Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Bilateral renal-cell carcinoma associated with an acquired VHL mutation and long-term trichloroethylene exposure.

BACKGROUND/AIMS: The genetic basis for clear-cell renal carcinomas has been established in familial and many sporadic forms. Whether the latter can be induced by environmental carcinogens remains controversial, with concern over solvents such as trichloroethylene (TCE). To study this putative relationship, we analyzed the VHL gene from a patient with long-term TCE exposure. METHODS: PCR amplification and sequencing of VHL exons 1 - 3 were performed on peripheral blood and tumor tissue. RESULTS: The tumor alone had a previously undescribed mutation in exon 1 of the VHL gene: deletion of a cytidine residue at position 291 relative to the first ATG start codon of the wild-type sequence. This deletion causes a frameshift and predicts an altered protein sequence from position 98 onwards. CONCLUSION: The affected amino acids are in the functionally important beta-domain of the VHL protein that is implicated in substrate binding for ubiquitylation, and we hypothesize the mutation lowers that affinity. There is loss of suppressor function when substrates such as hypoxia-inducible factor have impaired degradation: they accumulate and ultimately cause uncontrolled cell turnover. This association of a proposed occupational cause and occurrence of renal-cell carcinoma emphasizes the availability and use of VHL sequencing for both studying the pathophysiology of malignant transformation and potentially playing a clinical role in genetic counseling or risk assessment.

The Educational Climate Inventory: Measuring Students' Perceptions of the Preclerkship and Clerkship Settings.

PURPOSE: To develop an instrument to assess educational climate, a critical aspect of the medical school learning environment that previous tools have not explored in depth. METHOD: Fifty items were written, capturing aspects of Dweck's performance-learning distinction, to distinguish students' perceptions of the educational climate as learning/mastery oriented (where the goal is growth and development) versus performance oriented (where the goal is appearance of competence). These items were included in a 2014 survey of first-, second-, and third-year students at six diverse medical schools. Students rated their preclerkship or clerkship experiences and provided demographic and other data. The final Educational Climate Inventory (ECI) was determined via exploratory and confirmatory factor analysis. Relationships between scale scores and other variables were calculated. RESULTS: Responses were received from 1,441/2,590 students (56%). The 20-item ECI resulted, with three factors: centrality of learning and mutual respect; competitiveness and stress; and passive learning and memorization. Clerkship students' ratings of their learning climate were more performance oriented than preclerkship students' ratings (P < .001). Among preclerkship students, ECI scores were more performance oriented in schools with grading versus pass-fail systems (P < .04). Students who viewed their climate as more performance oriented were less satisfied with their medical school (P < .001) and choice of medicine as a career (P < .001). CONCLUSIONS: The ECI allows educators to assess students' perceptions of the learning climate. It has potential as an evaluation instrument to determine the efficacy of attempts to move health professions education toward learning and mastery.

Multiple sclerosis as a cause of atrial fibrillation and electrocardiographic changes.

We present the case of a young woman with an acute exacerbation of multiple sclerosis associated with paroxysmal atrial fibrillation and electrocardiographic changes characteristic of central nervous system effects on cardiac conduction. The patient presented with ataxia, vertigo, and left facial paresthesia, and was found to have a large demyelinating lesion involving the left middle and inferior cerebellar peduncles with extension rostrally into the brain stem. Profound pulmonary edema, out of proportion with the cardiac abnormalities, also developed. This confirms that demyelinating disease, like other central nervous system abnormalities, can lead to alterations in cardiac conduction, and may induce neurogenic pulmonary edema.

Development and multicenter evaluation of Multistation Clinical Teaching Scenarios on immunization: the ATPM-CDC Teaching Immunization for Medical Education (TIME) Project.

INTRODUCTION: The objective of this project was to develop and evaluate case-based immunization education materials that use a new teaching method called Multistation Clinical Teaching Scenarios (MCTS) for use in medical school clerkships and primary care residencies. METHODS: A multidisciplinary team developed objectives, abstracted clinical cases, and created MCTS modules, which use contextual learning, problem solving, and small-group interaction. RESULTS: Mean scores increased from the 10-item pretest to the posttest by 3.2 (95% confidence interval [CI] of 2.8 to 3.6) items for measles, 3.8 (CI = 3.4 to 4.1) for influenza, and 1.8 (CI = 1.4 to 2.1) for hepatitis B (P < .01 for each). To evaluate the materials, we administered questionnaires and conducted focus groups. Most (99%) of the students and residents rated the materials highly, as did most (89%) facilitators. CONCLUSIONS: This new method has been widely tested, increases content mastery, and is well received.

Adjusting the number needed to treat: incorporating adjustments for the utility and timing of benefits and harms.

The number needed to treat is a unique and cognitively useful summary measurement for the description of medical treatments. However, the original concept lacks the means to account for multiple benefits and harms or differences in the utilities or timings of patient outcomes. The authors describe an "adjusted" number needed to treat that allows for the inclusion of multiple harms and benefits, and also adjustments for the utilities and timings of these outcomes. The expanded version offers a richer description of medical outcomes, and may be utilized as an adjunct to traditional risk-benefit, cost-effectiveness, and decision-analytic techniques.

CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Perspective: deconstructing integration: a framework for the rational application of integration as a guiding curricular strategy.

In response to historical criticism, evolving accreditation standards, and recent reports on curricula, medical educators and medical schools have been eagerly pursuing integration as a goal of curricular reform. The general education literature broadly considers integration to be the deliberate unification of separate areas of knowledge, and it provides support for the concept that integration better meets the needs of adult learners in professional education. The use of integration as a curricular goal is not without its critics, however, nor is it free of difficulties in implementation. In this perspective, the authors propose that most of these difficulties arise from a failure to recognize that integration is a strategy for curricular development rather than a goal in itself, and they argue that adopting a systematic approach to integration offers many potential benefits. They articulate the conceptual and practical issues that they believe are critical to consider in order to achieve successful curricular integration, and they suggest that integration should be approached as a subset of broader curriculum development decisions. They propose a three-level framework for applying integration as a guiding curricular strategy, in which decisions about integration must follow curricular decisions made at the program level, the course level, and then the individual session level.

Effecting curricular change through comprehensive course assessment: using structure and process to change outcomes.

Effective curriculum oversight requires periodic assessment and continuous improvement of individual course offerings as well as their overall integration. The literature indicates that most course review processes do not use the breadth of information available or sufficiently encourage faculty feedback and reflection, limiting the value derived. Suggestions for which data to include in the course evaluations are available in the literature; however, there is little guidance on effective course review structures and processes. In this article, the authors discuss a course review process revised as part of a comprehensive reform of the George Washington University School of Medicine and Health Sciences undergraduate medical school curriculum management structure. The process improvements incorporated evaluation practices grounded in the medical and higher education literatures and included changes to the data reviewed as well as the review timing, participants, and structure. The revised process uses a broad array of information, requires significant faculty participation, and uses questioning, writing, and dialogue to encourage faculty reflection and learning. Course directors indicate that the process helps them focus, and the information and the perspectives of others lead to reflection and new ideas. Through the process, course directors have changed course content and teaching methods, improved assessments of learning, and expanded course integration across the curriculum. The procedural and content elements of the process can be easily transferred to other medical schools and are applicable to other curricular reform projects across the continuum of medical education.

Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma.

The therapeutic effect of tamoxifen depends on active metabolites, e.g., cytochrome P450 2D6 (CYP2D6) mediated formation of endoxifen. To test for additional relationships, 236 breast cancer patients were genotyped for CYP2D6, CYP2C9, CYP2B6, CYP2C19, CYP3A5, UGT1A4, UGT2B7, and UGT2B15; also, plasma concentrations of tamoxifen and 22 of its metabolites, including the (E)-, (Z)-, 3-, and 4'-hydroxymetabolites as well as their glucuronides, were quantified using liquid chromatography-tandem mass spectrometry (MS). The activity levels of the metabolites were measured using an estrogen response element reporter assay; the strongest estrogen receptor inhibition was found for (Z)-endoxifen and (Z)-4-hydroxytamoxifen (inhibitory concentration 50 (IC50) 3 and 7 nmol/l, respectively). CYP2D6 genotypes explained 39 and 9% of the variability of steady-state concentrations of (Z)-endoxifen and (Z)-4-hydroxytamoxifen, respectively. Among the poor metabolizers, 93% had (Z)-endoxifen levels below IC90 values, underscoring the role of CYP2D6 deficiency in compromised tamoxifen bioactivation. For other enzymes tested, carriers of reduced-function CYP2C9 (*2, *3) alleles had lower plasma concentrations of active metabolites (P < 0.004), pointing to the role of additional pathways.

The effect of education and drug samples on antihistamine prescribing costs in an HMO.

OBJECTIVE: To examine the effect of an intervention designed to reduce antihistamine prescribing costs in an HMO. DESIGN: A quasi-experimental design with clinicians at one HMO site receiving an intervention. Their prescribing behavior before and after the intervention was compared to the prescribing behavior of clinicians at other HMO sites in a non-randomized control group. SETTING: A mixed model HMO in metropolitan Washington, DC. PARTICIPANTS: Group model clinicians at a single site received the intervention; network and group model clinicians at other sites composed the control group. INTERVENTION: An education memo addressed to clinicians discussing antihistamine prescribing costs and strategies for initial use of nonprescription or less expensive prescription agents, coupled with free antihistamine sample "trial packs" for patient use. OUTCOME MEASURE: The prescribing costs of the intervention group were compared to the prescribing costs of the non-randomized control group. The intervention group was surveyed regarding their attitudes toward the intervention. RESULTS: A 2% decline in costs was noted between the baseline and intervention year for both the intervention and control groups. Though clinicians indicated they were well disposed toward the intervention, they believe patient expectations were a major obstacle to the use of cheaper agents. CONCLUSION: We conclude that an effective intervention would require the targeting of major patient-related barriers to clinician behavior change.

Utilization of medical services for the treatment of acute low back pain: conformance with clinical guidelines.

OBJECTIVE: To assess the utilization of diagnostic and therapeutic medical services for the management of acute low back pain in a primary care setting, and to determine whether such utilization conforms to suggested guidelines for the management of this condition. STUDY DESIGN: A retrospective chart audit of consecutive cases of acute low back pain. Specific elements of the diagnostic and therapeutic approach were judged appropriate or inappropriate based on comparison with published recommendations supported by the medical literature. SETTING: The primary care adult practice of a university-affiliated health maintenance organization. PATIENTS: One hundred eighty-three patients presenting with acute low back pain of musculoskeletal origin. MEASUREMENTS AND MAIN RESULTS: According to suggested guidelines for the care of acute low back pain, 26% of plain lumbar x-rays (10/38), 66% of computed tomography (CT) and magnetic resonance imaging (MRI) scans (12/18), and 82% (23/28) of subspecialty referrals were categorized as inappropriate. Among patients without indications for these services, 12% (10/85) had received lumbar x-rays, 7% (12/168) had received lumbar MRI or CT scans, and 14% (23/168) had received subspecialty referrals. Underutilization of these services had occurred in 71% (70/98) of patients with an indication for plain lumbar radiography, and 47% (7/15) of patients with potential indications for surgical referral or CT/MRI scanning. Neither overutilization nor underutilization had led to adverse outcomes or delays in diagnosis in this small sample. CONCLUSIONS: According to guidelines from the medical literature, the primary care physicians in this study both overutilized and underutilized diagnostic and referral services in cases of acute low back pain. It is necessary to determine whether underutilization of plain lumbar radiography adversely affects diagnostic accuracy and whether overutilization of other services improves important clinical outcomes, given the generally benign natural history of this condition.

Randomized controlled trial of education and feedback for implementation of guidelines for acute low back pain.

OBJECTIVE: The effect of clinical guidelines on resource utilization for complex conditions with substantial barriers to clinician behavior change has not been well studied. We report the impact of a multifaceted guideline implementation intervention on primary care clinician utilization of radiologic and specialty services for the care of acute low back pain. DESIGN: Physician groups were randomized to receive guideline education and individual feedback, supporting patient education materials, both, or neither. The impact on guideline adherence and resource utilization was evaluated during the 12-month period before and after implementation. PARTICIPANTS: Fourteen physician groups with 120 primary care physician and associate practitioners from 2 group model HMO practices. INTERVENTIONS: Guideline implementation utilized an education/audit/feedback model with local peer opinion leaders. The patient education component included written and videotaped materials on the care of low back pain. MAIN RESULTS: The clinician intervention was associated with an absolute increase in guideline-consistent behavior of 5.4% in the intervention group versus a decline of 2.7% in the control group (P =.04). The patient education intervention produced no significant change in guideline-consistent behavior, but was poorly adopted. Patient characteristics including duration of pain, prior history of low back pain, and number of visits during the illness episode were strong predictors of service utilization and guideline-consistent behavior. CONCLUSIONS: Implementation of an education and feedback-supported acute low back pain care guideline for primary care clinicians was associated with an increase in guideline-consistent behavior. Patient education materials did not enhance guideline effectiveness. Implementation barriers could limit the utility of this approach in usual care settings.