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Biomedical subjects

William R Miller

Publications and source records attributed to William R Miller.

At least 37 records · Page 2Linked to original sources
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↗
PubMed2005

A structured approach to medical management: a psychosocial intervention to support pharmacotherapy in the treatment of alcohol dependence.

OBJECTIVE: Given the national trend toward integrating substance abuse treatment into medical practice, experts in the field of alcoholism designed a psychosocial, medically based intervention to be used with pharmacotherapy in the COMBINE multisite national study, supported by the National Institute on Alcohol Abuse and Alcoholism. A main purpose of the COMBINE Study is to investigate optimal treatment for patients with alcohol dependence by combining pharmacotherapy and psychosocial interventions. METHOD: The medically based intervention, called Medical Management (MM), was specifically constructed to be implemented by medically trained practitioners in nonspecialty settings. Each visit includes evaluations of medication safety and adherence, monitoring of alcohol use and direct advice to the patient for achieving full recovery. RESULTS: There are several themes implicit in MM. Patient education about the disorder and about the treatment being provided are both essential. The clinician also educates the patient about how he or she has been affected by alcohol dependence. Information is given on how to take the medication(s) as prescribed, what the patient should expect from the medication(s) and what kinds of events the clinician will need to know about during treatment. Finally, the clinician and patient discuss strategies for ensuring medication safety and adherence to the prescribed regimen. CONCLUSIONS: MM was easily implemented in the COMBINE Study with the aid of the MM Treatment Manual.

Alcoholism↗
PubMed2005

Origins, issues and options in the development of the combined behavioral intervention.

OBJECTIVE: The aim of the investigators was to develop a moderate intensity comprehensive behavioral treatment based on the principles of motivational interviewing and Cognitive Behavioral Therapy that, within the confines of a standardized abstinence-oriented treatment, would provide a broad spectrum of modules to assist those seeking treatment to achieve reduction of problematic drinking. METHOD: The core issue of how to deliver a flexible therapy tailored to the needs of individual clients while at the same time providing a standardized treatment protocol for a randomized clinical trial provided the dilemma out of which this unique standardized protocol arose. By using a single decision tree, client choice, combined with limited options, we were able to reconcile these conflicting demands. RESULTS: Key decisions that were made in developing the treatment protocol and the thinking leading to these decisions are described. CONCLUSIONS: Understanding these key issues and the factors that led to the decisions made will assist would-be users in their own clinical and/or clinical research needs.

Alcoholism↗
PubMed2005

Training, supervision and quality monitoring of the COMBINE Study behavioral interventions.

OBJECTIVE: Current standards for clinical trials require that behavioral interventions be thoroughly specified, that clinicians be well trained and closely supervised and that performance be carefully monitored to ensure and document treatment fidelity. This article describes procedures developed and implemented for this purpose in the COMBINE Study, a multisite trial combining medications and behavioral interventions for alcohol dependence. METHOD: Two behavioral treatments were tested in COMBINE: a Medical Management (MM) protocol to accompany the delivery of trial medications and a Combined Behavioral Intervention (CBI) designed as a comprehensive and flexible evidence-based psychotherapy. RESULTS: Information is provided concerning (1) screening and qualifications of practitioners, (2) training and certification in the interventions, (3) on-site supervision and coordination of the two treatments, (4) central monitoring and coding of treatment sessions and (5) maintenance and documentation of treatment fidelity. CONCLUSIONS: Both interventions were delivered with fidelity. Problems encountered and important choices made in the implementation of training and quality assurance for CBI and MM are briefly described.

Alcoholism↗
PubMed2005

Use of a "psychotherapy with no pills" treatment condition as part of a combined pharmacotherapy-psychotherapy research study of alcohol dependence.

OBJECTIVE: The purpose of this article is to review issues related to the use of placebo medication in a study examining combined pharmacotherapy and psychotherapy for alcohol dependence. METHOD: Little is known about the strength of the placebo effect in alcohol-dependent patients. One way to study this is to compare placebo to no pharmacological treatment. The multisite National Institute on Alcohol Abuse and Alcoholism COMBINE Study is examining optimal combinations of two medications (acamprosate and naltrexone) and two behavioral treatments (a moderate-intensity treatment called Combined Behavioral Intervention [CBI] and a low-intensity treatment called Medical Management [MM]) for alcohol-dependent patients. The study initially included a 2 x 2 x 2 eight-cell design. This article relates our experience adding a ninth treatment condition (Cell 9), consisting of CBI alone, with no pills or MM. By comparing patients receiving CBI alone to patients receiving two placebos, MM and CBI, we can examine the strength of the placebo effect for these two medications in alcohol-dependent patients. Moreover, we can study CBI in the context in which it is frequently delivered clinically, that is, in the absence of pharmacotherapy and certainly in the absence of placebo medication. RESULTS: This article explains the background and rationale behind the decision to include Cell 9 in COMBINE. Recruitment challenges faced as a result of adding this condition are reviewed, as is the experience implementing this condition in a pilot feasibility study. CONCLUSIONS: The use of a "psychotherapy with no pills" treatment condition as part of a combined pharmacotherapy-psychotherapy study of alcohol dependence is feasible and can help enrich the results of this research.

Alcoholism↗
PubMed2004

Aromatase 2004, Edinburgh, UK, 6-8 September 2004.

Aromatase is the key enzyme involved in oestrogen biosynthesis. Oestrogens not only influence normal development and function but are also implicated in the aetiology and progression of many diseases. Over recent years rational drug design programmes have led to the development of agents that specifically and potently inhibit aromatase. The multidisciplinary international symposium Aromatase 2004 provided a forum in which basic scientists, translational researchers and practising clinicians reviewed latest results, exchanged opinions, and defined future needs for the regulation of oestrogen biosynthesis and the use of aromatase inhibitors.

Aromatase↗
PubMed2004

The phenomenon of quantum change.

Quantum change-the subject of this issue of In Session-refers to sudden, dramatic, and enduring transformations that affect a broad range of personal emotion, cognition, and behavior. This phenomenon has been described since the beginnings of psychology, most notably by William James in Varieties of Religious Experience. Quantum changes occur both within and (mostly) outside the context of psychotherapy and show certain common features in both process and content. This introduction provides an overview of the phenomenon of quantum change, describing its essential features, two qualitative subtypes, antecedents, course, and the nature of the enduring changes that ensue.

Alcoholics Anonymous↗
PubMed2004

A comparison of alcohol and drug disorders: is there evidence for a developmental sequence of drug abuse?

Whereas the model of Jellinek [Q. J. Stud. Alcohol 7 (1952) 673] of a predictable progression of alcoholism is generally supported, there have been few published studies regarding the natural history of illicit drug disorders. Identification of the development of drug abuse and/or dependence can inform clinicians and researchers on issues, such as diagnosis, prognosis, assessment, and prevention. This study employed a new measure adapted from the 46 events described in Jellinek's progression of alcoholism. Nine licit and illicit substances were also included within the cardsort. Fifty-two individuals motivated to enter drug treatment by a loved one were assessed pretreatment. The drug initiation sequence reported by this sample was as follows: alcohol, tobacco, inhalants, marijuana, and then other drugs. Spearman rank correlation coefficients were conducted between the drug sample and that of Jellinek yielding a modest correlation (r=.35, P=.019). These results suggest that Jellinek's model of progression of alcoholism may also apply to the development of drug disorders. However, important differences found between the alcohol and drug progressions are discussed.

Adolescent↗
PubMed2004

A randomized trial of methods to help clinicians learn motivational interviewing.

The Evaluating Methods for Motivational Enhancement Education trial evaluated methods for learning motivational interviewing (MI). Licensed substance abuse professionals (N = 140) were randomized to 5 training conditions: (a) clinical workshop only; (b) workshop plus practice feedback; (c) workshop plus individual coaching sessions; (d) workshop, feedback, and coaching; or (e) a waiting list control group of self-guided training. Audiotaped practice samples were analyzed at baseline, posttraining, and 4, 8, and 12 months later. Relative to controls, the 4 trained groups showed larger gains in proficiency. Coaching and/or feedback also increased posttraining proficiency. After delayed training, the waiting list group showed modest gains in proficiency. Posttraining proficiency was generally well maintained throughout follow-up. Clinician self-reports of MI skillfulness were unrelated to proficiency levels in observed practice.

Adult↗
PubMed2004

The effects of alcohol intoxication and gender on the social information processing of hostile provocations involving male and female provocateurs.

OBJECTIVE: The purpose of this study was to examine the effects of acute alcohol intoxication and gender on the social information processing of hostile provocations involving male and female provocateurs. METHOD: A sample of 82 participants (50% women) was randomly assigned to either an alcohol, placebo or control group. Participants completed a baseline assessment and a social information processing protocol. The protocol consisted of 12 videotaped provocation scenarios with gender of provocateur and level of hostility (hostile versus nonhostile) crossed (three scenarios for each combination). Note: Female participants viewed 12 scenarios that presented a female target and male participants viewed 12 scenarios that presented a male target. Participants viewed each scenario separately and responded to questions from an interviewer via an intercom. Questions tapped the social information processing domains of encoding, response representation, goal selection, response generation, response evaluation and response selection. RESULTS: Analyses showed a pattern of results whereby intoxicated men evidenced a greater degree of hostile response representation, a greater proportion of aggressive goal selection, greater aggressive response generation and greater aggressive response selection than all other group-by-gender combinations. These results were found most often for scenarios where the intent was hostile and the provocateur was male. CONCLUSIONS: The pattern of findings was consistent with past research on the relationship between alcohol, social information processing and aggression as well as with behavioral studies of the alcohol-aggression link. The social information processing model used in this study appears to be useful for the study of cognitive processes in the causal link between acute alcohol intoxication and aggressive behavior.

Adult↗
PubMed2003

Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.

BACKGROUND: The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy. METHODS: Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry. RESULTS: The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001). CONCLUSION: Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells.

Antineoplastic Agents, Hormonal↗
PubMed2003

A meta-analysis of the effectiveness of bibliotherapy for alcohol problems.

There has been increased interest in the use of brief interventions and the delivery of alcohol treatment services through nonspecialist health care settings. One possible resource for reaching untreated individuals is "bibliotherapy," the provision of self-help materials to motivate and guide the process of changing drinking behavior. Research on the effectiveness of self-help materials for problem drinkers has been done for three decades. This report summarizes a meta-analytic review of 22 studies evaluating the effectiveness of such self-help materials. Each study was rated on 12 methodological criteria, and effect sizes of bibliotherapy were computed. The methodological quality of studies was generally high relative to other treatment-outcome studies. Modest support was found for the efficacy of self-help materials in decreasing at-risk and harmful drinking. The weighted mean pre/post-effect size for bibliotherapy was .80 with self-referred individuals seeking help for drinking problems, and .65 for individuals identified through health screening. Between-group comparisons of bibliotherapy with no-intervention controls appear to have a small to medium effect, with a weighted mean effect size of .31 with self-referred drinkers; effect size was more variable in opportunistic interventions based on health screening. Finally, between-group comparisons of effects on drinking of bibliotherapy versus more extensive interventions yielded effect size values near zero. These findings provide support for the cost-effective use of bibliotherapy with problem drinkers seeking such help to reduce their consumption, and to a lesser extent with drinkers who are identified through screening as at risk.

Alcoholism↗
PubMed2003

Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer.

The natural history of breast cancer is closely linked with estrogens. These hormones influence both risk to the disease and growth of many established tumors. Consequently, measures that either inhibit the synthesis or block the mechanism of action of estrogens are attractive strategies for therapeutic intervention. This is particularly true in postmenopausal women in whom hormone responsiveness is common and estrogen synthesis is primarily sited peripherally in adipose tissue, muscle and breast tissue, rather than in the ovaries as in premenopausal women. In terms of inhibiting production, the most specific effects are best achieved by blocking the last step in biosynthesis, the conversion of androgens to estrogens by the heme-containing enzyme, aromatase. Two major classes of aromatase inhibitors have been developed and are currently in clinical use. Type I steroidal drugs include formestane and exemestane; they are androgen substrate analogues that bind competitively but irreversibly to the enzyme and have been marketed as "inactivators." Type II nonsteroidal inhibitors such as anastrozole and letrozole are triazoles; they bind reversibly to the enzyme and fit into the substrate binding site, such that azole nitrogens interact with the heme prosthetic group. This type of association provides exquisite potency for and specificity against the aromatase enzyme. These agents represent several generations of development, with each step in the evolution producing an increase in both potency and specificity. The latest aromatase inhibitors are drugs of immense potential that will undoubtedly play a major role in the management of postmenopausal women with hormone-dependent breast cancer. They also represent tools by which to elucidate the roles of both aromatase and estrogen in the development and growth of breast cancer.

Antineoplastic Agents, Hormonal↗