Summary Background Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this ...agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. Methods In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov , NCT01900743. Findings From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9–2·3) with regorafenib versus 1·7 months (0·9–1·8) with placebo (HR 0·89 95% CI 0·48–1·64 p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5–5·0) with regorafenib versus 1·8 (1·0–2·8) months with placebo (HR 0·46 95% CI 0·46–0·80 p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4–11·6) with regorafenib versus 1·0 (0·8–1·4) with placebo (HR 0·10 95% CI 0·03–0·35 p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0–7·8) with regorafenib versus 1·0 (0·9–1·9) with placebo (HR 0·46 95% CI 0·25–0·81 p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 19% events in the 89 patients in the regorafenib group vs two 2% events in the 92 patients in the placebo group), hand and foot skin reaction (14 15% vs no events) and asthenia (12 13% vs six 6%). One treatment-related death occurred in the regorafenib group due to liver failure. Interpretation Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib. Funding Bayer HealthCare.
Treatment and outcomes of patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have dramatically improved over the past 20 years. This work evaluated treatment patterns and outcomes ...according to age.
Women who initiated a treatment for HER2+ MBC between 2008 and 2016 in one of the 18 French comprehensive centers part of the ESME program were included. Objectives were the description of first-line treatment patterns, overall survival (OS), first-line progression-free survival (PFS), and prognostic factors among patients aged 70 years or more (70+), or less than 70 (<70).
Of 4045 women diagnosed with an HER2+ MBC, 814 (20%) were 70+. Standard first-line treatment (chemotherapy combined with an anti-HER2 therapy) was prescribed in 65% of 70+ versus 89% of <70 patients (p < 0.01). Median OS was 49.2 (95% CI, 47.1–52.4), 35.3 (95% CI, 31.5–37.0) and 54.2 months (95% CI, 50.8–55.7) in the whole population, in patients 70+ and <70, respectively. Corresponding median PFS1 were 12.8 (95% CI, 12.3–13.3), 11.1 (95% CI, 10.0–12.3) and 13.2 months (95% CI, 12.7–13.9), respectively. In 70+ women, initiation of non-standard first-line treatment had an independent detrimental time-varying effect on both OS and PFS (HR on OS at 1 year: chemotherapy without anti-HER2 2.79 95% CI: 2.05–3.79; endocrine therapy and/or anti-HER2 1.96 95% CI: 1.43–2.69).
In this large retrospective real-life database, older women with HER2+ MBC received standard first-line treatment less frequently than younger ones. This was independently associated with a worse outcome, but confounding factors and usual selection biases cannot be ruled out.
•Only 65% of women aged 70+ with HER2+ MBC receive a standard first-line treatment.•Median PFS1 of women 70+ with HER2+ MBC is 11.1 months (95% CI, 10.0–12.3) vs 13.2 (95% CI, 12.7–13.9) for younger ones.•Non-standard first-line treatment has a detrimental time-varying effect on both OS and PFS.
Background Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about ...the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. Objective We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. Methods We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 ( CECR1 ). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. Results As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1β and TNF-α, which is consistent with the persistent systemic inflammation. Conclusions This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation.
Non-uniform terminology in the world's venous literature has continued to pose a significant hindrance to the dissemination of knowledge regarding the management of chronic venous disorders. This ...VEIN-TERM consensus document was developed by a transatlantic interdisciplinary faculty of experts under the auspices of the American Venous Forum (AVF), the European Venous Forum (EVF), the International Union of Phlebology (IUP), the American College of Phlebology (ACP), and the International Union of Angiology (IUA). It provides recommendations for fundamental venous terminology, focusing on terms that were identified as creating interpretive problems, with the intent of promoting the use of a common scientific language in the investigation and management of chronic venous disorders. The VEIN-TERM consensus document is intended to augment previous transatlantic/international interdisciplinary efforts in standardizing venous nomenclature which are referenced in this article.
Objectives The aim of this study was to determine if exercise testing could expose a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy (ARVC) in asymptomatic gene ...carriers. Background Management of asymptomatic ARVC gene carriers is challenging because of variable penetrance of disease and the recognition that sudden cardiac death may be the first clinical manifestation. Methods Exercise-induced abnormalities during exercise treadmill testing (ETT) were initially compared in 60 subjects: 30 asymptomatic ARVC gene carriers and 30 healthy controls. In phase 2 of the study, ETT results of 25 patients with ARVC with histories of sustained ventricular arrhythmia or cardiac arrest were evaluated to determine if ETT abnormalities in asymptomatic gene carriers were common to patients with a malignant electrical form of the disease. Results Depolarization abnormalities during ETT were found to develop more frequently in asymptomatic gene carriers compared with healthy controls: epsilon waves appeared in 4 of 28 (14%) compared with 0 of 30 (0%) (p = 0.048), premature ventricular contractions in 17 of 30 (57%) compared with 3 of 30 (10%) (p = 0.0003), and new QRS terminal activation duration ≥55 ms in 7 of 22 (32%) compared with 2 of 29 (7%) (p = 0.03). Superior axis premature ventricular contractions occurred only in gene carriers. In the second phase of the study, the frequency of these abnormalities was found to be high in patients with symptomatic ARVC: new epsilon waves appeared in 3 of 18 (17%), superior axis premature ventricular contractions in 21 of 25 (84%), and new terminal activation duration ≥55 ms in 8 of 12 (67%). Conclusions Exercise testing exposes a latent electrical substrate in asymptomatic ARVC gene carriers that is shared by patients with ARVC with histories of ventricular arrhythmia. ETT may be useful in guiding treatment decisions, exercise prescription, and prioritizing medical surveillance in asymptomatic ARVC gene carriers.
Abstract Objective Child sleep problems are prevalent and have been linked to poor behavior, worse school performance, and obesity. Low health literacy (HL) is associated with suboptimal parenting ...practices and worse health outcomes, but the relationship between parent HL and child sleep-related issues is not known. We examined the association between parent HL and child sleep-related issues. Methods This was a cross-sectional analysis of data from caregivers enrolled in a cluster randomized trial of a primary care-based child obesity prevention program in 4 pediatric clinics. Parent HL was assessed using the Short Test of Functional Health Literacy in Adults. At the 9-month well-child visit, sleep-related factors were assessed: presence of TV in room where child sleeps, regular naptimes and bedtimes (≥5 days/wk), low daytime and nighttime sleep duration (>1 SD below mean on the basis of national data). Multiple logistic regression analyses were performed. Results We enrolled 557 caregivers of 9-month-old children (49.7% Hispanic, 26.9% black, 56.2% <$20,000 annual income); 49.6% reported having a TV in the room where their child sleeps; 26.6% did not have regular naptimes norbedtimes. Median sleep duration was 2.3 (interquartile range, 1.5–3.0) hours (daytime), and 9.0 (interquartile range, 8.0–10.0) hours (night) (30.2% low daytime; 20.3% low nighttime sleep duration). Children of parents with low HL were more likely to have a bedroom TV (66.7% vs 47.7%, P = .01; adjusted odds ratio, 2.2; 95% confidence interval, 1.1–4.3) and low night-time sleep (37.0% vs 18.5%; P = .002; adjusted odds ratio, 2.4; 95% confidence interval, 1.2–4.8). Conclusions Low parent HL is associated with TV in the bedroom and low night sleep duration. Additional study is needed to further explore these associations and intervention strategies to address child sleep problems.
Abstract
We present high-resolution
12
CO and
13
CO 2–1 ALMA observations, as well as optical and near-infrared spectroscopy, of the highly inclined protoplanetary disk around SSTC2D ...J163131.2–242627. The spectral type we derive for the source is consistent with a 1.2
M
⊙
star inferred from the ALMA observations. Despite its massive circumstellar disk, we find little to no evidence for ongoing accretion on the star. The CO maps reveal a disk that is unusually compact along the vertical direction, consistent with its appearance in scattered light images. The gas disk extends about twice as far away as both the submillimeter continuum and the optical scattered light. CO is detected from two surface layers separated by a midplane region in which CO emission is suppressed, as expected from freeze-out in the cold midplane. We apply a modified version of the tomographically reconstructed distribution method presented by Dutrey et al. to derive the temperature structure of the disk. We find a temperature in the CO-emitting layers and the midplane of ∼33 K and ∼20 K at
R
< 200 au, respectively. Outside of
R
> 200 au, the disk’s midplane temperature increases to ∼30 K, with a nearly vertically isothermal profile. The transition in CO temperature coincides with a dramatic reduction in the submicron and submillimeter emission from the disk. We interpret this as interstellar UV radiation providing an additional source of heating to the outer part of the disk.
Objective To examine the relationship between parent health literacy and “obesogenic” infant care behaviors. Study design Cross-sectional analysis of baseline data from a cluster randomized ...controlled trial of a primary care-based early childhood obesity prevention program (Greenlight). English- and Spanish-speaking parents of 2-month-old children were enrolled (n = 844). The primary predictor variable was parent health literacy (Short Test of Functional Health Literacy in Adults; adequate ≥23; low <23). Primary outcome variables involving self-reported obesogenic behaviors were: (1) feeding content (more formula than breast milk, sweet drinks, early solid food introduction), and feeding style-related behaviors (pressuring to finish, laissez-faire bottle propping/television TV watching while feeding, nonresponsiveness in letting child decide amount to eat); and (2) physical activity (tummy time, TV). Multivariate logistic regression analyses (binary, proportional odds models) performed adjusting for child sex, out-of-home care, Women, Infants, and Children program status, parent age, race/ethnicity, language, number of adults/children in home, income, and site. Results Eleven percent of parents were categorized as having low health literacy. Low health literacy significantly increased the odds of a parent reporting that they feed more formula than breast milk, (aOR = 2.0 95% CI: 1.2-3.5), immediately feed when their child cries (aOR = 1.8 1.1-2.8), bottle prop (aOR = 1.8 1.002-3.1), any infant TV watching (aOR = 1.8 1.1-3.0), and inadequate tummy time (<30 min/d), (aOR = 3.0 1.5-5.8). Conclusions Low parent health literacy is associated with certain obesogenic infant care behaviors. These behaviors may be modifiable targets for low health literacy-focused interventions to help reduce childhood obesity.
Summary Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates ...respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation. Methods We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60–80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT01583088. Findings Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6–8·7) in the active stimulation group versus 8·8 months (4·2–not reached) in the control (sham stimulation) group (hazard ratio 1·96 95% CI 1·08–3·56, p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 65% patients in the active stimulation group vs 22 59% patients in the control group). No treatment-related death was reported. Interpretation Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement. Funding Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation.
PDF
