Citations

AbstractConventional magnetic resonance imaging (MRI) characteristics of canine brain diseases are often nonspecific. Single‐ and multi‐voxel spectroscopy techniques allow quantification of chemical biomarkers for tissues of interest and may help to improve diagnostic specificity. However, published information is currently lacking for the in vivo performance of these two techniques in dogs. The aim of this prospective, methods comparison study was to compare the performance of single‐ and multi‐voxel spectroscopy in the brains of eight healthy, juvenile dogs using 3 Tesla MRI. Ipsilateral regions of single‐ and multi‐voxel spectroscopy were performed in symmetric regions of interest of each brain in the parietal (n = 3), thalamic (n = 2), and piriform lobes (n = 3). In vivo single‐voxel spectroscopy and multi‐voxel spectroscopy metabolite ratios from the same size and multi‐voxel spectroscopy ratios from different sized regions of interest were compared. No significant difference was seen between single‐voxel spectroscopy and multi‐voxel spectroscopy metabolite ratios for any lobe when regions of interest were similar in size and shape. Significant lobar single‐voxel spectroscopy and multi‐voxel spectroscopy differences were seen between the parietal lobe and thalamus (P = 0.047) for the choline to N‐acetyl aspartase ratios when large multi‐voxel spectroscopy regions of interest were compared to very small multi‐voxel spectroscopy regions of interest within the same lobe; and for the N‐acetyl aspartase to creatine ratios in all lobes when single‐voxel spectroscopy was compared to combined (pooled) multi‐voxel spectroscopy datasets. Findings from this preliminary study indicated that single‐ and multi‐voxel spectroscopy techniques using 3T MRI yield comparable results for similar sized regions of interest in the normal canine brain. Findings also supported using the contralateral side as an internal control for dogs with brain lesions.

Background: Two-stage subpectoral implant-based breast reconstruction is the most common method for breast reconstruction. Recent advances in surgical techniques and technology have made prepectoral implant-based breast reconstruction feasible. There are limited data on outcomes after prepectoral implant-based breast reconstruction and postmastectomy radiation therapy. Methods: A retrospective review of consecutive patients undergoing immediate two-stage prepectoral implant-based breast reconstruction with postmastectomy radiation therapy was performed. Outcomes of irradiated breasts were compared with nonirradiated breasts in bilateral cases. Results: Ninety-three cases of prepectoral implant-based breast reconstruction in 54 women who underwent immediate two-stage reconstruction (39 bilateral and 15 unilateral) and unilateral postmastectomy radiation therapy were identified. Mean follow-up was 19 months from mastectomy and tissue expander reconstruction and 9 months from implant placement. Crude complication rates in irradiated versus nonirradiated sides were as follows: surgical-site infection, 18.5 percent versus 7.7 percent; seroma, 5.6 percent versus 5.1 percent; mastectomy skin flap necrosis, 1.9 percent versus 2.6 percent; wound dehiscence, 1.9 percent versus 7.7 percent; capsular contracture, 1.9 percent versus 0 percent; hematoma, 1.9 percent versus 2.6 percent; and extrusion, 1.9 percent versus 0 percent. On univariate analysis, there were no risk factors associated with any complication, including radiation therapy, surgical-site infection, unplanned readmissions, and unplanned return to the operating room. To date, reconstruction has been completed in 96 percent of patients, with successful implant-based breast reconstruction in 81 breasts (45 irradiated breasts and 36 nonirradiated breasts). Conclusions: Early data of prepectoral implant-based breast reconstruction in patients with postmastectomy radiation therapy show promising results. Postmastectomy radiation therapy should not be an absolute contraindication to prepectoral implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Abstract Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n = 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR = 1.9; P = 0.012). Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients. Clin Cancer Res; 24(14); 3433–46. ©2018 AACR.

Abstract Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation. Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.

5 Background: Triple-negative breast cancer (TNBC) is an immunogenic breast cancer subtype, with a greater percentage of tumors containing tumor-infiltrating lymphocytes (TILs) compared to non-TNBC. TILs are prognostic for recurrence and predictive for chemotherapy benefit in TNBC, but not in estrogen receptor (ER)-positive tumors. A subset of TNBC expresses the androgen receptor (AR), and resembles ER-positive breast cancer in terms of demographics (older age) and clinical course (later recurrences that tend to involve bone). However, little is known regarding the association between TILs and AR expression in TNBC. Methods: From a cohort of 9982 women with surgically-treated non-metastatic breast cancer, patients who met criteria for TNBC (ER/PR < 1% and HER2-negative) by centralized-pathology review were included as previously published [Leon-Ferre et al, Breast Cancer Res Treat 2017]. Stromal TILs in these tumors were quantified on full-face hematoxylin and eosin sections from the surgical specimen, following the 2014 TIL Working Group recommendations [Salgado et al, Ann Oncol 2014]. The expression of AR [EPR1535(2), Abcam] was scored as a continuous variable (1% increments), and categorized as absent (0%), low (1-25% ), low-moderate (26-50%) moderate (51-75%) and high (> 75%) and correlated with TIL density. Results: 605 patients met criteria for TNBC. The median age was 56 years. Most tumors were T1-2 (95%), N0-1 (86%), and high grade (88%). The median stromal TIL content was 20% (0-90%). Tumor tissue was available for AR staining in 509/605 patients. 165 (32%) tumors expressed AR as follows: low: 12%, low-moderate: 7%, moderate: 5%, and high: 8%. Apocrine tumors (n = 30) expressed AR most frequently (86%) and at higher levels (AR high: 50%). For all 509 tumors, the median stromal TIL content according to AR expression was AR absent: 20%, AR low: 20%, AR low-moderate: 15%, AR high: 10%. AR and stromal TILs (both as continuous variables) demonstrated a weak inverse correlation (correlation coefficient -0.1064, p = 0.017). Conclusions: AR expression in TNBC is associated with lower levels of stromal TILs. Additional data correlating the AR, stromal TILs and outcomes in this cohort will be presented at the meeting.

Abstract This abstract was withdrawn by the authors.