Element abundance patterns in stars indicate fission of nuclei heavier than uranium.

The heaviest chemical elements are naturally produced by the rapid neutron-capture process (r-process) during neutron star mergers or supernovae. The r-process production of elements heavier than uranium (transuranic nuclei) is poorly understood and inaccessible to experiments so must be extrapolated by using nucleosynthesis models. We examined element abundances in a sample of stars that are enhanced in r-process elements. The abundances of elements ruthenium, rhodium, palladium, and silver (atomic numbers Z = 44 to 47; mass numbers A = 99 to 110) correlate with those of heavier elements (63 ≤ Z ≤ 78, A > 150). There is no correlation for neighboring elements (34 ≤ Z ≤ 42 and 48 ≤ Z ≤ 62). We interpret this as evidence that fission fragments of transuranic nuclei contribute to the abundances. Our results indicate that neutron-rich nuclei with mass numbers >260 are produced in r-process events.

Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.

PURPOSE: Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. PATIENTS AND METHODS: Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. RESULTS: The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. CONCLUSION: Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.

Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.

PURPOSE: Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. PATIENTS AND METHODS: In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. RESULTS: Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). CONCLUSION: In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus.

OBJECTIVE: To study the effect of the innate cytokine macrophage migration inhibitory factor (MIF) on the susceptibility and severity of systemic lupus erythematosus (SLE) in a multinational population of 1,369 Caucasian and African American patients. METHODS: Two functional polymorphisms in the MIF gene, a -794 CATT(5-8) microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were assessed for association with SLE in 3,195 patients and healthy controls. We also measured MIF plasma levels in relation to genotypes and clinical phenotypes, and assessed Toll-like receptor 7 (TLR-7)-stimulated MIF production in vitro. RESULTS: Both Caucasians and African Americans with the high-expression MIF haplotype -794 CATT(7)/-173*C had a lower incidence of SLE (in Caucasians, odds ratio [OR] 0.63, 95% confidence interval [95% CI] 0.53-0.89, P = 0.001; in African Americans, OR 0.46, 95% CI 0.23-0.95, P = 0.012). In contrast, among patients with established SLE, reduced frequencies of low-expression MIF genotypes (-794 CATT(5)) were observed in those with nephritis, those with serositis, and those with central nervous system (CNS) involvement when compared to patients without end-organ involvement (P = 0.023, P = 0.005, and P = 0.04, respectively). Plasma MIF levels and TLR-7-stimulated MIF production in vitro reflected the underlying MIF genotype of the studied groups. CONCLUSION: These findings suggest that MIF, which has both proinflammatory properties and macrophage and B cell survival functions, exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE and may contribute to an enhanced clearance of infectious pathogens. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage.

Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy.

PURPOSE: There is a need for new agents to treat metastatic breast cancer (MBC) in patients for whom anthracycline therapy has failed or is contraindicated. This study was conducted to assess the efficacy and safety of the novel antineoplastic, the epothilone B analog ixabepilone, in patients with MBC previously treated with an adjuvant anthracycline. PATIENTS AND METHODS: Patients were age >or= 18 years and had received a prior anthracycline-based regimen as adjuvant treatment. Ixabepilone as first-line metastatic chemotherapy was administered as a 40 mg/m(2) intravenous infusion during 3 hours every 3 weeks. The primary efficacy end point was objective response rate (ORR). Secondary efficacy end points included duration of response, time to response, time to progression, and survival. RESULTS: All 65 patients were assessable for response. Their median age was 52 years (range, 33 to 80 years). ORR was 41.5% (95% CI, 29.4% to 54.4%), median duration of response was 8.2 months (95% CI, 5.7 to 10.2 months), and median time to response was 6 weeks (range, 5 to 17 weeks). Median survival was 22.0 months (95% CI, 15.6 to 27.0 months). Treatment-related adverse events were manageable and mostly grades 1/2: the most common of these (other than alopecia) was mild to moderate neuropathy, which was primarily sensory and mostly reversible in nature. CONCLUSION: Ixabepilone is efficacious and has a predictable and manageable safety profile in women with MBC previously treated with an adjuvant anthracycline.

Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy.

Although imatinib induces marked responses in patients with chronic myeloid leukemia (CML), resistance is increasingly problematic, and treatment options for imatinib-resistant or -intolerant CML are limited. Dasatinib, a novel, highly potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, induced cytogenetic responses in a phase 1 study in imatinib-resistant or -intolerant CML and was well tolerated. Initial results are presented from a phase 2 study of 186 patients with imatinib-resistant or -intolerant chronic-phase CML (CML-CP) designed to further establish the efficacy and safety of dasatinib (70 mg twice daily). At 8-months' follow-up, dasatinib induced notable responses, with 90% and 52% of patients achieving complete hematologic and major cytogenetic responses (MCyR), respectively. Responses were long lasting: only 2% of patients achieving MCyR progressed or died. Importantly, comparable responses were achieved by patients carrying BCR-ABL mutations conferring imatinib resistance. Dasatinib also induced molecular responses, reducing BCR-ABL/ABL transcript ratios from 66% at baseline to 2.6% at 9 months. Nonhematologic adverse events were generally mild to moderate, and most cytopenias were effectively managed with dose modifications. Cross-intolerance with imatinib was not evident. To conclude, dasatinib induces notable responses in imatinib-resistant or -intolerant CML-CP, is well tolerated, and represents a promising therapeutic option for these patients. This trial was registered at www.clinicaltrials.gov as CA180013.

Renal insufficiency predicts the time to first appropriate defibrillator shock.

BACKGROUND: Indications for implantable cardioverter defibrillator (ICD) implantation are expanding, but many primary and secondary ICD trials have excluded patients with advanced renal insufficiency. We investigated the effect of renal function on the incidence and time to first appropriate ICD shock. METHOD: We analyzed data from all new ICD implantations at a tertiary care center from July 2001 to December 2002. RESULTS: During a mean follow-up time of 445 +/- 285 days, 29 (13%) of 230 patients (age 63 +/- 14 years, 79% men, 77% white, 75% coronary artery disease, left ventricular ejection fraction 0.28 +/- 0.14) received 41 appropriate shocks. Patients were divided into tertiles according to their serum creatinine level. The 1-year incidence of appropriate ICD shock was 3.8%, 10.8%, and 22.7% in the first, second, and third tertiles, respectively (P = .003). Using the same cut off values of serum creatinine, the 1-year incidence of appropriate ICD therapy (shock and antitachycardia pacing) was 8.8%, 20.8%, and 26.3% (P = .02). After correcting for age, sex, race, left ventricular ejection fraction, indication for ICD implantation, and use of beta-blockers in a Cox regression model, serum creatinine was still an independent predictor of the time to first appropriate ICD shock (hazard ratio 6.0 for the third compared with the first tertile, P = .001). CONCLUSION: Renal insufficiency is a strong predictor of appropriate ICD shocks. Defibrillator therapy should therefore not be withheld based on the presence of this comorbidity. The mechanisms underlying the relationship between renal function and ventricular arrhythmias deserve further investigation.

Relation of advanced heart failure symptoms to risk of inappropriate defibrillator shocks.

Inappropriate implantable cardioverter-defibrillator (ICD) shocks continue to be a major source of distress to patients and a drain on the health care system. Expanding indications for ICD implantation include a large portion of patients with heart failure. This study investigated the relation between inappropriate ICD shocks and the severity of heart failure symptoms. Predictors of the time to first inappropriate ICD therapy were investigated in 230 consecutive patients implanted in 2001 and 2002. Thirty-two patients received 42 inappropriate shocks during a median follow-up of 501 days. Inappropriate shocks were due to atrial fibrillation (AF) or tachycardia (n = 31), other supraventricular tachycardias (n= 6), sinus tachycardia (n = 3), and noise or double counting (n = 2). The time to first inappropriate ICD shock was earliest in patients with advanced classes of heart failure (1- and 2-year shock-free survival of 79% and 70% for patients in New York Heart Association [NYHA] class III or IV vs 92% and 88% for patients in NYHA class I or II, respectively, p = 0.02). After correcting for age, gender, the presence of coronary artery disease, the presence of AF, the use of beta blockers, and indication for ICD implantation in a Cox regression model, advanced heart failure (NYHA class III or IV) remained an independent predictor of first inappropriate ICD shocks (hazard ratio 2.7, p = 0.01). Other predictors of the time to first inappropriate ICD shock included the presence of AF as the baseline rhythm at the time of the ICD implantation and the absence of coronary disease. In conclusion, inappropriate ICD shocks are predominantly due to AF. Advanced heart failure is an independent predictor of the time to first inappropriate ICD shocks. The effect of ICD programming and antiarrhythmic drug therapy on the incidence of inappropriate shocks deserves further investigation.

Indications for internal cardioverter defibrillator implantation predict time to first shock and the modulating effect of beta-blockers.

BACKGROUND: Patients receive implantable cardioverter defibrillator (ICD) for varying indications. Whether these indications influence the time to first ICD shock is suspected but not confirmed. The modulating effect of beta-blockers on shock-free survival is not fully elucidated. METHOD: A retrospective analysis of 230 consecutive patients (age 63 +/- 14 years, 79% men, 75% ischemic, 70% beta-blockers) implanted with an ICD was performed. Patients were divided into 4 groups depending on the ICD indication: groups A (secondary prevention of sudden death), B (left ventricular ejection fraction < or = 35% and positive electrophysiology study [EPS]), C (left ventricular ejection fraction < or = 35% and negative EPS or no EPS performed), and D (patients who did not meet inclusion criteria for groups A, B, or C). Time to shock was analyzed by the Kaplan-Meier method. RESULTS: During a mean follow-up of 489 +/- 280 days, 57 (24.7%) patients received 82 shocks (49% appropriate). The 1-year shock-free survival for patients in groups A, B, C, and D were 57%, 77%, 79%, and 91%, respectively (P = .03), for total shocks and 75%, 92%, 92%, and 100%, respectively (P = .007), for appropriate shocks. For patients in group A, the use of beta-blockers increased the 1-year shock-free survival from 48% to 61% for total shocks and from 65% to 79% for appropriate shocks. CONCLUSION: Time to first shock is determined by the indication for ICD implantation and is not predicted by the results of EPS. Patients with secondary indications for ICD implantation are at highest risk of shocks and may deserve consideration for prophylactic antiarrhythmic drugs. beta-Blockers increase the time to first ICD shock in patients implanted for secondary prevention of sudden death.

Utilization of implantable cardioverter-defibrillators in survivors of cardiac arrest in the United States from 1996 to 2001.

OBJECTIVES: We analyzed the incidence of implantable cardioverter-defibrillator (ICD) therapy in survivors of cardiac arrest (CA) in the U.S. from 1996 through 2001. BACKGROUND: Cardiac arrest is a class I indication for ICD therapy. The current patterns of ICD utilization in survivors of CA have not been fully examined. METHODS: We searched a representative sample of all hospital discharges for patients admitted with the primary diagnosis of CA who survived to hospital discharge. Patients with a concomitant diagnosis of acute myocardial infarction or previous ICD in situ were excluded. RESULTS: From 1996 to 2001, 113,262 patients were admitted for CA. Of those, 63,745 (56.3%) did not survive to hospital discharge. Of the remaining 49,517 patients, 30.7% received an ICD before discharge, with a gradual increase in implantation rates from 1996 (23.6%) to 2001 (46.3%). Using logistic regression for the years 2000 and 2001, patients who were discharged without an ICD were older (odds ratio [OR] 0.93 for every 10-year increase in age, p < 0.001), more likely to be African American (OR 0.19, p < 0.001), and more likely to be admitted to a smaller hospital (OR 2.24 for each additional 100 beds, p < 0.001). These predictors were independent of other co-morbid illnesses. CONCLUSIONS: Although they are increasing, the rates of ICD therapy after CA remain very low. There are gross discrepancies by race. At a time when newer indications for ICD implantation are emerging, efforts should be focused on identifying the causes of this underutilization and discrepancies in survivors of CA.