Serum brain‐derived neurotrophic factor and platelet activation evaluated by soluble P‐selectin and soluble CD‐40‐ligand in patients with acute myocardial infarction

Little is known about the role of neurotrophins (NT) under adult vascular homeostasis in normal and pathological conditions. The NT family, including nerve growth factor and brain‐derived neurotrophic factor (BDNF) are expressed in atherosclerotic vessels. Previous studies demonstrated that plasma BDNF levels were increased in the coronary circulation in patients with unstable angina. However, the role of BDNF during the onset and evolution of unstable angina remains to be elucidated. The objective of this study was to evaluate the relationship between BDNF, functional parameters and biological markers associated with inflammatory processes and platelet activation. BDNF serum levels were assessed in patients with acute myocardial infarction (MI) (n = 20) or stable angina pectoris (SAP) (n = 20) who underwent coronary angiography. Serum levels of IL‐6, MCP1, sVCAM, soluble CD‐40‐ligand (sCD40L) and soluble P‐selectin (sP‐selectin) were measured simultaneously by flux cytometry. Median BDNF levels were higher in the MI than in the SAP group (1730 vs. 877 pg/mL, respectively; P = 0.025). In MI patients, we observed a significant correlation between BDNF and sP‐selectin (r = 0.58, P = 0.023), although we found a non‐significant trend between BDNF and sCD40L (r = +0.35, P = 0.144). By contrast, no such correlation was observed in SAP patients (r = ?0.22, P = 0.425). No difference was observed between the two groups regarding baseline demographics, risk factors, biological data and angiographic findings. The study suggests that BDNF serum levels in MI patients could be related to platelet activation and the inflammatory response. Further studies are needed to investigate the role of NT in the setting of acute MI.     

Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors.

PURPOSE: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. EXPERIMENTAL DESIGN: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. RESULTS: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. CONCLUSIONS: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.     

All trans retinoic acid enhances CDDP-induced apoptosis: modulation of the CDDP effect on cell cycle progression

We have previously shown that ATRA potentiates CDDP cytotoxicity in various ovarian carcinoma cell lines. In the present study, we found that the enhanced sensitivity to CDDP was due to an increase of CDDP-induced apoptosis in OVCCR1 and NIH-OVCAR-3 cells. In these cell lines, flow cytometric analysis indicated that CDDP induced an initial accumulation of cells in the S-phase, followed by an increase in the proportion of cells in G2/M phase. Pretreatment of OVCCR1 and NIH-OVCAR-3 cells with ATRA did not modify cell cycle parameters, but delayed S-phase exit of CDDP-treated cells. Bcl-2 over-expression inhibited both delay in S-phase exit and CDDP-induced apoptosis in ATRA-pretreated cells. The CDDP-induced S-phase accumulation of OVCCR1 cells resulted from an activation of CDK2/cyclin A activity. Our results indicate that ATRA-pretreatment modified the CDDP-induced regulation of CDK2 activity by the CDK inhibitors p21 and p27. Taken together, our findings suggest that ATRA potentiates the apoptosis induced by CDDP in ovarian carcinoma cells and that this action is sustained by modulation of the activity of CDK2/cyclin A.     

A Preoperative Scoring System for Adnexal Mass in Children and Adolescents to Preserve Their Future Fertility

Study Objective

To develop a predictive score for ovarian malignancy to avoid unnecessary adnexectomy in cases of adnexal mass in pediatric and adolescent girls.

Efficacy of laparoscopic fundoplication in controlling pulmonary symptoms associated with gastroesophageal reflux disease

BACKGROUND: Gastroesophageal reflux disease (GERD)-induced pulmonary symptoms (PS) can be difficult to control. The effectiveness of laparoscopic fundoplication (LF) in controlling PS among patients with medically recalcitrant GERD is poorly documented. We evaluated our results in controlling important PS in patients with GERD undergoing LF. METHODS: Seventy-four patients (28 men, 46 women) were identified with clinically important PS from a prospective cohort of 155 patients undergoing elective LF for recalcitrant GERD. Median age was 52.5 years (range, 29-84 years). Sixty-seven (91%) patients were taking proton pump inhibitors at the time of operation. Quality of life by using the SF36 physical (PCS) and mental (MCS) component summary scores (normal, 50) and heartburn severity by using the health-related quality of life (HRQOL) (best score, 0; worst score, 45) were measured. RESULTS: All 74 patients with PS survived operation, and minor morbidity occurred in 5 (7%) patients. Median hospital stay was 2 days (range, 1-6 days), and return to normal activity was seen at 2.2 weeks (range, 1-8 weeks). Median follow-up was 12 months. PS were improved significantly (P < .01) for hoarseness (62% to 17.6%), bronchospasm (60% to 9.5%), and aspiration (22% to 1.4%). Before LF, 11 (14.9%) patients required bronchodilators or oral steroids. Postoperatively such therapy was required in only 3 (4.2%) patients (P = .019), with no patient requiring oral steroids. Patients with poorer control of their GERD on the basis of high HRQOL scores had significantly more PS after operation. CONCLUSIONS: A significant number of patients with medically recalcitrant GERD (46% from our prospective database) have important PS. LF can improve PS, decrease requirement for pulmonary medications, as well as improve typical reflux symptoms and quality of life.     

Cardiovascular response to dopamine and early prediction of outcome in septic shock: a prospective multiple-center study

OBJECTIVES: To compare mortality rates between dopamine-sensitive (Dopa-S) and dopamine-resistant (Dopa-R) septic shock patients, the latter group defined by a mean arterial pressure <70 mm Hg despite the use of 20 mug/kg/min dopamine. DESIGN: A human, prospective observational, multiple-center, clinical trial. SETTING: Ten intensive care units from ten hospitals. PATIENTS: 110 patients with septic shocks. INTERVENTIONS: Following volume resuscitation, patients were treated by a rapid increase in dopamine infusion from 10 to 20 mug/kg/min. If mean arterial pressure remained <70 mm Hg, dopamine treatment was promptly switched to norepinephrine or epinephrine. MEASUREMENTS AND MAIN RESULTS: Dopamine sensitivity, arterial gas, lactate, and organ system failure scores were measured at admission and after 6, 12, 24, 48, 72, 96, and 120 hrs. The overall 28-day mortality rate was 54% for the entire population under study. In multivariate analysis, independent predictors of death were dopamine resistance (odds ratio, 9.5; 95% confidence interval, 3-25), arterial lactate >3.5 mmol/L (odds ratio, 1.75; 95% confidence interval, 1.06-2.55), and Sepsis-related Organ Failure Assessment score >10 (odds ratio, 1.40; 95% confidence interval, 1.07-2.12). Of the 110 patients studied, 66 were observed to be resistant to dopamine (60%). In the Dopa-S group, the 28-day mortality rate was 16% (seven of 44 patients) compared with 78% (52 of 66 patients) in the Dopa-R group (p = .0006). The capacity of dopamine resistance to predict death was associated with a sensitivity of 84% and a specificity of 74%. At 24 hrs, the association of dopamine resistance to a lactate level >3.5 mmol/L improved the prognostic value (sensitivity, 90%, specificity, 92%). CONCLUSIONS: Dopamine sensitivity is associated with decreased mortality rate. Early recognition of dopamine resistant septic shock could allow for better screening of patients with an ominous prognosis.