Faculty Bibliography

Diffusion-weighted imaging plays important roles in cancer diagnosis, monitoring, and treatment. Although most applications measure restricted diffusion by tumor cellularity, diffusion-weighted imaging is also sensitive to vascularity through the intravoxel incoherent motion effect. Hypervascularity can confound apparent diffusion coefficient measurements in breast cancer. We acquired multiple b-value diffusion-weighted imaging at 3 T in a cohort of breast cancer patients and performed biexponential intravoxel incoherent motion analysis to extract tissue diffusivity (D(t) ), perfusion fraction (f(p) ), and pseudodiffusivity (D(p) ). Results indicated significant differences between normal fibroglandular tissue and malignant lesions in apparent diffusion coefficient mean (+/-standard deviation) values (2.44 +/- 0.30 vs. 1.34 +/- 0.39 mum(2) /msec, P < 0.01) and D(t) (2.36 +/- 0.38 vs. 1.15 +/- 0.35 mum(2) /msec, P < 0.01). Lesion diffusion-weighted imaging signals demonstrated biexponential character in comparison to monoexponential normal tissue. There is some differentiation of lesion subtypes (invasive ductal carcinoma vs. other malignant lesions) with f(p) (10.5 +/- 5.0% vs. 6.9 +/- 2.9%, P = 0.06), but less so with D(t) (1.14 +/- 0.32 mum(2) /msec vs. 1.18 +/- 0.52 mum(2) /msec, P = 0.88) and D(p) (14.9 +/- 11.4 mum(2) /msec vs. 16.1 +/- 5.7 mum(2) /msec, P = 0.75). Comparison of intravoxel incoherent motion biomarkers with contrast enhancement suggests moderate correlations. These results suggest the potential of intravoxel incoherent motion vascular and cellular biomarkers for initial grading, progression monitoring, or treatment assessment of breast tumors. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc

Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and overexpressed by many tumors. Here, we documented the presence of MMP-2-specific CD4(+) T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4(+) T cells displayed an inflammatory T(H)2 profile, i.e., mainly secreting TNF-alpha, IL-4, and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naive CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type 2 'conditioner' and may play a role in the observed prevalence of detrimental type 2 responses in melanoma

BACKGROUND: There are little data on the appropriate endpoint for slow pathway ablation that balances acceptable procedural times, recurrence rates, and complication rates. This study compared recurrence rates of three commonly utilized endpoints of slow pathway ablation for atrioventricular nodal reentrant tachycardia (AVNRT). METHODS: We performed a meta-analysis of AVNRT slow pathway ablation cohorts by searching electronic databases, the Internet, and conference proceedings. Inclusion criteria were age >18 years, >20 human subjects per study, primary AVNRT ablation, English language publication, and >1 month of follow-up. Data were analyzed with a fixed-effects model using Comprehensive Meta-Analysis software version 2.2.046 (Biostat, Englewood, NJ, USA). RESULTS: We included 10 studies encompassing 1,204 patients with a mean age of 41-53 years. Endpoints were complete slow pathway ablation, residual jump only, and single remaining echo beat. Pooled estimates revealed 28 of 641 patients (4.4%) with complete slow pathway ablation, 13 of 192 patients (6.8%) with a residual jump only, and 24 of 371 patients (6.5%) with one echo had recurrences. With uniform isoproterenol use after ablation, there was no significant difference in recurrence rates among the endpoints. However, when isoproterenol was utilized after ablation only if needed to induce AVNRT before ablation, a significantly higher recurrence rate occurred in patients with a residual jump (P = 0.002), a single echo (P = 0.003), or the combined group of a residual jump and/or one echo (P = 0.001). CONCLUSIONS: Isoproterenol should be used routinely after slow pathway modification, when a residual jump and/or single echo remain

OBJECTIVE: Functional ischemic mitral regurgitation is a complication of ventricular remodeling; standard therapy is reduction annuloplasty and coronary artery bypass grafting. Unfortunately, outcomes are retrospective and contradictory. We report a multicenter study that documents the outcomes of reduction annuloplasty for functional ischemic mitral regurgitation. METHODS: Twenty-one centers randomized 75 patients to the coronary artery bypass grafting + reduction annuloplasty subgroup that was the control arm of the Randomized Evaluation of a Surgical Treatment for Off-pump Repair of the Mitral Valve trial. Entry criteria included patients requiring revascularization, patients with severe or symptomatic moderate functional ischemic mitral regurgitation, an ejection fraction 25% or greater, a left ventricular end-diastolic dimension 7.0 cm or less, and more than 30 days since acute myocardial infarction. All echocardiograms were independently scored by a core laboratory. Reduction annuloplasty was achieved by device annuloplasty. Two patients underwent immediate intraoperative conversion to a valve replacement because reduction annuloplasty was unable to correct mitral regurgitation; as-treated results are presented. RESULTS: Thirty-day mortality was 4.1% (3/73). Patients received an average of 2.8 bypass grafts. Mean follow-up was 24.6 months. Mitral regurgitation was reduced from 2.6 +/- 0.8 preoperatively to 0.3 +/- 0.6 at 2 years. Freedom from death or valve reoperation was 78% +/- 5% at 2 years. There was significant improvement in ejection fraction and New York Heart Association class with reduction of left ventricular end-diastolic dimension. Cox regression analyses suggested that increasing age (P = .001; hazard ratio, 1.16 per year; 95% confidence interval, 1.06-1.26) and renal disease (P = .018; hazard ratio, 3.48; 95% confidence interval, 1.25-9.72) were associated with decreased survival. CONCLUSIONS: Coronary artery bypass grafting + reduction annuloplasty for functional ischemic mitral regurgitation predictably reduces mitral regurgitation and relieves symptoms. This treatment of moderate to severe mitral regurgitation is associated with improved indices of ventricular function, improved New York Heart Association class, and excellent freedom from recurrent mitral insufficiency. Although long-term prognosis remains guarded, this multicenter study delineates the intermediate-term benefits of such an approach

OBJECTIVES: We sought to determine whether patients with functional mitral regurgitation (FMR) would benefit from ventricular reshaping by the Coapsys device (Myocor, Inc., Maple Grove, Minnesota). BACKGROUND: FMR occurs when ventricular remodeling impairs valve function. Coapsys is a ventricular shape change device placed without cardiopulmonary bypass to reduce FMR. It compresses the mitral annulus and reshapes the ventricle. We hypothesized that Coapsys for FMR would improve clinical outcomes compared with standard therapies. METHODS: RESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) was a randomized, prospective, multicenter study of patients with FMR and coronary disease with core laboratory analysis. After enrollment, patients were stratified to the standard indicated surgery: either coronary artery bypass graft alone or coronary artery bypass graft with mitral valve repair. In each stratum, randomization was to either control (indicated surgery) or treatment (coronary artery bypass graft with Coapsys ventricular reshaping). RESULTS: The study was terminated when the sponsor failed to secure ongoing funding; 165 patients were randomized. Control and Coapsys both produced decreases in left ventricular (LV) end-diastolic dimension and MR at 2 years (p < 0.001); Coapsys provided a greater decrease in LV end-diastolic dimension (p = 0.021). Control had lower MR grades during follow-up (p = 0.01). Coapsys showed a survival advantage compared with control at 2 years (87% vs. 77%) (hazard ratio: 0.421; 95% confidence interval: 0.200 to 0.886; stratified log-rank test; p = 0.038). Complication-free survival (including death, stroke, myocardial infarction, and valve reoperation) was significantly greater with Coapsys at 2 years (85% vs. 71%) (hazard ratio: 0.372; 95% confidence interval: 0.185 to 0.749; adjusted log-rank test; p = 0.019). CONCLUSIONS: Analysis of RESTOR-MV indicates that patients with FMR requiring revascularization treated with ventricular reshaping rather than standard surgery had improved survival and a significant decrease in major adverse outcomes. This trial validates the concept of the ventricular reshaping strategy in this subset of patients with heart failure. (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve [RESTOR-MV]; NCT00120276)

We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m(2) intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response

BACKGROUND: Agents of opportunity (AO) are potentially harmful biological, chemical, radiological, and pharmaceutical substances commonly used for health care delivery and research. AOs are present in all academic medical centers (AMC), creating vulnerability in the health care sector; AO attributes and dissemination methods likely predict risk; and AMCs are inadequately secured against a purposeful AO dissemination, with limited budgets and competing priorities. We explored health care workers' perceptions of AMC security and the impact of those perceptions on AO risk. METHODS: Qualitative methods (survey, interviews, and workshops) were used to collect opinions from staff working in a medical school and 4 AMC-affiliated hospitals concerning AOs and the risk to hospital infrastructure associated with their uncontrolled presence. Secondary to this goal, staff perception concerning security, or opinions about security behaviors of others, were extracted, analyzed, and grouped into themes. RESULTS: We provide a framework for depicting the interaction of staff behavior and access control engineering, including the tendency of staff to 'defeat' inconvenient access controls. In addition, 8 security themes emerged: staff security behavior is a significant source of AO risk; the wide range of opinions about 'open' front-door policies among AMC staff illustrates a disparity of perceptions about the need for security; interviewees expressed profound skepticism concerning the effectiveness of front-door access controls; an AO risk assessment requires reconsideration of the security levels historically assigned to areas such as the loading dock and central distribution sites, where many AOs are delivered and may remain unattended for substantial periods of time; researchers' view of AMC security is influenced by the ongoing debate within the scientific community about the wisdom of engaging in bioterrorism research; there was no agreement about which areas of the AMC should be subject to stronger access controls; security personnel play dual roles of security and customer service, creating the negative perception that neither role is done well; and budget was described as an important factor in explaining the state of security controls. CONCLUSIONS: We determined that AMCs seeking to reduce AO risk should assess their institutionally unique AO risks, understand staff security perceptions, and install access controls that are responsive to the staff's tendency to defeat them. The development of AO attribute fact sheets is desirable for AO risk assessment; new funding and administrative or legislative tools to improve AMC security are required; and security practices and methods that are convenient and effective should be engineered

Agents of opportunity (AO) in academic medical centers (AMC) are defined as unregulated or lightly regulated substances used for medical research or patient care that can be used as 'dual purpose' substances by terrorists to inflict damage upon populations. Most of these agents are used routinely throughout AMC either during research or for general clinical practice. To date, the lack of careful regulations for AOs creates uncertain security conditions and increased malicious potential. Using a consensus-based approach, we collected information and opinions from staff working in an AMC and 4 AMC-affiliated hospitals concerning identification of AO, AO attributes, and AMC risk and preparedness, focusing on AO security and dissemination mechanisms and likely hospital response. The goal was to develop a risk profile and framework for AO in the institution. Agents of opportunity in 4 classes were identified and an AO profile was developed, comprising 16 attributes denoting information critical to preparedness for AO misuse. Agents of opportunity found in AMC present a unique and vital gap in public health preparedness. Findings of this project may provide a foundation for a discussion and consensus efforts to determine a nationally accepted risk profile framework for AO. This foundation may further lead to the implementation of appropriate regulatory policies to improve public health preparedness. Agents of opportunity modeling of dissemination properties should be developed to better predict AO risk

p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients