Grouped Amorphous Calcifications at Mammography: Frequently Atypical but Rarely Associated with Aggressive Malignancy.

Purpose To determine rate of malignancy at stereotactic biopsy of amorphous calcifications with different distributions using current imaging, clinical, and histopathologic criteria. Materials and Methods From January 2009 to September 2013, this retrospective study reviewed a large set of stereotactic biopsies to identify amorphous calcifications and their clinical, imaging, and histopathologic characteristics. Calcification distribution was correlated with malignancy rate after adjusting for known risk factors using logistic regression. Results Of 1903 sequential biopsies, 546 (28.7%) were for amorphous calcifications. After excluding atypical lesions not excised and patients with more than one biopsy in the same year, 497 lesions from 494 women (median age, 52 years; age range, 30-81 years) remained. Fifty-two (10.5%; 95% confidence interval [CI]: 7.9, 13.5) lesions proved malignant, with 17 of 52 (42.7%) being invasive cancers (median, 0.3 cm; range, 0.1-1.3 cm) and all 17 of them being estrogen and progesterone receptor positive and node negative. Malignancy rates in a segmental (six of 21 [28.6%]), linear (eight of 32 [25.0%]), or multiple group same quadrant (nine of 36 [25.0%]) distribution were significantly higher than malignancy rate in a solitary group of amorphous calcifications (25 of 356 [7.0%]) (P = .004, P = .003, and P = .002, respectively). Of 356 grouped amorphous calcifications, 102 (28.7%) yielded atypical results prompting excision, with three of 102 (2.9%) upgraded to ductal carcinoma in situ at excision. In women younger than 50 years without a personal history of cancer, grouped amorphous calcifications showed four of 127 (3.1%) (95% CI: 0.9, 7.9) were malignant and 39 of 127 (30.7%) were atypical at final histopathology. Conclusion Biopsy of amorphous calcifications remains necessary, with an overall malignancy rate of 10.5%; only 17 of 497 (3.4%) biopsies showed invasive cancer, and all of these were estrogen and progesterone receptor positive. Grouped amorphous calcifications in women younger than 50 years without history of breast or ovarian cancer showed a low malignancy rate of 3.1% (four of 127).

Kidney fibrosis in hypertensive rats: role of oxidative stress.

Fibrosis of the glomerulus and the tubulointerstitium occurs in patients with hypertension. Studies have shown that renal oxidative stress appears in hypertensive kidney disease. The potential role of oxidative stress in renal fibrogenesis remains to be elucidated. Herein, we tested the hypothesis that oxidative stress contributes to the development of renal fibrosis during hypertension.Sprague-Dawley rats received angiotensin II (AngII; 9 microg/h s.c.) for 4 weeks with/without co-treatment of antioxidants, apocynin and tempol (120 mg/kg/day each, p.o.). Untreated rats served as controls. Appearance of renal oxidative stress and its effect on the expression of transforming growth factor (TGF)-beta(1), population of myofibroblasts, collagen synthesis/degradation and fibrosis in kidneys were examined. Chronic AngII infusion elevated systemic blood pressure (228 +/- 6 mm Hg), which was accompanied with extensive renal fibrosis and oxidative stress represented as upregulated NADPH oxidase and suppressed superoxide dismutase (SOD). Co-treatment with antioxidants led to: (1) markedly decreased renal NADPH oxidase; (2) significantly attenuated gene expression of TGF-beta(1), type I collagen, and tissue inhibitors of matrix metalloproteinase (TIMP)-I/-II in the kidney; (3) largely reduced population of myofibroblasts in both the cortex and medulla; (4) significantly reduced renal collagen volume, and (5) partially suppressed blood pressure (190 +/- 8 mm Hg). Thus, prolonged AngII administration promotes renal oxidative stress, which is associated with hypertensive renal disease. AngII induces renal oxidative stress by increasing NADPH oxidase and reducing SOD in the kidney, which, in turn, upregulates collagen synthesis, while suppressing collagen degradation, thereby promoting the development of fibrosis in kidneys of hypertensive rats.

Temporal and spatial characteristics of apoptosis in the infarcted rat heart.

Following myocardial infarction (MI), tissue repair/remodeling occurs in both the infarcted and noninfarcted myocardium. Apoptosis has been demonstrated to play an important role in these processes. In the present study, we sought to determine the temporal and spatial characteristics of apoptosis in the infarcted heart as well as to identify cells undergoing programmed cell death at different stages of repair/remodeling and their relationship to the expression of anti-/pro-apoptotic genes following MI. Our study has shown that apoptosis appears in both infarcted and noninfarcted myocardium, and cells undergoing apoptosis depend on the stage of healing. In the infarcted myocardium, apoptosis contributes to the loss of cardiomyocytes during the early stage of healing, elimination of inflammatory cells during the inflammatory phase of healing, and reduction of myofibroblasts with the fibrogenic phase of repair in the infarcted myocardium. In noninfarcted myocardium, cardiomyocyte apoptosis was observed from day 3 to 28 postMI. Cardiac apoptosis following MI is correlated with the increase of Bax expression.

Activation of nuclear factor-kappaB and its proinflammatory mediator cascade in the infarcted rat heart.

Nuclear transcription factor (NF)-kappaB regulates inflammatory and immune responses by increasing the expression of specific inflammatory genes in various tissues. Whether the infarcted heart includes the activation of NF-kappaB and a proinflammatory mediator cascade that it regulates has not been fully explored. Herein, we monitored the temporal and spatial activation of NF-kappaB, together with expression of tumor necrosis factor (TNF)-alpha, vascular cell adhesion molecule-1 (VCAM-1), and transforming growth factor (TGF)-beta(1), in the infarcted rat heart at and remote to MI from day 3 to day 28 following left coronary artery ligation. Compared to the normal heart, we observed NF-kappaB activation, together with the elevated expression of VCAM-1 in endothelial cells, TNF-alpha and TGF-beta(1) in inflammatory cells at sites of repair in the infarcted heart, which started on day 3, peaked on day 7, and gradually declined thereafter. Our findings suggest NF-kappaB activation and its proinflammatory mediator cascade are contributory to the inflammatory response and remodeling that appear at various sites of repair in the infarcted rat heart.

Aldosterone-induced inflammation in the rat heart : role of oxidative stress.

Heart failure and hypertension have each been linked to an induction of oxidative stress transduced by neurohormones, such as angiotensin II and catecholamines. Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury found in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment. Uninephrectomized rats received ALDO (0.75 micro g/hour) together with 1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o. daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg s.c. daily) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and untreated age- and gender-matched rats served as controls. We monitored spatial and temporal responses in molecular and cellular events using serial, coronal sections of right and left ventricles. Our studies included: assessment of systolic blood pressure; immunohistochemical detection of NADPH oxidase expression and activity; analysis of redox-sensitive nuclear factor-kappaB activation; in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha mRNA expression; monitoring cell growth and infiltration of macrophages and T cells; and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart. However, at weeks 4 and 5 of treatment, increased gp91(phox) and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in time and space with these events was increased mRNA expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. Macrophages, lymphocytes, and proliferating endothelial and vascular smooth muscle cells and fibroblast-like cells were seen at each of these sites, together with an accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant increase in ventricular collagen volume fraction. Co-treatment with spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as well as the appearance of fibrosis at vascular and nonvascular sites of injury. Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt treatment is accompanied by a time-dependent sustained activation of NADPH oxidase with 3-nitrotyrosine generation and nuclear factor-kappaB activation expressed by endothelial cells and inflammatory cells. This leads to a proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of injury found, respectively, in both normotensive and hypertensive right and left ventricles. Spionolactone, PDTC, and NAC each attenuated these responses suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for the appearance of this proinflammatory phenotype.