Citations

The purpose of this pictorial essay is to demonstrate the imaging features (ultrasound, mammogram, and magnetic resonance imaging (MRI)) of AlloDerm®(LifeCell Corp.; Branchburg, NJ), an acellular dermal matrix sometimes used in both primary and reconstructive breast surgeries. AlloDerm®is derived from cadaveric dermis and provides an immunologically inert scaffold in tissue reconstruction. Since there is little literature on the imaging of this substance, radiologists may be unfamiliar with its appearance in breast imaging. For this manuscript,ex vivoandin vivoimages of AlloDerm®in postmastectomy patients were evaluated using different imaging modalities. The appearance of AlloDerm®can vary based on length of time postsurgery and incorporation into the host. AlloDerm®appears as an isodense to glandular tissue on a mammogram and isoechoic to glandular tissue on ultrasound imaging. On MRI, in comparison with normal breast parenchyma, AlloDerm®is hyperintense on T2-weighted imaging and isointense on T1-weighted imaging and demonstrates mild enhancement. To the best of the authors’ knowledge, this is the first multimodality imaging description of AlloDerm®used in postmastectomy patients. The conformation of AlloDerm®at surgical placement and the degree of host cell migration and neoangiogenesis are factors to take into consideration when performing diagnostic evaluations; and, familiarity with the various imaging appearances of AlloDerm®can be helpful to exclude residual or recurrent disease.

Abstract Androgen has been implicated as a negative regulator of host immune function and a factor contributing to the gender dimorphism of autoimmunity. Conversely, androgen deprivation has been suggested to potentiate male host immunity. Studies have shown that removal of androgen in postpubertal male mice produces an increase in size and cellularity of primary and peripheral lymphoid organs, and enhances a variety of immune responses. Yet, few details are known about the effect of androgen removal on T cell-mediated immunity. In this study, we demonstrate two pronounced and independent alterations in T cell immunity that occur in response to androgen deprivation, provided by castration, in postpubertal male mice. First, we show that levels of T cells in peripheral lymphoid tissues of mice are increased by androgen deprivation. Second, T cells from these mice transiently proliferate more vigorously to TCR- and CD28-mediated costimulation as well as to Ag-specific activation. In addition, androgen deprivation accelerates normalization of host T and B cell levels following chemotherapy-induced lymphocyte depletion. Such alterations induced by androgen deprivation may have implications for enhancing immune responses to immunotherapy and for accelerating the recovery of the immune system following chemotherapy.

Abstract Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.

Background Exercise testing provides valuable information in addition to ST ‐segment changes. The present study evaluated the associations among exercise test parameters and all‐cause mortality in a referral population. Methods and Results We examined conventional cardiovascular risk factors and exercise test parameters in 6546 individuals (mean age 49 years, 58% men) with no known cardiovascular disease who were referred to our clinic for exercise stress testing between 1993 and 2003. The association of exercise parameters with mortality was assessed during a follow‐up of 8.1±3.7 years. A total of 285 patients died during the follow‐up period. Adjusting for age and sex, the variables associated with mortality were: smoking, diabetes, functional aerobic capacity ( FAC ), heart rate recovery ( HRR ), chronotropic incompetence, and angina during the exercise. Adjusting for cardiovascular risk factors (diabetes, smoking, body mass index, blood pressure, serum total, HDL , LDL cholesterol, and triglycerides) and other exercise variables in a multivariable model, the only exercise parameters independently associated with mortality were lower FAC (adjusted hazard ratio [ HR ] per 10% decrease in FAC , 1.21; 95% confidence interval [ CI ], 1.13 to 1.29; P <0.001), and abnormal HRR , defined as failure to decrease heart rate by 12 beats at 1 minute recovery (adjusted HR per 1‐beat decrease, 1.05; 95% CI , 1.03 to 1.07; P <0.001). The additive effects of FAC and HRR on mortality were also highly significant when considered as categorical variables. Conclusion In this cohort of patients with no known cardiovascular disease who were referred for exercise electrocardiography, FAC and HRR were independently associated with all‐cause mortality.

Abstract The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

Abstract A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P &lt; 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

Abstract Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs. Experimental Design: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood–brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. Results: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin–dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models. Conclusion: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 20(1); 56–67. ©2013 AACR.

ObjectivesTo compare procedural outcomes of transcatheter balloon pulmonary valvuloplasty (BPV) in adults to a concurrent pediatric cohort and to identify whether BPV leads to improvement in symptoms among adults.BackgroundBPV has long been utilized to relieve right ventricular outflow tract (RVOT) obstruction in neonates and young children. More recently, BPV has been performed in adults, but outcome data are limited in this population.MethodsWe reviewed all cases of BPV performed at Mayo Clinic's Congenital Cardiac Cath Lab from December 1993 to July 2012. Patients were excluded if they had additional congenital heart defects, other than simple left‐to‐right shunt lesions.Results89 children and 40 adults underwent 132 BPV procedures. Among the adults, 78% were symptomatic at the time of BPV. The most common symptoms were dyspnea and fatigue. RVOT systolic gradient was 42 ± 19 mmHg (children) and 54 ± 26 mmHg (adults) prior to BPV (P = 0.002). Adults experienced a greater reduction in gradient following BPV (32 ± 21 mmHg vs. 23 ± 19 mmHg; P = 0.007). No patients exhibited “suicide right ventricle” physiology after BPV. Among adults, mean follow‐up was 1.9 years (30 days–11 years). Symptoms improved in 20 of the 24 previously symptomatic adults for whom follow‐up data were available. Mean NYHA score improved from 2.2 to 1.4 following BPV. At last follow‐up, 52% of adults were free of any symptoms, a significant improvement from pre‐BPV (P = 0.0003). Only one patient described worsening of symptoms after BPV.ConclusionsBPV is an effective procedure for symptomatic adults with pulmonary valve stenosis. In addition to immediate relief of RVOT gradient, adult patients may experience symptomatic improvement following BPV.© 2013 Wiley Periodicals, Inc.