BMP-2 upregulates the AKT/mTOR pathway in breast cancer with microcalcification and indicates a poor prognosis.

BACKGROUND: As a reliable biomarker of breast cancer, breast microcalcification has been reported to be correlated with poor prognosis. Bone morphogenetic protein 2 (BMP-2) plays an important role in microcalcification of breast cancer. Studies in other tissues have shown an association between BMP-2 and AKT/mTOR pathway, while their relationship in breast cancer still remains largely undetermined. To clarify the relationship of these three factors, we collected patients of invasive breast cancer with/without microcalcification and immunohistochemical examination was performed. METHOD/PATIENTS: A total of 272 patients with primary invasive breast cancer were selected from the First Hospital of China Medical University from January 2010 to January 2012. Immunohistochemical examination of the BMP-2, p-AKT and p-mTOR was performed on 4-µm tissue microarray (TMA) sections. Then, we analyzed the relationship of BMP-2, p-AKT, and p-mTOR and their correlation with disease-free survival (DFS) in breast cancer with/without microcalcification. RESULTS: We found that breast cancer patients with microcalcification were correlated with HER-2 positive expression and poor prognosis. Immunohistochemical examination showed that the expressions of BMP-2 and p-mTOR were increased in breast cancer with microcalcification and the expressions of BMP-2, p-AKT, and p-mTOR were correlated with each other. Moreover, the high expressions of BMP-2, p-AKT, and p-mTOR were significantly correlated with poor prognosis. CONCLUSIONS: Based on the abovementioned findings, we hypothesized that the high expression of BMP-2 not only played a vital role in the formation of microcalcification, but also activated the AKT/mTOR pathway. Collectively, breast cancer patients with microcalcification were more likely to be resistant to targeted or endocrine therapy and be correlated with poor prognosis.

Congenital Zika Syndrome: The Main Cause of Death and Correspondence Between Brain CT and Postmortem Histological Section Findings From the Same Individuals.

In the present case series, the cause of death of infants diagnosed with congenital Zika syndrome (CZS) was lung disease (pneumonia and sepsis with massive pulmonary aspiration), probably secondary to dysphagia and reflux. The main findings in infants with a confirmed diagnosis of CZS who died were as follows: (1) calcification and hypoplasia of the lentiform nuclei, hypoplasia of the caudate nuclei, and calcification at the cortical-subcortical junction was noted in all cases (100%) and calcification of the caudate nuclei was noted in 66.7% of cases; (2) calcification in the brainstem and along the lateral wall of the lateral ventricles was noted in only the case with arthrogryposis (33.3%); and (3) lesions in the posterior fossa (hypoplasia of the brainstem and cerebellum) were noted in two cases (66.7%), including the case with arthrogryposis. The findings concerning calcifications and brain malformations obtained from non-contrast computed tomography (CT) demonstrated good agreement with findings obtained from the postmortem pathological analysis; however, CT failed to detect discontinuity of the pia mater with heterotopia, invasion of the cerebral tissue into the subarachnoid space, and discontinuity of the ependyma in the lateral ventricles with gliosis; this last feature was only imaged in the most severe case of extreme microcephaly with a simplified gyral pattern. Only histopathology showed grouped calcifications associated with scattered calcifications suggestive of the neuron morphology.

Transcatheter Mitral Valve Replacement in Native Mitral Valve Disease With Severe Mitral Annular Calcification: Results From the First Multicenter Global Registry.

OBJECTIVES: This study sought to evaluate the outcomes of the early experience of transcatheter mitral valve replacement (TMVR) with balloon-expandable valves in patients with severe mitral annular calcification (MAC) and reports the first large series from a multicenter global registry. BACKGROUND: The risk of surgical mitral valve replacement in patients with severe MAC is high. There are isolated reports of successful TMVR with balloon-expandable valves in this patient population. METHODS: We performed a multicenter retrospective review of clinical outcomes of patients with severe MAC undergoing TMVR. RESULTS: From September 2012 to July of 2015, 64 patients in 32 centers underwent TMVR with compassionate use of balloon-expandable valves. Mean age was 73 ± 13 years, 66% were female, and mean Society of Thoracic Surgeons score was 14.4 ± 9.5%. The mean mitral gradient was 11.45 ± 4.4 mm Hg and the mean mitral area was 1.18 ± 0.5 cm(2). SAPIEN valves (Edwards Lifesciences, Irvine, California) were used in 7.8%, SAPIEN XT in 59.4%, SAPIEN 3 in 28.1%, and Inovare (Braile Biomedica, Brazil) in 4.7%. Access was transatrial in 15.6%, transapical in 43.8%, and transseptal in 40.6%. Technical success according to Mitral Valve Academic Research Consortium criteria was achieved in 46 (72%) patients, primarily limited by the need for a second valve in 11 (17.2%). Six (9.3%) had left ventricular tract obstruction with hemodynamic compromise. Mean mitral gradient post-procedure was 4 ± 2.2 mm Hg, paravalvular regurgitation was mild or absent in all. Thirty-day all-cause mortality was 29.7% (cardiovascular = 12.5% and noncardiac = 17.2%); 84% of the survivors with follow-up data available were in New York Heart Association functional class I or II at 30 days (n = 25). CONCLUSIONS: TMVR with balloon-expandable valves in patients with severe MAC is feasible but may be associated with significant adverse events. This strategy might be an alternative for selected high-risk patients with limited treatment options.

New Braile Inovare transcatheter aortic prosthesis: clinical results and follow-up.

AIMS: Transcatheter aortic valve implantation has emerged as an alternative to conventional aortic valve replacement in high-risk patients. Diverse prostheses are currently under investigation. The aim of this study was the clinical, safety and efficacy assessment of Braile Inovare Transcatheter Aortic Prosthesis usage. METHODS AND RESULTS: Ninety high-risk or inoperable patients underwent transcatheter aortic valve implantation. The mean logistic EuroSCORE was 39.3%. All patients presented calcified aortic stenosis. The procedures were performed under fluoroscopic and echocardiographic guidance. Prostheses were implanted through the transapical approach under rapid ventricular pacing. Echocardiographic and angiographic controls were included. Implantation was feasible in 87 cases. There was only one case of operative mortality, and 30-day mortality was 13.3%. The median transvalvular aortic gradient was reduced from 44.8±15.3 to 14.1±8.0 mmHg. Left ventricular function improved in the first seven postoperative days. Paravalvular aortic regurgitation was present in 29.7% of cases, mostly trace. One case presented a major vascular complication, and there were two cases of permanent pacemaker implantation. Two cases of major stroke occurred. CONCLUSIONS: Transcatheter aortic valve replacement using the Braile Inovare prosthesis is able to provide encouraging results with significant functional and structural cardiac improvement. It is mandatory to continue follow-up to measure the benefits of this device as well as to improve selection criteria of patients.

Transcatheter aortic valve implantation without balloon predilation: a single-center pilot experience.

AIM: To assess the results of transcatheter aortic valve implantation (TAVI) using the Medtronic CoreValve prosthesis (Medtronic, Minneapolis, MN), without balloon predilation, in high-risk patients with degenerated severe aortic stenosis. METHODS AND RESULTS: Fifty-one consecutive patients who underwent direct TAVI, 98% through a transfemoral approach. Patients were 79 ± 8 years of age, 74% in New York Heart Association classes III or IV and at high risk for surgical valve replacement (mean logistic EuroScore 20 ± 15). Mean aortic valve area was 0.7 ± 0.2 cm(2). Procedural success rate was 94.2%. In-hospital, there were 2 deaths, 1 minor stroke with minimal sequelae, and 14 (28%) pacemaker implantation. At 30 days, there was one additional stroke and no new deaths. The mean postprocedural transprosthetic gradient was 15 ± 5 mm Hg; periprosthetic severe regurgitation was absent and moderate in one case. After a median follow-up of 7 months, there were five additional deaths (two cardiac), while 84% of survivors were in New York Heart Association classes I or II. CONCLUSIONS: These results suggest that direct CoreValve implantation in patients with severe aortic stenosis is feasible and may lead to hemodynamic and clinical improvement in patients who are poor candidates for aortic valve surgery, pending confirmation in larger series with longer follow-up.

Phosphorus is associated with coronary artery disease in patients with preserved renal function.

High serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m(2). Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score ≤ 10 (3.63 ± 0.55 versus 3.49 ± 0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6 ± 0.5 versus 3.5 ± 0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score (p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function.

Phosphate binders, cardiovascular calcifications and mortality: do we need another survival study with sevelamer?

In chronic renal failure patients, hyperphosphatemia has been associated with vascular calcifications and increased cardiovascular morbidity and mortality. In vitro observations have shown that calcium and phosphate independently and synergistically induce calcifications in human vascular smooth muscle cells, suggesting an important role for both in the calcification process. Because non-calcium phosphate binders reduce serum phosphate without increasing the calcium load, as is the case with calcium-based phosphate binders, it has been speculated that treatment with sevelamer leads to less vascular calcification and better survival in chronic kidney disease. Although the use of sevelamer may slow the progression of vascular calcifications compared with calcium-based phosphate binders, the relationship of this surrogate marker with patients' cardiovascular mortality and survival is far from certain. To resolve this uncertainty and to determine the most cost-effective way to treat hyperphosphatemia in patients with end-stage renal disease, another randomized study analyzing mortality comparing sevelamer with calcium phosphate binders should be undertaken.

Impact of cardiovascular calcification in nondialyzed patients after 24 months of follow-up.

BACKGROUND AND OBJECTIVES: Coronary artery calcification (CAC) is highly prevalent among patients with chronic kidney disease (CKD), and it has been described as a strong predictor of mortality in the dialysis population. Because there is a lack of information regarding cardiovascular calcification and clinical outcomes in the earlier stages of the disease, we aimed to evaluate the impact of CAC on cardiovascular events, hospitalization, and mortality in nondialyzed patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a prospective study including 117 nondialyzed patients with CKD (age, 57 +/- 11.2 years; 61% male; 23% diabetics; creatinine clearance, 36.6 +/- 17.8 ml/min per 1.73 m(2)). CAC was quantified by multislice computed tomography. The occurrence of cardiovascular events, hospitalization, and death was recorded over 24 months. RESULTS: CAC >10 Agatston units (AU) was observed in 48% of the patients [334 (108 to 858.5) AU; median (interquartiles)], and calcification score >or=400 AU was found in 21% [873 (436-2500) AU]. During the follow-up, the occurrence of 15 cardiovascular events, 19 hospitalizations, and 4 deaths was registered. The presence of CAC >10 AU was associated with shorter hospitalization event-free time and lower survival. CAC >or=400 AU was additionally associated with shorter cardiovascular event-free time. Adjusting for age and diabetes, CAC >or=400 AU was independently associated with the occurrence of hospitalization and cardiovascular events. CONCLUSIONS: Cardiovascular events, hospitalization, and mortality were associated with the presence of CAC in nondialyzed patients with CKD. Severe CAC was a predictor of cardiovascular events and hospitalization in these patients.

Coronary calcification and its association with mortality in haemodialysis patients.

AIM: Coronary artery calcification (CAC) has been associated with higher mortality in chronic renal disease. The purpose of this study was to assess coronary artery calcium score (CaCs) in haemodialysis patients and to correlate calcium scores with clinical parameters and mortality. METHODS: A cross-sectional study was conducted in 59 haemodialysis patients. CaCs was assessed by multidetector-row computed tomography and stratified as: CaCs of less than 10 Agatston units (U), no calcification; CaCs of 10-400 U, mild-to-moderate; and CaCs of more than 400 U, severe calcification. The effects of age, haemodialysis duration and biochemical and inflammatory markers on CaCs logarithm were evaluated by multiple linear regression analysis. Cox regression analysis was used to measure the impact of CaCs of more than 400 on 2-year mortality. RESULTS: Coronary calcifications were detected in 64.5% of patients, and the median of CaCs was 31.7 U (0-589.7) with a range of 0-5790.0 U. Twenty-one (35.5%) patients had mild-to-moderate and 17 (29%) severe CaCs. Patients with severe CaCs were older and showed a higher prevalence of ischaemic heart disease and a higher body mass index (P=0.04). A trend towards higher C-reactive protein levels was found in patients with severe CaCs. Advanced age was the only variable that influenced CaCs logarithm independently. The effect of severe CaCs on 2-year mortality did not persist after adjustment for other covariates. CONCLUSION: Coronary calcification was highly prevalent in these uraemic patients on chronic haemodialysis. A correlation was evidenced between CaCs and advanced age, but severity of the CAC score did not have an impact on 2-year mortality of this cohort.

Recurrence after a first unprovoked cryptogenic/idiopathic seizure in children: a prospective study from São Paulo, Brazil.

PURPOSE: To evaluate the recurrence risk after a first unprovoked seizure in a large population of children and adolescents of a developing country. METHODS: This prospective study was conducted at two tertiary hospitals, between September 1989 and August 1998. Children were enrolled if they had a first unprovoked cryptogenic/idiopathic seizure and maximal interval to the enrollment < or =90 days. EEG and computed tomography (CT) were performed in most patients. Potential predictors of recurrence were compared by using the Cox proportional hazards model in univariate and multivariate analyses. Survival analysis was performed by using the Kaplan-Meier curves. RESULTS: Two hundred thirteen children were included. Recurrence occurred in 34% of the patients, and mean time for recurrence was 12 months. Statistical analysis showed significance for seizure recurrence only for patients with abnormal EEGs. CT was performed in 182 patients, and abnormalities were found in 9.5%. Small calcifications were the most frequent finding, and this was not a predictor for recurrence. CONCLUSIONS: The risk of recurrence after a first unprovoked seizure in children from a developing country is similar to that found in developed countries. An abnormal EEG is a risk factor for seizure recurrence in children with a cryptogenic/idiopathic seizure. Calcifications on CT do not increase the risk of recurrence.

Evaluation of the surgical treatment of chronic calcifying pancreatitis.

In the last 20 years, we have observed 264 instances of CCP. Of these, 136 (50.5 per cent) had 171 surgical procedures. Pancreatic calcifications were present in 83.1 per cent of the patients. One hundred and twenty-one were alcoholics (88.9 per cent) and 15 (11.0 per cent) abstained from alcohol. The surgical indications involved clinical uncontrollable pain and organic complications of the disease. The operations performed consisted of 62 wide side to side pancreaticojejunostomies, with loop excluded in Roux-en-Y, 40 pancreatectomies and 69 other operations. The choice of operation depended upon the analysis of each patient. The postoperative period of observation varied from two to 198 months, the average being 56.9 +/- 49.1 months. Thirty-five reoperations were performed for persistence or relapse of pain or the appearance of complications. Immediate post-operative complications and deaths occurred in 44 (25.7 per cent) and in six patients (3.5 per cent), respectively, considering the 71 operations performed. A satisfactory pain relief was evidenced in 61.0 per cent of the patients and total mortality reached 42.6 per cent. When the patients who underwent pancreaticojejunostomy, pancreatectomy and other operations were compared, no significant statistical difference was noticed with regard to the incidence of immediate post-operative complications and deaths, pain relief, appearance of diabetes or steatorrhea and mortality. There was also no significant difference as to the mortality among the alcoholic CCP, calcified or not, and idiopathic CCP (all calcified). On the other hand, the difference was statistically significant concerning the reoperation incidence in the group of patients who underwent the three types of operations mentioned. The longest survival time after pancreaticojejunostomy, pancreatectomy and other operations was 192, 137 and 198 months, respectively. The mean age at the time of death was 44.5 +/- 10.0 years, significantly inferior to the life expectation of the Brazilian male, which is 62 years. The mortality was higher in the first five postoperative years, corresponding to 77.6 per cent of the over-all mortality. There was no significant difference of survival time among the groups of patients undergoing the different types of operations. CCP is an extremely serious disease, progressive in spite of adequate treatment, sensibly diminishing the expectation and quality of lives of those with the condition, often interfering with the activity and productivity of the patient.(ABSTRACT TRUNCATED AT 400 WORDS)