Keith D. Amos

Magnetic resonance imaging as a predictor of pathologic response in patients treated with neoadjuvant systemic treatment for operable breast cancer. Translational Breast Cancer Research Consortium trial 017.

Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast.

Competence and confidence with basic procedural skills: the experience and opinions of fourth-year medical students at a single institution.

Purpose Data indicate that students are unprepared to perform basic medical procedures on graduation. The authors’ aim was to characterize graduating students’ experience with and opinions about these skills. Method In 2011, an online survey queried 156 fourth-year medical students about their experience with, and actual and desired levels of competence for, nine procedural skills (Foley catheter insertion, nasogastric tube insertion, venipuncture, intravenous catheter insertion, arterial puncture, basic suturing, endotracheal intubation, lumbar puncture, and thoracentesis). Students self-reported competence on a four-point Likert scale (4 = independently performs skill; 1 = unable to perform skill). Data were analyzed by analysis of variance and Student t test. A five-point Likert scale was used to assess student confidence. Results One hundred thirty-four (86%) students responded. Two skills were performed more than two times by over 50% of students: Foley catheter insertion and suturing. Mean level of competence ranged from 3.13 ± 0.75 (Foley catheter insertion) to 1.7 ± 0.7 (thoracentesis). A gap in desired versus actual level of competence existed for all procedures (P < .0001). There was a correlation between the number of times a procedure had been performed and self-reported competence for all skills except arterial puncture and suturing. Conclusions Participants had performed most skills infrequently and rated themselves as being unable to perform them without assistance. Strategies to improve student experience and competence of procedural skills must evolve to improve the technical competency of graduating students because their current competency varies widely.

Gene expression in extratumoral microenvironment predicts clinical outcome in breast cancer patients

IntroductionA gene expression signature indicative of activated wound responses is common to more than 90% of non-neoplastic tissues adjacent to breast cancer, but these tissues also exhibit substantial heterogeneity. We hypothesized that gene expression subtypes of breast cancer microenvironment can be defined and that these microenvironment subtypes have clinical relevance.MethodsGene expression was evaluated in 72 patient-derived breast tissue samples adjacent to invasive breast cancer or ductal carcinoma in situ. Unsupervised clustering identified two distinct gene expression subgroups that differed in expression of genes involved in activation of fibrosis, cellular movement, cell adhesion and cell-cell contact. We evaluated the prognostic relevance of extratumoral subtype (comparing the Active group, defined by high expression of fibrosis and cellular movement genes, to the Inactive group, defined by high expression of claudins and other cellular adhesion and cell-cell contact genes) using clinical data. To establish the biological characteristics of these subtypes, gene expression profiles were compared against published and novel tumor and tumor stroma-derived signatures (Twist-related protein 1 (TWIST1) overexpression, transforming growth factor beta (TGF-β)-induced fibroblast activation, breast fibrosis, claudin-low tumor subtype and estrogen response). Histological and immunohistochemical analyses of tissues representing each microenvironment subtype were performed to evaluate protein expression and compositional differences between microenvironment subtypes.ResultsExtratumoral Active versus Inactive subtypes were not significantly associated with overall survival among all patients (hazard ratio (HR) = 1.4, 95% CI 0.6 to 2.8, P = 0.337), but there was a strong association with overall survival among estrogen receptor (ER) positive patients (HR = 2.5, 95% CI 0.9 to 6.7, P = 0.062) and hormone-treated patients (HR = 2.6, 95% CI 1.0 to 7.0, P = 0.045). The Active subtype of breast microenvironment is correlated with TWIST-overexpression signatures and shares features of claudin-low breast cancers. The Active subtype was also associated with expression of TGF-β induced fibroblast activation signatures, but there was no significant association between Active/Inactive microenvironment and desmoid type fibrosis or estrogen response gene expression signatures. Consistent with the RNA expression profiles, Active cancer-adjacent tissues exhibited higher density of TWIST nuclear staining, predominantly in epithelium, and no evidence of increased fibrosis.ConclusionsThese results document the presence of two distinct subtypes of microenvironment, with Active versus Inactive cancer-adjacent extratumoral microenvironment influencing the aggressiveness and outcome of ER-positive human breast cancers.

The role of organizational affiliations and research networks in the diffusion of breast cancer treatment innovation.

Introduction:The National Institutes of Health (NIH) sees provider-based research networks and other organizational linkages between academic researchers and community practitioners as promising vehicles for accelerating the translation of research into practice. This study examines whether organizational research affiliations and teaching affiliations are associated with accelerated diffusion of sentinel lymph node biopsy (SLNB), an innovation in the treatment of early-stage breast cancer. Methods:Surveillance Epidemiology and End Results-Medicare data were used to examine the diffusion of SLNB for treatment of early-stage breast cancer among women aged 65 years and older diagnosed between 2000 and 2002, shortly after Medicare approved and began reimbursing for the procedure. Results:In this population, patients treated at an organization affiliated with a research network—-the American College of Surgeons Oncology Group (ACOSOG) or other National Cancer Institute (NCI) cooperative groups—-were more likely to receive the innovative treatment (SLNB) than patients treated at unaffiliated organizations (odds ratio: 2.70, 95% confidence interval: 1.77–4.12; odds ratio: 1.84, 95% confidence interval: 1.26–2.69, respectively). Neither hospital teaching status nor surgical volume was significantly associated with differences in SLNB use. Discussion:Patients who receive cancer treatment at organizations affiliated with cancer research networks have an enhanced probability of receiving SLNB, an innovative procedure that offers the promise of improved patient outcomes. Study findings support the NIH Roadmap and programs such as the NCIs Community Clinical Oncology Program, as they seek to accelerate the translation of research into practice by simultaneously accelerating and broadening cancer research in the community.

Transition to surgical residency: a multi-institutional study of perceived intern preparedness and the effect of a formal residency preparatory course in the fourth year of medical school.

Purpose To evaluate interns’ perceived preparedness for defined surgical residency responsibilities and to determine whether fourth-year medical school (M4) preparatory courses (“bootcamps”) facilitate transition to internship. Method The authors conducted a multi-institutional, mixed-methods study (June 2009) evaluating interns from 11 U.S. and Canadian surgery residency programs. Interns completed structured surveys and answered open-ended reflective questions about their preparedness for their surgery internship. Analyses include t tests comparing ratings of interns who had and had not participated in formal internship preparation programs. The authors calculated Cohen d for effect size and used grounded theory to identify themes in the interns’ reflections. Results Of 221 eligible interns, 158 (71.5%) participated. Interns self-reported only moderate preparation for most defined care responsibilities in the medical knowledge and patient care domains but, overall, felt well prepared in the professionalism, interpersonal communication, practice-based learning, and systems-based practice domains. Interns who participated in M4 preparatory curricula had higher self-assessed ratings of surgical technical skills, professionalism, interpersonal communication skills, and overall preparation, at statistically significant levels (P < .05) with medium effect sizes. Themes identified in interns’ characterizations of their greatest internship challenges included anxiety or lack of preparation related to performance of technical skills or procedures, managing simultaneous demands, being first responders for critically ill patients, clinical management of predictable postoperative conditions, and difficult communications. Conclusions Entering surgical residency, interns report not feeling prepared to fulfill common clinical and professional responsibilities. As M4 curricula may enhance preparation, programs facilitating transition to residency should be developed and evaluated.

Role of HGF in epithelial–stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ

IntroductionBasal-like and luminal breast cancers have distinct stromal–epithelial interactions, which play a role in progression to invasive cancer. However, little is known about how stromal–epithelial interactions evolve in benign and pre-invasive lesions.MethodsTo study epithelial–stromal interactions in basal-like breast cancer progression, we cocultured reduction mammoplasty fibroblasts with the isogenic MCF10 series of cell lines (representing benign/normal, atypical hyperplasia, and ductal carcinoma in situ). We used gene expression microarrays to identify pathways induced by coculture in premalignant cells (MCF10DCIS) compared with normal and benign cells (MCF10A and MCF10AT1). Relevant pathways were then evaluated in vivo for associations with basal-like subtype and were targeted in vitro to evaluate effects on morphogenesis.ResultsOur results show that premalignant MCF10DCIS cells express characteristic gene expression patterns of invasive basal-like microenvironments. Furthermore, while hepatocyte growth factor (HGF) secretion is upregulated (relative to normal, MCF10A levels) when fibroblasts are cocultured with either atypical (MCF10AT1) or premalignant (MCF10DCIS) cells, only MCF10DCIS cells upregulated the HGF receptor MET. In three-dimensional cultures, upregulation of HGF/MET in MCF10DCIS cells induced morphological changes suggestive of invasive potential, and these changes were reversed by antibody-based blocking of HGF signaling. These results are relevant to in vivo progression because high expression of a novel MCF10DCIS-derived HGF signature was correlated with the basal-like subtype, with approximately 86% of basal-like cancers highly expressing the HGF signature, and because high expression of HGF signature was associated with poor survival.ConclusionsCoordinated and complementary changes in HGF/MET expression occur in epithelium and stroma during progression of pre-invasive basal-like lesions. These results suggest that targeting stroma-derived HGF signaling in early carcinogenesis may block progression of basal-like precursor lesions.

A Pilot Study of a Home-Based Motivational Exercise Program for African American Breast Cancer Survivors Clinical and Quality-of-Life Outcomes

Introduction. African American breast cancer survivors engage in less physical activity compared with their Caucasian counterparts. There is a need for exercise intervention research that focuses on improving the overall health and long-term survivorship of African American breast cancer survivors, especially because they often have worse outcomes than Caucasian survivors. Study objectives were to determine whether African American participants increase physical activity and explore whether exercise had a positive impact on fitness and health. Methods. African American breast cancer survivors, stage 0 to IIIA, within 2 years of completing primary cancer treatments were recruited for a 16-week home-based aerobic and resistance training exercise pilot study. Outcome measures assessed at baseline and postintervention included physical activity questionnaires and accelerometry, cardiopulmonary function (VO2peak) with gas exchange, muscle strength, Selective Functional Movement Assessment, and dual energy X-ray absorptiometry scans for body composition analysis. Assessments for fatigue and quality of life (QOL) were also completed at baseline and postintervention. Motivational interviewing was utilized to determine goals and explore exercise facilitators/barriers. Participants completed weekly exercise logs and received weekly phone calls. Wilcoxon signed rank tests were used to detect significant changes in physical activity and also changes in fitness/health parameters, fatigue, and QOL. Spearman correlation coefficients were used to examine relationships between physical activity and health measures. Results. A total of 17 women enrolled; 13 completed the intervention (76%). Mean age of the participants was 51 years. There was a significant increase in total minutes of weekly physical activity postintervention (M = 271 minutes, SD = 151; P = .001). Significant improvements were found in cardiopulmonary fitness as measured by VO2peak with a mean increase of 2.03 mL/kg/min (P = .01). Several strength measures significantly increased and also functional movement (P = .005). Positive correlations existed between physical activity and several physical measures, with significant relationships between functional movement and some strength measures (eg, left arm extension: rs = 0.61, P = .002). Total QOL and fatigue scores improved, but neither was significant. Conclusions. The intervention led to increased physical activity. As a result of increased levels of physical activity, improvements on several fitness/health parameters occurred.

Triple-Negative Breast Cancer: An Update on Neoadjuvant Clinical Trials

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. This scenario highlights the need to develop novel therapies and/or treatment strategies to reduce the mortality associated with TNBC. The neoadjuvant setting provides a model for rapid assessment of treatment efficacy with smaller patient accruals and over shorter periods of time compared to the traditional adjuvant setting. In addition, a clear surrogate endpoint of improved survival, known as pathologic complete response, already exists in this setting. Here, we review current data from completed and ongoing neoadjuvant clinical trials for TNBC.

Routine restaging PET/CT and detection of initial recurrence in sentinel lymph node positive stage III melanoma

BACKGROUND Follow-up of patients with sentinel lymph node-positive stage III melanoma uses history, physical exam, and cross-sectional imaging. The aim of this study was to evaluate positron emission tomographic (PET)/computed tomographic (CT) scans in the detection of recurrence. METHODS From 2003 to 2009, a single-institution prospective database of all cutaneous melanoma patients was used to identify sentinel lymph node-positive stage III patients with disease-free survival >1 year and 1 restaging PET/CT scan. RESULTS Thirty-eight patients were identified, with a median follow-up period of 27.5 months. Seven (18%) developed recurrence (median time to recurrence, 25 months). Recurrences were detected as follows: 3 by patients, 1 by physician, 1 by PET/CT scan and lactate dehydrogenase, 1 by PET/CT scan, and 1 by brain magnetic resonance imaging. One hundred eight follow-up PET/CT scans were performed. Two of 38 patients had asymptomatic metastases detected by routine restaging PET/CT scan, and there were 9 scans with false-positive results. CONCLUSIONS With short follow-up, the utility of routine PET/CT scans in identifying unsuspected recurrence in patients with sentinel lymph node-positive stage III melanoma appears minimal.

Who teaches basic procedural skills: student experience versus faculty opinion.

INTRODUCTION Learning procedural skills as a medical student has evolved, as task trainers and simulators are now ubiquitous. It is yet unclear whether they have supplanted bedside teaching or are adjuncts to it, and whether faculty or residents are responsible for student skills education in this era. In this study we sought to characterize the experience and opinions of both medical students and faculty on procedural skills training. METHODS Surveys were sent to clinical medical students and faculty at UNC Chapel Hill. Opinions on the ideal learning environment for basic procedural skills, as well as who serves as primary teacher, were gathered using a 4-point Likert scale. Responses were compared via Fisher exact test. RESULTS A total of 237 students and 279 faculty responded. Third-year students were more likely to report simulation as the primary method of education (64%), compared to either fourth-year students (35%; P < 0.0001) or faculty (43%; P = 0.0018). Third- and fourth-year students were also more likely to report interns as a primary teacher (15% and 10%, respectively) as opposed to faculty (2%), and less likely to suggest faculty were the primary teacher (30% and 21%, respectively, versus 35%), P < 0.0001. Residents were the primary teachers for all three groups (55%, 70%, and 63% respectively). CONCLUSIONS Our data suggest that both medical students and faculty recognize the utility of simulation in procedural skills training, but vary in the degree to which they think simulation is or should be the primary instructional tool. Both groups suggest residents are the primary teacher of these skills.