The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

BACKGROUND: The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. METHODS: In 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. RESULTS: Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. CONCLUSION: Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Recommendation for Inclusion of Surface Echocardiography in Evaluation of Chest Pain in Acute Emergency Care

Objective  A significant number of conditions may mimic acute myocardial infarction when patients present to acute emergency care (AEC) with chest pain. A proportion of such patients may exhibit ST segment abnormality on the electrocardiogram (ECG) which is due to conditions other than acute coronary syndromes (ACS) or myocardial infarction. The American Heart Association/American College of Cardiology guidelines (2015) algorithm for ACS does not include echocardiographic evaluation in the assessment of chest pain. Patients with chest pain may be subjected to investigations and interventions based on ECG leading unwarranted invasive procedures, which may prove unnecessary, futile, and even detrimental. This study was performed to determine if a bedside echocardiography would help identify the conditions that do not need intervention and might possibly change the treatment pathway at the right time. Materials and Methods In a prospective observational study design, adult patients presenting to AEC with chest pain were included in the study. After the assessment of airway, breathing and circulation, and initiation of bed side monitoring, a 12-lead ECG was obtained. Patients exhibiting a significant ST change on ECG were subjected to bedside echocardiography, that is, two-dimensional (2D) transthoracic echocardiography (2D-TTE) with a cross reference to a consultant cardiologist for the precise assessment and diagnosis. The findings of echocardiography were correlated with electrocardiogram for possible diagnostic coronary angiography and percutaneous coronary intervention. The results of ECG, echocardiography, and coronary angiography (if done) were analyzed to determine the sensitivity and specificity of echocardiography for ACS. Results Among 385 patients in the study, 312 were suspected to suffer acute coronary syndrome; among these patients, eight patients turned out to have chest pain due to non-ACS. Of the 73 patients, the chest pain was suspected to be not of cardiac ischemia origin; among these patients, 66 patients were true negative and 7 patients were false positive. Echocardiography was the predictive of ischemic chest pain with a predictive value of 97.7%. The specificity of echocardiography calculated from the above confusion matrix was 90.4% and sensitivity was 97.4%. The positive predictive value of 2D-TTE was 97.7% and negative predictive value was 89.1%. The overall accuracy of bedside 2D-TTE was 96.1%. Conclusion Echocardiography was found to be an effective tool in aiding diagnosis of a patient presenting to AEC with chest pain and ST-T changes in ECG. A significant percentage of patients (18.7%) presented to AEC with chest pain, ST-T changes and found to have causes other than ACS, and screening echocardiography (2D-TTE) was able to identify 90.4% of those cases. From this study, we conclude that bedside echocardiography had high specificity (90.4%) and sensitivity (97.43%) in identifying regional wall motion abnormality due to ACS. Hence, bedside echocardiography is recommended in patients with chest pain and ST-segment abnormality to avoid unnecessary delay in diagnosis and invasive interventions in non-ACS