ABSTRACT The detection of periodicity in the broadband non-thermal emission of blazars has so far been proven to be elusive. However, there are a number of scenarios that could lead to quasi-periodic ...variations in blazar light curves. For example, an orbital or thermal/viscous period of accreting matter around central supermassive black holes could, in principle, be imprinted in the multi-wavelength emission of small-scale blazar jets, carrying such crucial information about plasma conditions within the jet launching regions. In this paper, we present the results of our time series analysis of the ∼9.2 yr long, and exceptionally well-sampled, optical light curve of the BL Lac object OJ 287. The study primarily used the data from our own observations performed at the Mt. Suhora and Kraków Observatories in Poland, and at the Athens Observatory in Greece. Additionally, SMARTS observations were used to fill some of the gaps in the data. The Lomb-Scargle periodogram and the weighted wavelet Z-transform methods were employed to search for possible quasi-periodic oscillations in the resulting optical light curve of the source. Both methods consistently yielded a possible quasi-periodic signal around the periods of ∼400 and ∼800 days, the former with a significance (over the underlying colored noise) of . A number of likely explanations for this are discussed, with preference given to a modulation of the jet production efficiency by highly magnetized accretion disks. This supports previous findings and the interpretation reported recently in the literature for OJ 287 and other blazar sources.
Summary Background Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved ...rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response. Methods We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m2 ). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 ) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov , number NCT00553358. Findings 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50–4·22), 3-year event-free survival was 78% (95% CI 70–84) in the lapatinib group, 76% (68–82) in the trastuzumab group, and 84% (77–89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66–1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47–1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60–4·24), and 3-year overall survival was 93% (95% CI 87–96) for lapatinib, 90% (84–94) for trastuzumab, and 95% (90–98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45–1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30–1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22–0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15–0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events. Interpretation Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response. Funding GlaxoSmithKline.
We explore the disk-jet connection in the broad-line radio quasar 4C+74.26, utilizing the results of multiwavelength monitoring of the source. The target is unique in that its radiative output at ...radio wavelengths is dominated by a moderately beamed nuclear jet, at optical frequencies by the accretion disk, and in the hard X-ray range by the disk corona. Our analysis reveals a correlation (local and global significance of 96% and 98% respectively) between the optical and radio bands, with the disk lagging behind the jet by 250 42 days. We discuss the possible explanation for this, speculating that the observed disk and the jet flux changes are generated by magnetic fluctuations originating within the innermost parts of a truncated disk, and that the lag is related to a delayed radiative response of the disk when compared with the propagation timescale of magnetic perturbations along a relativistic outflow. This scenario is supported by re-analysis of NuSTAR data, modeled in terms of a relativistic reflection from the disk illuminated by the coronal emission, which returns an inner disk radius . We discuss the global energetics in the system, arguing that while the accretion proceeds at the Eddington rate, with the accretion-related bolometric luminosity Lbol ∼ 9 × 1046 erg s−1 ∼ 0.2LEdd, the jet total kinetic energy Lj ∼ 4 × 1044 erg s−1, inferred from the dynamical modeling of the giant radio lobes in the source, constitutes only a small fraction of the available accretion power.
Summary Background Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but ...the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0–10) is also reported. This study is registered with ClinicalTrials.gov , number NCT00045032. Findings We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio HR 0·99, 95% CI 0·85–1·14, p=0·86). Grade 3–4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 20·4% vs 275 16·3% grade 3–4 adverse events, and 120 7·2% vs 69 4·1% decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67–0·86, p<0·0001) for disease-free survival and 0·76 (0·65–0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy. Interpretation 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care. Funding F Hoffmann-La Roche (Roche).
Background Early termination of clinical trials due to low recruitment represents an understudied challenge for clinical research. We aimed to describe characteristics of cardiovascular trials ...terminated because of low recruitment and identify the major predictors of such early termination. Methods We reviewed all cardiovascular clinical trials (7,042 studies) registered in ClinicalTrials.gov from February 29, 2000, to January 17, 2013, and assessed information about trials that were completed and those that were terminated early. Logistic regression models were developed to identify independent predictors of early termination due to low recruitment. Results Our search strategy identified 6,279 cardiovascular clinical trials, of which 684 (10.9%) were terminated prematurely. Of these halted trials, the main reason for termination was lower than expected recruitment (278 trials; 53.6%). When comparing trials that terminated early because of low recruitment with those that were completed, we found that studies funded by the National Institutes of Health or other US federal agencies (odds ratio OR 0.35, 95% confidence interval CI 0.14-0.89), studies of behavior/diet intervention (OR 0.35, 95% CI 0.19-0.65), and single-arm design studies (OR 0.57, 95% CI 0.42-0.78) were associated with a lower risk of early termination. University/hospital-funded (OR 1.52, 95% CI 1.10-2.10) and mixed-source–funded studies (OR 2.14, 95% CI 1.52-3.01) were associated with a higher likelihood of early termination due to lower than expected recruitment rates. Conclusions Low recruitment represents the main cause of early termination of cardiovascular clinical trials. Funding source, type of intervention, and study design are factors associated with early termination due to low recruitment and might be good targets for improving enrollment into cardiovascular clinical trials.
Summary Background Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant ...trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. Methods We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5–4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. Results Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 2% of 1703 patients) and the observation group (32 2% of 1698; p=0·55 Gray's test). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 57% of 227) than in the group given trastuzumab for 1 year (88 47% of 186; p=0·06 Gray's test). Most CNS relapses were symptomatic (189 87% of 217). Conclusion Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. Funding None.
Summary Background Revaccination with double-dose hepatitis B vaccine has been recommended in HIV-infected patients who do not respond to standard vaccination, but has not yet been assessed. We aimed ...to compare the safety and immunogenicity of a reinforced hepatitis B revaccination protocol with the standard revaccination schedule in HIV-infected patients not responding to primary vaccination. Methods We did this multicentre, open-label, randomised controlled trial, at 53 centres in France. HIV-infected adults (aged ≥18 years), with CD4 counts of 200 cells per μL or more and no response to a previous hepatitis B vaccination or a 20 μg booster dose, were randomly assigned (1:1), according to a computer-generated randomisation list with permuted blocks (block sizes of two to six), to receive either standard-dose (20 μg) or double-dose (40 μg) recombinant hepatitis B vaccine at weeks 0, 4, and 24. Randomisation was stratified by baseline CD4 count (200–349 vs ≥350 cells per μL). Patients and treating physicians were not masked to treatment allocation, but the randomisation list was concealed from the investigators who assigned participants to the vaccination groups. The primary endpoint was the proportion of responders, defined as patients with hepatitis B surface antibody (anti-HBs) titres of 10 mIU/mL or more, at week 28. We did analysis by modified intention to treat. This study is registered with ClinicalTrials.gov , number NCT00670839. Findings Between May 19, 2008, and May 8, 2011, 178 participants were randomly assigned to the standard-dose group (n=90) or the double-dose group (n=88), of whom 176 (98%) participants were included in the primary efficacy analysis. At week 28, we recorded a response in 60 patients (67%, 95% CI 57–77) in the standard-dose group versus 64 patients (74%, 63–82) in the double-dose group (p=0·334). Except for more frequent local reactions in the double-dose group than the standard-dose group (13 15% vs four 4% patients; p=0·020), there was no difference in safety between groups. Interpretation In adults with HIV-1 who have not responded to previous hepatitis B vaccination, double-dose revaccination did not achieve a higher response rate than did revaccination with standard single-dose regimen. However, the safety profile was similar between treatment groups. Our results should be assessed in future studies before double-dose vaccine can be considered for the standard of care of vaccine non-responders. Funding French National Institute for Medical Research–French National Agency for Research on AIDS and Viral Hepatitis.
The rainfall and temperature conditions are evaluated for the first time during the 1989–2006 period, in six main cocoa production areas (Abengourou, Agboville, Daloa, Dimbokro, Guiglo, and Soubre) ...of Côte d’Ivoire using data from SODEXAM (ground-based observation) and the ex-CAISTAB. Statistical analysis shows an important sensitivity of cocoa production to rainfall conditions in all regions. It is worth noting that only the major rainy season from April to July and the rainfall amount of the little dry season from August to September affect the cocoa production for an 80% confidence level. This influence varies from one cacao production area to another. Moreover, the effects related to temperature on the cocoa yield seem to represent a smaller contribution of climate impact than those related to precipitation during the studied period. The temperature change remains in the acceptable range of values, between 25°C and 29°C, which is a favorable condition for cocoa growing. These findings are obtained despite the significant contributions from nonclimatic factors, to year-to-year variability in cocoa production.
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