Citations

Background In epidemiologic studies, obesity has been associated with reduced natriuretic peptide ( NP ) concentrations. Reduced NP production could impair the ability of obese individuals to respond to salt loads, increasing the risk of hypertension and other disorders. We hypothesized that weight loss enhances NP production before and after salt loading. Methods and Results We enrolled 15 obese individuals (mean BMI 45±5.4 kg/m 2 ) undergoing gastric bypass surgery. Before and 6 months after surgery, subjects were admitted to the clinical research center and administered a large‐volume intravenous saline challenge. Echocardiography and serial blood sampling were performed. From the pre‐operative visit to 6 months after surgery, subjects had a mean BMI decrease of 27%. At the 6‐month visit, N‐terminal pro‐atrial NP (Nt‐pro ANP ) levels were 40% higher before, during, and after the saline infusion, compared with levels measured at the same time points during the pre‐operative visit ( P <0.001). The rise in Nt‐pro‐ ANP induced by the saline infusion (≈50%) was similar both before and after surgery (saline, P <0.001; interaction, P =0.2). Similar results were obtained for BNP and Nt‐pro BNP ; resting concentrations increased by 50% and 31%, respectively, after gastric bypass surgery. The increase in NP concentrations after surgery was accompanied by significant decreases in mean arterial pressure ( P =0.004) and heart rate ( P <0.001), and an increase in mitral annular diastolic velocity ( P =0.02). Conclusion In obese individuals, weight loss is associated with a substantial increase in the “setpoint” of circulating NP concentrations. Higher NP concentrations could contribute to an enhanced ability to handle salt loads after weight loss.

BACKGROUND Based on its cytologic features, and its co‐occurrence with atypical hyperplasia and breast cancer, flat epithelial atypia (FEA) has been proposed as a precursor lesion on the pathway to the development of breast cancer. It is often referred to as an “atypical” or high‐risk lesion. However, to the authors' knowledge, the long‐term risk of breast cancer in women with FEA is undefined. METHODS Specimens with FEA were identified among excisional breast biopsies in the Mayo Clinic Benign Breast Disease Cohort, which includes 11,591 women who had benign biopsy findings at the Mayo Clinic in Rochester, Minnesota between 1967 and 2001. Breast cancer risk among subsets of patients with FEA and nonproliferative, proliferative, and atypical hyperplasia (AH) was assessed using standardized incidence ratios (SIRs) compared with the Iowa Surveillance, Epidemiology, and End Results registry. RESULTS FEA was identified in 282 women (2.4%); 130 had associated AH (46%) and 152 (54%) were classified as having proliferative disease without atypia (PDWA). With median follow‐up of 16.8 years, the SIR for breast cancer in patients with AH plus FEA was 4.74 (95% confidence interval [95% CI], 3.17‐6.81) versus 4.23 (95% CI, 3.44‐5.13) for those with AH without FEA ( P = .59). The SIR for patients with PDWA plus FEA was 2.04 (95% CI, 1.23‐3.19) versus 1.90 (95% CI, 1.72‐2.09) for patients with PDWA without FEA ( P = .76). CONCLUSIONS FEA is an uncommon finding in women with benign breast disease. FEA does not appear to convey an independent risk of breast cancer beyond that of the associated PDWA or AH. Cancer 2015;121:1548–1555 . © 2015 American Cancer Society .

Dysplasia of the hip, hypotonia, osteopenia, ligamentous laxity, and mental retardation increase the complexity of performing and managing patients with Down syndrome who require total hip replacement (THR). We identified 14 patients (six males, eight females, 21 hips) with Down syndrome and degenerative disease of the hip who underwent THR, with a minimum follow-up of two years from 1969 to 2009. In seven patients, bilateral THRs were performed while the rest had unilateral THRs. The mean clinical follow-up was 5.8 years (standard deviation (sd) 4.7; 2 to 17). The mean Harris hip score was 37.9 points (sd 7.8) pre-operatively and increased to 89.2 (sd 12.3) at final follow-up (p = 1x10-9). No patient suffered a post-operative dislocation. In three patients, four hips had revision THR for aseptic loosening at a mean follow-up of 7.7 years (sd 6.3; 3 to 17). This rate of revision THR was higher than expected. Our patients with Down syndrome benefitted clinically from THR at mid-term follow-up. Cite this article: Bone Joint J 2014;96-B:1455–8.

Prostate movement imposes limits on safe dose-escalation with external beam radiation therapy. If the precise daily location of the prostate is known, dose escalation becomes more feasible. We have developed an approach to dose escalation using a combination of prostate brachytherapy followed by external beam radiation therapy in which fiducial markers are placed along with 125 I seeds during transperineal interstitial permanent prostate brachytherapy. These markers serve to verify daily prostate location during the subsequent external beam radiotherapy. Prior to implementing this approach, preliminary studies were performed to test visibility of the markers. Three different 125 I seed models, as well as gold and silver marker seeds were placed within tissue-equivalent phantoms. Images were obtained with conventional x-rays (75–85 kV) and 6 MV photons from a linear accelerator. All 125 I seed models were clearly visible on conventional x-rays but none were seen with 6 MV photons. The gold markers were visible with both energies. The silver markers were visible with conventional x-rays and 6 MV x-rays, but not as clearly as the gold seeds at 6 MV. Subsequently, conventional x-rays, CT scans, and 6 MV port films were obtained in 29 patients in whom fiducial gold marker seeds were implanted into the prostate during 125 I prostate brachytherapy. To address the possibility of “seed migration” within the prostate, CT scans were repeated 5 weeks apart in 14 patients and relative positions of the gold seeds were evaluated. The repeated CT scans showed no change in intraprostatic gold marker location, suggesting minimal migration. The gold seeds were visible with conventional x-rays, CT, and 6 MV port films in all patients. During the course of external beam radiation therapy, the gold markers were visible on routine 6 MV port films and were seen in different locations from film to film suggesting prostate motion. Mean daily displacement was 4–5 mm in the anterior-posterior, and 4–5 mm in superior-inferior dimensions. Left-right displacement appeared less, averaging 2–3 mm. We conclude that implantation of gold marker seeds during prostate brachytherapy represents an easily implemented and practical means of prostate localization during subsequent image-guided external beam radiotherapy. With such markers, conformality of the external beam component can be confidently improved without expensive new equipment.

Abstract Background: Women with benign breast disease (BBD) have increased breast cancer risk, and histologic features of the lesion stratify individual risk. We hypothesized that the concentration and type of terminal duct lobular units in BBD tissue is associated with future breast cancer risk. Methods: A nested case-control series of 770 breast cancer cases and 1273 age- and year of biopsy-matched controls was identified within a cohort of 13,647 women with BBD from 1967-2001 (median follow-up 15.3 years). One representative H&E slide from each biopsy was reviewed by a single pathologist, who recorded total # of lobules present, and # of fibrocystic lobules (total and # with epithelial proliferation). Samples were also evaluated for lobular involution and primary BBD histology. Lobule density (LD) was calculated as # of lobules/cm2 in each tissue section. Breast cancer associations with LD's (total, fibrocystic, proliferative) were examined with conditional logistic regression. Odds ratios are reported per 1 SD increase in LD. Results: Each LD measure was significantly associated with involution and primary BBD histology (p&lt;0.0001 for each). Fibrocystic (OR 1.17, 95% CI 1.06-1.28) and proliferative (OR 1.37, 95% CI 1.16-1.61) LD were each associated with case status (p≤0.001) but total LD did not reach significance (OR 1.09, 95% CI 1.0-1.20; p=0.06). LD associations were somewhat attenuated after adjusting for involution (total OR 1.04 p=0.41; fibrocystic OR 1.13 p=0.02; proliferative OR 1.28 p=0.002) and primary BBD histology (total OR 1.04 p=0.49; fibrocystic OR 1.08 p=0.15; proliferative OR 1.18 p=0.07). Conclusions: The density of proliferative lobules in benign breast biopsy tissue is related to other BBD histologic features but may provide additional breast cancer risk stratification among women with proliferative BBD. Additional research will more fully evaluate the ability of this promising novel measure to predict breast cancer risk. Lobule Density Measures (lobules per square cm) All values are Medians Total Lobule Density Fibrocystic Lobule Density Proliferative Lobule Density Overall 17.5 4.5 0.7 Cases 18.1 4.9 1.3 Controls 17.0 4.2 0.4 Primary BBD Histology Nonproliferative disease 16 3.3 0 Proliferative disease 18.6 5.8 2.7 Atypical hyperplasia 20.9 6.2 3.3 Involution Category None 28.7 5.3 1.0 Partial 19.0 5 1.2 Complete 8.5 2.1 0 Citation Format: Amy C. Degnim, Lynn C. Hartmann, Tanya L. Hoskin, Marlene H. Frost, V Shane Pankratz, Derek C. Radisky, Lorelle L. Benetti, Celine M. Vachon, Teresa M. Allers, Robert A. Vierkant, Daniel W. Visscher. Density of breast lobules in benign breast tissue and association with future breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 155. doi:10.1158/1538-7445.AM2013-155

Abstract Despite significant progress in the treatment of breast cancer particularly through the use of targeted therapy, relapse and chemo-resistance remain a major hindrance in the fight to minimize the burden of the disease. Accumulating evidence suggest that breast cancer stem cells (BCSCs), which show resistance to chemotherapy and radiation, drive tumor initiation and disease recurrence. It is becoming increasingly clear that a rare subpopulation of cells known as cancer stem cells (CSC), able to be generated through epithelial to mesenchymal transition (EMT) and capable of tumor initiation and self-renewal, contributes to treatment resistance and metastases. This means that a more effective therapy should target both the chemoresistant CSCs and the proliferating epithelial cells that give rise to them in order to reverse EMT and attenuate their conversion to CSCs. Here, we demonstrate a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism and regulate breast CSC (BCSC) self-renewal and chemoresistance. Downregulation of AXL expression using AXL inhibitor MP470 (amuvatinib) or shRNA reversed EMT in mesenchymal normal human mammary epithelial cells and murine BCSCs attenuating self-renewal and restored chemosensitivity of the BCSCs. AXL expression was also found to be associated with expression of stem cell genes, regulation of metastases genes, increased tumorigenicity, and was important for BCSC invasion and migration. Inactivation of AXL also led to downregulation of NFκB pathway and reduced tumor formation in vivo. Together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anti-cancer therapies and to reduce breast cancer recurrence and metastases. Citation Format: Michael K. Asiedu, Francis Beauchamp-Perez, James N. Ingle, Marshall D. Behrens, Derek C. Radisky, Keith Knutson. AXL induces epithelial to mesenchymal transition and regulates the function of breast cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-272. doi:10.1158/1538-7445.AM2013-LB-272

Abstract Matrix metalloproteinases (MMPs), a family of extracellular matrix degrading proteins, have been found to be upregulated in many human cancers and have been shown to contribute to cancer progression. There have been many aborted attempts to target MMPs therapeutically using small molecule inhibitors; the limited selectivity of most MMP inhibitors may be a major factor contributing to their poor effectiveness. As an alternative to small molecule MMP inhibitors, we are developing new methodology to create selective protein inhibitors of MMPs, based on the scaffold of the natural inhibitor TIMP-1, that may be used as protein therapeutics. Because TIMP-1 has a very short plasma half-life, we have developed methods for PEGylation that extend the plasma half-life to about 24h while preserving MMP inhibitory activity, rendering it more suitable for in vivo applications. We have also generated mutations in TIMP-1 that confer selective binding toward particular MMPs. The targets thus far pursued include MMP-9, MMP-3, and MMP-10, which represent therapeutic targets of interest in breast cancer and lung cancer. In the future, the methods developed here can be used to identify TIMP-1 variants selective toward additional MMPs, which may be of utility in the research and treatment of many human cancers. Citation Format: Christine Mehner, Jyotica Batra, Jessica Robinson, Derek C. Radisky, Evette S. Radisky. Engineering TIMP-1 for selective MMP inhibition and future use as a protein therapeutic. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5069. doi:10.1158/1538-7445.AM2013-5069

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and has the highest propensity to manifest as metastatic disease. Recent characterizations of the genetic signature of ccRCC have revealed several factors correlated with tumor cell migration and invasion; however, the specific events driving malignancy are not well defined. Furthermore, there remains a lack of targeted therapies that result in long-term, sustainable response in patients with metastatic disease. We show here that neuronal pentraxin 2 (NPTX2) is overexpressed specifically in ccRCC primary tumors and metastases, and that it contributes to tumor cell viability and promotes cell migration through its interaction with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR4. We propose NPTX2 as a novel molecular target for therapy for patients with ccRCC diagnosed with or at risk of developing metastatic disease. Cancer Res; 74(17); 4796–810. ©2014 AACR.