Care on Chronic Low Back Pain: A Randomized, Controlled Trial

BACKGROUND Few studies have evaluated the effectiveness of massage for chronic low back pain. OBJECTIVE To compare the effectiveness of 2 types of massage and usual care for chronic back pain. DESIGN Parallel-group randomized, controlled trial. Randomization was computer-generated, with centralized allocation concealment. Participants were blinded to massage type but not to assignment to massage versus usual care. Massage therapists were unblinded. The study personnel who assessed outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00371384) SETTING An integrated health care delivery system in the Seattle area. PATIENTS 401 persons 20 to 65 years of age with nonspecific chronic low back pain. INTERVENTION Structural massage (n = 132), relaxation massage (n = 136), or usual care (n = 133). MEASUREMENTS Roland Disability Questionnaire (RDQ) and symptom bothersomeness scores at 10 weeks (primary outcome) and at 26 and 52 weeks (secondary outcomes). Mean group differences of at least 2 points on the RDQ and at least 1.5 points on the symptom bothersomeness scale were considered clinically meaningful. RESULTS The massage groups had similar functional outcomes at 10 weeks. The adjusted mean RDQ score was 2.9 points (95% CI, 1.8 to 4.0 points) lower in the relaxation group and 2.5 points (CI, 1.4 to 3.5 points) lower in the structural massage group than in the usual care group, and adjusted mean symptom bothersomeness scores were 1.7 points (CI, 1.2 to 2.2 points) lower with relaxation massage and 1.4 points (CI, 0.8 to 1.9 points) lower with structural massage. The beneficial effects of relaxation massage on function (but not on symptom reduction) persisted at 52 weeks but were small. LIMITATION Participants were not blinded to treatment. CONCLUSION Massage therapy may be effective for treatment of chronic back pain, with benefits lasting at least 6 months. No clinically meaningful difference between relaxation and structural massage was observed in terms of relieving disability or symptoms. PRIMARY FUNDING SOURCE National Center for Complementary and Alternative Medicine.

Short term patterns of early smoking acquisition

Objective: To describe short term patterns of smoking acquisition exhibited by adolescent smokers. Design: Interview records from the prospective development and assessment of nicotine dependence in youth study were examined retrospectively. Interviews were conducted three times per year over 30 months. Subjects: 164 students in grades 7–9 (ages 12–15 years, 86 girls, 78 boys) who had used cigarettes at least twice. Main outcome measures: A continuous timeline of smoking activity, beginning with the subject’s first use of tobacco and continuing through follow up, was translated into six patterns—abstinent, sporadic, occasional, daily, escalating, and intermittent. Outcome measures were the proportion of subjects starting/ending in each pattern, and the number of transitions per subject between patterns. Results: There was a general but discontinuous progression from infrequent to more frequent use, with many interspersed periods of not smoking. Escalation to daily smoking was common after the development of dependence symptoms, but was rare among those who did not have symptoms. After the appearance of symptoms, both transitions to heavier daily smoking and attempts at cessation increased. Conclusions: Movement to heavier, more frequent smoking is generally unidirectional, although many youths attempt to quit one or more times. The appearance of any symptom of dependence altered the subsequent pattern of smoking behaviour. Future investigators might consider using more frequent data points and a continuous timeline to track smoking behaviour.

Sensitization to nicotine : How the animal literature might inform future human research

Despite a rich neuroscience literature on sensitization, this phenomenon has been neglected in clinical nicotine research. This paper offers a primer on the neuroscience of nicotine sensitization for behavioral scientists, identifying key concepts, potential theoretical and clinical implications, and directions for future research. Sensitization to a drug occurs when repeated exposures to the same dose produce greater responses. In animals, sensitization to nicotine, morphine, alcohol, cocaine, amphetamine, and methamphetamine manifests as increased locomotor activity. In animals, sensitization to nicotine begins with the first dose and is maximal within 5-7 days. It involves multiple neurotransmitters, receptors, and brain structures and cannot be attributed to any single alteration. The processes involved in its induction and expression are not identical. The neurologic changes associated with sensitization are not consistent across drugs, suggesting that sensitization is not an accident of neurophysiology but perhaps an exaggerated adaptive response. Sensitization is incorporated into two theories of addiction: incentive-sensitization and sensitization-homeostasis. Whether sensitization occurs in humans and how it is expressed is unclear, as is its role in human addiction.

Measuring adults' loss of autonomy over nicotine use: the Hooked on Nicotine Checklist

The Hooked on Nicotine Checklist (HONC) is a 10-item screening tool originally developed to assess loss of autonomy over tobacco in adolescent smokers. A smokers endorsement of any item indicates some loss of autonomy, and the sum of endorsed items indicates the degree to which autonomy has been lost. This study extends the HONC to adult smokers. Self-administered questionnaires were completed by a convenience sample of 1,102 adults who were recruited in their natural environments while observed smoking. Subjects were mostly experienced smokers who consumed a mean of 17.5 cigarettes per day and had smoked an average of 20.9 years. HONC scores ranged from 0 to 10, with a mean of 7.1. The HONC appears to measure a single dimension. Internal HONC consistency was high (alpha = .83), and interitem correlations were low to moderate. HONC scores correlated positively with levels of current and peak lifetime cigarette consumption. The HONC scores of heavy, moderate, and light smokers differed significantly in the expected direction. Subjects with higher HONC scores were more likely to report a shorter duration of abstinence and greater use of pharmacological aids when quitting. The HONC appears to be psychometrically sound in both adolescents and adults. It is a reliable and valid measure of lost autonomy for both novice and experienced smokers, and it allows for comparisons between these populations.

The Autonomy Over Smoking Scale

Our goal was to create an instrument that can be used to study how smokers lose autonomy over smoking and regain it after quitting. The Autonomy Over Smoking Scale was produced through a process involving item generation, focus-group evaluation, testing in adults to winnow items, field testing with adults and adolescents, and head-to-head comparisons with other measures. The final 12-item scale shows excellent reliability (alphas = .91-.97), with a one-factor solution explaining 59% of the variance in adults and 61%-74% of the variance in adolescents. Concurrent validity was supported by associations with age of smoking initiation, lifetime use, smoking frequency, daily cigarette consumption, history of failed cessation, Hooked on Nicotine Checklist scores, and Diagnostic and Statistical Manual of Mental Disorder (4th ed., text rev.; American Psychiatric Association, 2000) nicotine dependence criteria. Potentially useful features of this new instrument include (a) it assesses tobacco withdrawal, cue-induced craving, and psychological dependence on cigarettes; (b) it measures symptom intensity; and (c) it asks about current symptoms only, so it could be administered to quitting smokers to track the resolution of symptoms.