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Biomedical subjects

William R Miller

Publications and source records attributed to William R Miller.

At least 19 recordsLinked to original sources
PubMed2006

Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole.

PURPOSE: To investigate the impact of human epidermal growth factor receptor (HER) 1 and HER2 gene amplification on endocrine therapy responsiveness, a fluorescence in situ hybridization (FISH) study was conducted on tumor samples from 305 postmenopausal patients with stage II and III estrogen receptor (ER) -positive (ER > or = 10%) breast cancers treated on two independent neoadjuvant endocrine therapy trials. PATIENTS AND METHODS: FISH analysis focused on HER1 and/or HER2 immunohistochemistry (IHC) -positive patients and a random selection of HER1/2 IHC-negative patients. HER2 FISH status was correlated with response and changes in the proliferation marker Ki67. RESULTS: HER1 was rarely amplified (< 1%), and HER2 amplification was observed in 9.2% of patients. Letrozole response by clinical measurement (71% HER2 FISH positive v 71% HER2 FISH negative), mammogram (44% HER2 FISH positive v 47% HER2 FISH negative), or ultrasound (47% HER2 FISH positive v 54% HER2 FISH negative) was not impaired by HER2 FISH-positive status. In contrast, HER2 FISH-positive tumors showed higher histologic grade (P = .009), higher pretreatment Ki67 (P = .005), and less Ki67 suppression after letrozole when compared with HER2 FISH-negative tumors (P = .0001). Similar observations regarding Ki67 were made in a smaller cohort of tamoxifen-treated tumors. CONCLUSION: Neoadjuvant letrozole is clinically effective in ER-positive HER2 FISH-positive tumors, indicating sensitivity to short-term estrogen deprivation. However, continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER-positive HER2 FISH-positive samples (88%) could imply therapeutic resistance that may manifest later in the clinical course of the disease. Discordance between clinical and biomarker findings in this study serves to emphasize the need for surrogate end point validation in neoadjuvant endocrine trials through correlation with information on long-term outcomes.

Aged↗
PubMed2006

Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial.

CONTEXT: Alcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings. OBJECTIVES: To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence. INTERVENTIONS: Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment. MAIN OUTCOME MEASURES: Percent days abstinent from alcohol and time to first heavy drinking day. RESULTS: All groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone x behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant. CONCLUSIONS: Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00006206.

Acamprosate↗
PubMed2006

Is alcoholism typology a predictor of both Alcoholics Anonymous affiliation and disaffiliation after treatment?

Twelve Steps (TS) has demonstrated effectiveness; induction into Alcoholics Anonymous (AA) is a primary objective of TS and is a pivotal mechanism explaining its effectiveness. However, evidence suggests that, after treatment, dropout from AA is high. This study investigated whether alcohol problem severity predicted both AA affiliation and disaffiliation among clients receiving TS. This study of a Project MATCH sample included 453 alcohol-dependent clients randomly assigned to TS who reported AA attendance during treatment. Greater alcohol problem severity predicted AA attendance; opposite to prediction, less alcohol-impaired clients were more than twice as likely to discontinue AA attendance after treatment. When sustained AA attendance is desired, the evaluation of client pretreatment alcohol involvement may be useful for identifying potential AA dropout after TS treatment. Findings also indicate that, among treatment-seeking problem drinkers, AA dropout and disaffiliation are distinct, albeit correlated, constructs that require future investigation.

Adaptation, Psychological↗
PubMed2006

Disseminating evidence-based practices in substance abuse treatment: a review with suggestions.

Although substance abuse professionals are generally open to new and better therapeutic methods, most evidence-based treatments do not easily find their way into practice. Natural diffusion processes for innovations in substance abuse treatments are relatively informal and have yielded a widely acknowledged gap between science and community practice. This review focuses on methods for effectively disseminating new treatment methods into practice. Therapist manuals and one-time workshops are in themselves relatively ineffective in helping practitioners gain proficiency in new clinical approaches. Individual performance feedback and coaching improve the acquisition of clinical skills. Specific incentives for implementation may also be needed to encourage treatment providers, programs, and systems to adopt new approaches.

Behavior Therapy↗
PubMed2006

Trauma center brief interventions for alcohol disorders decrease subsequent driving under the influence arrests.

BACKGROUND: A substantial number of trauma center admissions are related to driving under the influence (DUI); however, there has been no prior report of brief intervention (BI) after injury reducing subsequent DUI arrests. The hypothesis of this study was that injured patients receiving BI would have a lower risk of DUI arrest within 3 years of discharge than those receiving standard care (SC). METHODS: This prospective, randomized clinical trial randomly allocated patients involved in motor vehicle collisions to receive SC or a BI regarding alcohol use. The primary outcome measure was DUI arrest within 3 years of hospital discharge. DUI arrests were documented by matching demographic information to state traffic safety data. RESULTS: After randomization (N = 126), BI and SC groups were similar in age, prior DUI arrests, and alcohol screening score. BI sessions lasted an average of 30 minutes and were performed by either a social worker or a trauma surgeon. Approximately one in six participants (n = 21, 16.7%) had a DUI arrest within 3 years of hospital discharge. Within 3 years of hospital discharge, 14 of 64 patients (21.9%) in the SC group had an arrest for DUI compared with only 7 of 62 patients (11.3%) who received the BI. Multivariate analysis demonstrated that BI was the strongest protective factor against DUI arrest (odds ratio [OR], 0.32; 95% confidence interval < or =CI], 0.11-0.96). Prior number of DUIs (OR, 1.43; 95% CI, 1.03-2.01) and age (OR, 0.94; 95% CI, 0.88-0.99) were also associated with DUI arrest post-hospitalization, but alcohol screening score (OR, 1.06; 95% CI, 0.99-1.13) was not. The absolute risk reduction implies that only nine patients would need to receive a BI to prevent one DUI arrest. CONCLUSION: Patients who receive BI during a trauma center admission are less likely to be arrested for DUI within 3 years of discharge. BI represents a viable intervention to reduce DUI after trauma center admission.

Accidents, Traffic↗
PubMed2006

Addressing substance abuse in health care settings.

This article summarizes the proceedings of a roundtable discussion at the 2005 annual meeting of the Research Society on Alcoholism in Santa Barbara, California. The chair was William R. Miller. The presentations were as follows: (1) Screening and Brief Intervention for Alcohol Problems, by Allen Zweben; (2) Three Intervention Models and Their Impact on Medical Records, by Denise Ernst; (3) Pharmacotherapies for Managing Alcohol Dependence in Health Care Settings, by Roger D. Weiss; (4) The Trauma Center as an Opportunity, by Carol R. Schermer; (5) Motivational Interviewing by Telephone and Telemedicine, by Catherine Baca; (6) Health Care as a Context for Treating Drug Abuse and Dependence, by Wilson M. Compton; and (7) Interventions for Heavy Drinking in Health Care settings: Barriers and Strategies, by Mark L. Willenbring.

Alcohol Deterrents↗
PubMed2006

Neoadjuvant endocrine therapy models.

Neoadjuvant therapy is therapy administered before surgical intervention and while the tumor remains in the breast. It may be given to treat large, locally advanced tumors, with the aim of shrinking them and thus making their surgical excision either simply possible or less radical. Most neoadjuvant therapy is chemotherapy, but adjuvant endocrine therapy is increasingly used in hormone-sensitive tumors; for example, those responsive to tamoxifen. Repeat biopsies aimed at assessing response to treatment--for example, by examining estrogen receptor status or markers of proliferation in tumor tissue--may be taken during the course of adjuvant therapy. In this chapter, the essential protocols associated with designing neoadjuvant trials are described, methods of assessing response to neoadjuvant therapy are detailed, and various approaches to collecting appropriate clinical samples and their assessment are presented.

Biopsy↗
PubMed2006

Examining the effects of alcoholism typology and AA attendance on self-efficacy as a mechanism of change.

OBJECTIVE: Existing research indicates that increased self-efficacy to sustain abstinence is a strong causal mechanism explaining later reduction of drinking. Little is known about how mechanisms of change may differ among distinct subgroups of alcoholics. The purpose of this study was to evaluate the mediational role of self-efficacy on changes in drinking associated with Alcoholics Anonymous (AA) attendance in Type-A and Type-B alcoholics. METHOD: Analysis of covariance and structural equation modeling were used to model 6-, 9-, 12-, and 15-month data from Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) participants who were classified as Type-A or Type-B alcoholics (N=1,284; 72% male). Measures of AA attendance and percent days abstinent were taken from the Form 90. Self- efficacy was assessed with the Alcohol Abstinence Self-Efficacy Scale. RESULTS: Alcoholism typology and AA attendance were independent predictors of later self-efficacy, but there was no interaction between typology and AA attendance. Abstinence self-efficacy mediated a modest proportion of the effect of posttreatment AA attendance on later abstinence in both Type-A and Type-B alcoholics. The strength of this mediation did not differ by typology. CONCLUSIONS: Self-efficacy for abstinence has a strong direct relationship to abstinence across treatment conditions and typologies. Increases in self-efficacy mediate some of the beneficial effects of AA for Type-A and Type-B alcoholics. Further work is necessary to determine whether self-efficacy plays a different role in the recovery of Type-A versus Type-B alcoholics.

Adult↗
PubMed2005

Translation elongation factor eEF1A2 is a potential oncoprotein that is overexpressed in two-thirds of breast tumours.

BACKGROUND: The tissue-specific translation elongation factor eEF1A2 was recently shown to be a potential oncogene that is overexpressed in ovarian cancer. Although there is no direct evidence for an involvement of eEF1A2 in breast cancer, the genomic region to which EEF1A2 maps, 20q13, is frequently amplified in breast tumours. We therefore sought to establish whether eEF1A2 expression might be upregulated in breast cancer. METHODS: eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-alpha) making analysis with commercial antibodies difficult. We have developed specific anti-eEF1A2 antibodies and used them in immunohistochemical analyses of tumour samples. We report the novel finding that although eEF1A2 is barely detectable in normal breast it is moderately to strongly expressed in two-thirds of breast tumours. This overexpression is strongly associated with estrogen receptor positivity. CONCLUSION: eEF1A2 should be considered as a putative oncogene in breast cancer that may be a useful diagnostic marker and therapeutic target for a high proportion of breast tumours. The oncogenicity of eEF1A2 may be related to its role in protein synthesis or to its potential non-canonical functions in cytoskeletal remodelling or apoptosis.

Apoptosis↗
PubMed2005

Assessing competence in the use of motivational interviewing.

This report presents reliability, validity and sensitivity indices for the Motivational Interviewing Treatment Integrity (MITI) scale. Factor analysis of MI treatment sessions coded with the Motivational Interviewing Skills Code (MISC) was used to derive 10 elements of MI practice, forming the MITI. Canonical correlation revealed that the MITI captured 59% of the variability in the MISC. Reliability estimates for the MITI were derived using three masked, independent coders. Intra-class coefficients ranged from .5 to .9 and were generally in the good to excellent range. Comparison of MITI scores before and after MI workshops indicate good sensitivity for detecting improvement in clinical practice as result of training. Implications for the use of this instrument in research and supervision are discussed.

Clinical Competence↗
PubMed2005

Evidence-based treatment: why, what, where, when, and how?

Research and clinical perspectives are blended in this commentary on the rapidly emerging requirement for evidence-based treatment (EBT) in substance abuse programs. Although, historically, it has not been a standard of care in behavioral health, there are sound scientific, ethical, and compassionate reasons to learn and deliver an EBT as it becomes available. This article explores a series of issues, including the following: (1) Why should EBTs be used in substance abuse treatment? (2) What kinds of treatment are EBTs, and how are they determined? (3) Where can EBTs be implemented--at what levels of service delivery? (4) When should EBTs be used? and (5) How do clinicians learn EBTs? Potential pitfalls in implementing EBTs are also considered.

Evidence-Based Medicine↗
PubMed2005

Aromatase inhibitors: cellular and molecular effects.

Marked cellular and molecular changes may occur in breast cancers following treatment of postmenopausal breast cancer patients with aromatase inhibitors. Neoadjuvant protocols, in which treatment is given with the primary tumour still within the breast, are particularly illuminating. In Edinburgh, we have shown that 3 months treatment with either anastrozole, exemestane or letrozole produces pathological responses in the majority of oestrogen receptor (ER)-rich tumours (39/59) as manifested by reduced cellularity/increased fibrosis. Changes in histological grading may also take place, most notably a reduction in mitotic figures. This probably reflects an influence on proliferation as most tumours (82%) show a marked decrease in the proliferation marker, Ki67. These effects are generally more dramatic than seen with tamoxifen given in the same setting. Differences between aromatase inhibitors and tamoxifen are also apparent in changes in steroid hormone expression. Thus, immuno-staining for progesterone receptor (PgR) is reduced in almost all cases by aromatase inhibitors, becoming undetectable in many. This contrasts with effects of tamoxifen in which the most common change on PgR is to increase expression. Changes in proliferation occur rapidly following the onset of exposure to aromatase inhibitors. Thus, neoadjuvant studies with letrozole in which tumour was sampled before and after 14 days and 3 months treatment show that decreased expression of Ki67 occur at 14 days and, in many cases, the effect is greater at 14 days than 3 months. These early changes precede evidence of clinical response but do not predict for it. However, this study design has allowed RNA analysis of sequential biopsies taken during the neoadjuvant therapy. Based on clustering techniques, it has been possible to subdivide tumours into groups showing distinct patterns of molecular changes. These changes in tumour gene expression may allow definition of tumour cohorts with differing sensitivity to aromatase inhibitors and permit early recognition of response and resistance.

Anastrozole↗
PubMed2005

Surgical issues surrounding use of aromatase inhibitors.

There are important surgical issues related to the use of the third generation aromatase inhibitors in both the neoadjuvant and adjuvant settings. Neoadjuvant hormone therapy is effective at downstaging tumours, particularly large tumours initially thought to be inoperable or requiring mastectomy. Randomised trials have shown that the newer aromatase inhibitors letrozole and anastrozole increase the numbers of women who are suitable for breast-conservation compared with tamoxifen, and that letrozole is superior to tamoxifen in terms of clinical response. Aromatase inhibitors are most effective in ER-rich tumours and are clinically and biologically effective in both HER2 positive and negative tumours, whereas HER2 positive tumours show a level of resistance to tamoxifen. In neoadjuvant studies comparing aromatase inhibitors with tamoxifen, the duration of use has been 3-4 months, by which time any response is usually evident but longer treatment periods produce continued shrinkage and response. The re-excision rate following breast conservation surgery after neoadjuvant hormone therapy is favourable compared with the rates following immediate wide local excision. Local recurrence rates are acceptable in patients undergoing neoadjuvant therapy and breast-conserving surgery providing post-operative radiotherapy is given. Adjuvant aromatase inhibitors, as well as having an effect on metastatic disease and survival, reduce local and regional recurrence.

Antineoplastic Agents, Hormonal↗
PubMed2005

How does motivational interviewing work? Therapist interpersonal skill predicts client involvement within motivational interviewing sessions.

Although many studies have shown that motivational interviewing (MI) is effective in reducing problem behaviors, few have investigated purported causal mechanisms. Therapist interpersonal skills have been proposed as an influence on client involvement during MI sessions and as a necessary precursor to client commitment language. Using the Motivational Interviewing Skills Code (MISC; Version 1.0) rating system, the authors investigated 103 unique MI sessions for substance abuse and found that therapist interpersonal skills were positively associated with client involvement as defined by cooperation, disclosure and expression of affect. An unexpected finding indicated that behaviors inconsistent with MI enhanced the impact of therapist interpersonal skills upon client involvement. Drawbacks to the study include a potential sampling bias and uneven reliability of the variables measured.

Clinical Competence↗
PubMed2005

When worlds collide: blending the divergent traditions of pharmacotherapy and-psychotherapy outcome research.

OBJECTIVE: The multisite COMBINE Study brought together a team of alcoholism investigators who varied in whether their expertise was primarily in pharmacotherapy research or in studying psychotherapy. The process of designing a single trial that tested combinations of psychotherapy and pharmacotherapy highlighted the differences in these two research traditions and necessitated a number of compromises that are the focus of this article. METHOD: The COMBINE trial was designed to investigate the efficacy, separately and in combination, of two medications (i.e., naltrexone, acamprosate) with Medical Management and a state-of-the-art psychotherapy, known as the Combined Behavioral Intervention. RESULTS: Pharmacotherapy researchers favored studying outcome during the treatment period when medications were administered, viewing behavioral intervention as a means for minimizing variance during treatment and providing ethical care in placebo-controlled studies. In contrast, psychotherapy researchers focused on assessment of outcomes after treatment, regarding the behavioral intervention as a source of long-lasting change, necessitating careful training and monitoring of its implementation. The two traditions also differed on variables of interest in studying treatment process and secondary outcomes and methods of data collection and analysis. Some of the solutions reached by the COMBINE Study Research Group included studying both the short-term and long-term effects of treatment and selective inclusion of measures designed to evaluate processes specific to medications and to behavioral interventions. CONCLUSIONS: The successful compromises reached by the COMBINE Study Research Group may be helpful to other transdisciplinary research teams undertaking a combined evaluation of promising medications and behavioral interventions for alcoholism.

Alcoholism↗