Citations

The Florida Initiative for Quality Cancer Care has identified how multiple aspects of breast cancer care can be improved.

Object Deep brain stimulation (DBS) is an established neurosurgical technique used to treat a variety of neurological disorders, including Parkinson disease, essential tremor, dystonia, epilepsy, depression, and obsessive-compulsive disorder. This study reports on the use of intraoperative MR imaging during DBS surgery to evaluate acute hemorrhage, intracranial air, brain shift, and accuracy of lead placement. Methods During a 46-month period, 143 patients underwent 152 DBS surgeries including 289 lead placements utilizing intraoperative 1.5-T MR imaging. Imaging was supervised by an MR imaging physicist to maintain the specific absorption rate below the required level of 0.1 W/kg and always included T1 magnetization-prepared rapid gradient echo and T2* gradient echo sequences with selected use of T2 fluid attenuated inversion recovery (FLAIR) and T2 fast spin echo (FSE). Retrospective review of the intraoperative MR imaging examinations was performed to quantify the amount of hemorrhage and the amount of air introduced during the DBS surgery. Results Intraoperative MR imaging revealed 5 subdural hematomas, 3 subarachnoid hemorrhages, and 1 intraparenchymal hemorrhage in 9 of the 143 patients. Only 1 patient experiencing a subarachnoid hemorrhage developed clinically apparent symptoms, which included transient severe headache and mild confusion. Brain shift due to intracranial air was identified in 144 separate instances. Conclusions Intraoperative MR imaging can be safely performed and may assist in demonstrating acute changes involving intracranial hemorrhage and air during DBS surgery. These findings are rarely clinically significant and typically resolve prior to follow-up imaging. Selective use of T2 FLAIR and T2 FSE imaging can confirm the presence of hemorrhage or air and preclude the need for CT examinations.

Purpose Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER) –positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations. Patients and Methods Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis. Results On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004). Conclusion Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.

Abstract Background: Neoadjuvant endocrine therapy (NET) trials serve to inform design and selection of agents for larger adjuvant endocrine trials. The neoadjuvant aromatase inhibitor (AI) trial ACOSOG Z1031 randomized the treatment of postmenopausal women with ER rich (Allred 6-8) clinical stage 2/3 breast cancer to either EXE, ANA and LET. The results are therefore of interest in the context of new data that compares these AIs in the adjuvant setting. The opportunity to develop predictive biomarker tests for NET sensitivity was also a key study objective in order guide future selection of patients for inclusion in studies that compare NET versus neoadjuvant chemotherapy (NCT). The value of a baseline PAM50 intrinsic subtype test for NET patient selection was therefore an embedded objective of the study. Methods: Of the 374 women who began study treatment on Z1031, pretreatment biopsy specimen for central IHC testing for ER and Ki67 was available on 304 patients. The PAM50 intrinsic subtype test (PMCID: 2667820) could be conducted on 170 baseline samples. The Preoperative Endocrine Prognostic Index (PEPI) an approach to predicting long term outcomes based on pathological stage and surgical specimen ER and Ki67 status was also conducted because patients with a PEPI of zero (T1/2 N0, ER+, Ki67<=2.7%) have been found to have an excellent long term prognosis and therefore unlikely to benefit from chemotherapy (PMCID: 255670). Results: The degree of Ki67 suppression, the absolute level of Ki67 in the surgical specimen and the PEPI results were not significantly different by treatment arm (Kruskal-Wallis tests p >0.05). Thirty Percent (95%CI: 19.6-42.9%) of women with pre-AI LumA subtype and 12% (95%CI: 6.4-20.0%) of women with pre-AI LumB subtype had a PEPI of zero predicting excellent prognosis. Multivariate logistic modeling found that the likelihood of a PEPI score of zero is 3.2 fold higher (95%CI: 1.43 7.12) among 66 women with a pre-AI LumA subtype compared to 100 women with a pre-AI LumB subtype. Additional baseline variables (clinical T and N stage, HER2 status, pre-AI Ki-67 level (< = 10% vs. >10%) were not found to modify the chance of a PEPI of zero. Baseline PAM50 Subtype versus PEPI Conclusion: The results of Z1031 show no differences in clinical or biologic response between LET, EXE, and ANA in the neoadjuvant setting; predicting that no difference in efficacy will be seen between these agents in adjuvant studies. Pre-AI LumA versus LumB status, defined by the PAM50 subtype, identifies patients who are more likely to be in the most favorable PEPI score following neoadjuvant AI therapy. Patients with pretreatment LumA status may, therefore, not be suitable for a randomized trial of NET versus NCT since approximately one third of these patients may be able to avoid chemotherapy altogether. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-2.

Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients. Clin Cancer Res; 17(7); 1924–34. ©2011 AACR.

Abstract Abstract #4037 Background: Mammographic breast density is a strong and consistent risk factor for breast cancer. Women with dense tissue in over 60 to 75% of the breast are at 4 to 6 times greater risk than women with little or no density. However, the biology of breast density is not well understood and studies at the tissue level are limited. We present the first report of a tissue-based study of breast density, sampling mammographically dense and non-dense areas of the breast of healthy women with the goal of examining histologic correlates.
 Materials and Methods: Healthy women volunteers aged 40 to 85 years, with no breast symptoms, normal screening mammogram within 6 months, and no personal history of breast cancer were considered eligible. Women with breast-related symptoms, those on endocrine therapy, or with bleeding tendencies were excluded from participation. Sixty consecutive eligible women were enrolled in the study- results are based on the first 34 participants. Eligible women underwent an ultrasound-guided, core-needle breast biopsy of mammographically dense and non-dense areas of the breast, performed by a single experienced radiologist. Quantitative assessment of breast tissue from dense and non-dense areas was performed for epithelium, stroma, and fat. In addition, we assessed the difference in the extent of lobular involution (complete, partial and none) between dense and non-dense areas. We used means and SD to describe distributions in each tissue type. Signed rank test was used to assess within woman differences between dense and non-dense tissue.
 Results: The mean age of the participants was 50.1 years (range 40 to 79 years). The histological findings are outlined below.
 
 Dense tissue is comprised of increased stroma and epithelium and decreased fat, consistent with prior reports on breast density. The finding of 'no involution' was greater in dense tissue compared to non-dense tissue (24% versus 8.8%); non-dense tissue had greater proportion of complete involution compared to dense tissue (82.5% versus 35.2%).
 Discussion: This report is the first to quantify histology in tissue sampled from dense and non-dense regions of the healthy breast. We find a dramatic difference in tissue composition between dense and non-dense tissue in the breast. Future studies using this tissue to assess molecular markers will further help to characterize pathways through which density may increase breast cancer risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4037.

Abstract Abstract #4033 Background: Aromatase activity within the breast is a source of estrogen that may cause breast cancer. Mammographic density (MD) is a risk factor for breast cancer whose biologic basis is unknown. Our study compared aromatase expression in tissue from dense and non-dense areas of the breasts of healthy volunteers.
 Methods: Participants were 40+ yrs, had a screening mammogram with visible MD, no history of cancer and were not on endocrine therapy. Ultrasound-guided core biopsies were done within 6 months of mammography to obtain three paired cores from mammographically dense and non-dense regions of the breast. Immunostaining for aromatase expression employed the streptavidin-biotin amplification method using the recently developed 677 mouse monoclonal antibody. Immunoreactivity (IR) was scored in terms of proportion of cells staining positive for aromatase (PPC) (0=<1%, 1=1-25%, 2=26-50%, 3=51+% (and 4=75%+ for adipocytes)) and relative immunointensity (0=none, 1=weak, 2=moderate, 3=intense) for each cell type (stroma, normal ductal epithelium, adipocytes). A composite score weighting the PPC by their relative intensity (range 0-9; 0-12 for adipocytes) was also calculated. The sum of the composite score across the three cell types provided a global assessment of aromatase IR. Repeated measures analyses evaluated differences in aromatase IR for dense compared to non-dense tissue within and across cell types. Parameter estimates (β) indicated the average difference between dense and non-dense IR.
 Results: 18 (37%) of the 49 participants were premenopausal (median age 46 yrs). Summing across cell types, the global composite score showed increased aromatase IR on sections sampled from dense vs. non-dense regions (β=5.3,p<0.001). This global difference reflected increased aromatase IR in the stroma and normal ductal epithelium from dense sections (vs. non-dense). For 42 women with >1% stromal cells on each section, there was evidence for increased IR on dense sections as indicated by the greater PPCs (β=0.9), relative intensity (β=0.7) and composite score (β=2.7)(p's<0.001). Similarly, for 20 women with >1% normal ductal epithelium in both dense and non-dense sections, there was a greater composite score (β=1.4,p=0.004) for cells on dense sections although differences for PPC (β=0.3,p=0.11) and relative intensity (β=0.3,p=0.09) did not reach statistical significance. No differences were seen in IR for adipocytes from the two density regions (46 women). Findings were unchanged with adjustment for covariates, including proportions of each cell type per section.
 Conclusions: There is strong evidence for increased aromatase expression in the stromal and normal ductal epithelium of dense vs. non-dense tissue. These results support ongoing research into mammographic density as a biomarker of effect of aromatase inhibitors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4033.

ABSTRACT Because of the bioterrorism threat posed by agents such as variola virus, considerable time, resources, and effort have been devoted to biodefense preparation. One avenue of this research has been the development of rapid, sensitive, high-throughput assays to validate immune responses to poxviruses. Here we describe the adaptation of a β-galactosidase reporter-based vaccinia virus neutralization assay to large-scale use in a study that included over 1,000 subjects. We also describe the statistical methods involved in analyzing the large quantity of data generated. The assay and its associated methods should prove useful tools in monitoring immune responses to next-generation smallpox vaccines, studying poxvirus immunity, and evaluating therapeutic agents such as vaccinia virus immune globulin.