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Communicating a Pediatric Leukemia Diagnosis to a Child and Their Family: A Qualitative Study into Oncologists’ Perspectives
Full text linkBackground: A pediatric cancer diagnosis is overwhelming and stressful for the whole family. Patient-centered communication during the diagnostic conversation can support medical and psychosocial adaptation to the disease. Treatment of pediatric leukemia has become increasingly complex and requires a specific skillset from clinicians in effectively conveying information to families. The objective of the current study was to gain insight in the experiences and perspectives of pediatric oncologists when communicating leukemia diagnoses to families. Procedure: In this exploratory qualitative study, oncologists were eligible to participate for each diagnostic conversation between May 2022 and February 2023 of families participating in a larger study. Twenty-six semi-structed interviews with 16 oncologists were thematically analyzed. Results: Two interrelated conversational goals were identified: (i) informing the family about the illness, prognosis, and treatment; and (ii) creating trust and comfort for the family implying they are in the right place for maximal chance of survival. Oncologists experienced a challenge in balancing a high amount of information provision in a short timespan with simultaneously monitoring the (emotional) capacity and needs of the family to process information. Remarkably, oncologists commonly seem to rely on intuition to guide the family through the diagnostic conversation. They mentioned to sometimes postpone answering to family-specific informational needs and prioritized information they assume to be more helpful for the family at that time. Conclusions: During diagnostic conversations, oncologists aim to convey information they assume supports the needs of the family. Future research should investigate how these communication strategies are perceived by families
Advancing treatment response prediction in first-episode psychosis: integrating clinical and electroencephalography features
Full text linkAIMS: Prompt diagnosis and intervention are crucial for first-episode psychosis (FEP) outcomes, but predicting the response to antipsychotics remains challenging. We studied whether adding electroencephalography (EEG) characteristics improves clinical prediction models for treatment response and whether EEG-based predictors are influenced by initial treatment. METHODS: We included 115 antipsychotic-naïve patients with FEP. Positive and Negative Syndrome Scale (PANSS) and sociodemographic items were included as clinical features. Additionally, we analyzed resting-state EEG data (n = 45) for (relative) power, functional connectivity, and network organization. Treatment response, measured as change in PANSS positive subscale scores (∆PANSS+), was predicted using a random forest regression model. We analyzed whether the most predictive EEG characteristics were influenced after treatment. RESULTS: The clinical model explained 12% variance in symptom reduction in the training set and 32% in the validation set. Including EEG variables in the model led to a nonsignificant increase of 2% (total 34%) explained variance in symptom reduction. High hallucination symptom scores and a more hierarchical organization of alpha band networks (tree hierarchy) were associated with ∆PANSS+ reduction. The tree hierarchy in the alpha band decreased after medication. EEG source analysis revealed that this change was driven by alterations in the degree and centrality of frontal and parietal nodes in the functional brain network. CONCLUSIONS: Both clinical and EEG characteristics can inform treatment response prediction in patients with FEP, but the combined model may not be beneficial over a clinical model. Nevertheless, adding a more objective marker such as EEG could be valuable in selected cases
Development of a Double Tuned ²H/31P Whole-Body Birdcage Transmit Coil for 2H and 31P MR Applications From Head to Toe at 7 T
Full text linkDeuterium ( 2H) and phosphorus ( 31P) magnetic resonance spectroscopy (MRS) are complementary methods for evaluating tissue metabolism noninvasively in vivo. Combined 2H and 31P MRS would therefore be of interest for various applications, from cancer to diabetes. Loop coils are commonly used in X-nuclei studies in the human body for both transmit and receive. However, loop coils suffer from limited penetration depth and inhomogeneous B 1 + field. The purpose of this work is to develop a double tuned 2H/ 31P whole-body birdcage transmit coil for 7 T for 2H and 31P MRS imaging (MRSI) with homogeneous excitation over a large field-of-view. The performance of the 2H/ 31P birdcage coil was assessed on B 1 + fields over a body-sized phantom at 2H and 31P frequencies using an 8-channel 2H/ 31P receive array. Using two elements of the 2H/ 31P receive array, natural abundance 2H and 31P 3D MRSI data at rest were acquired consecutively in the brain and lower leg muscles. Additionally, 2H and 31P 3D MRSI data were acquired from one volunteer 90 min after [6,6'- 2H 2]-glucose intake, using 8-channel 2H/ 31P receive array around the abdomen. The B 1 + variation of the whole-body birdcage coil over the phantom was 12.1% for 2H and 19.2% for 31P. High-quality 2H and 31P 3D MRSI data were acquired from the brain and the lower leg. Whole liver coverage was achieved in both 2H and 31P 3D MRSI data. The developed 2H/ 31P whole-body birdcage transmit coil allows simultaneous 3D mapping of glucose and energy metabolism and membrane turnover throughout the human body
Estimation of respiratory syncytial virus-associated hospital admissions in five European countries: a modelling study
Full text linkBackground: Respiratory syncytial virus (RSV) can cause severe disease, notably among infants, older adults, and individuals with comorbidities. Non-systematic testing and differences in coding practices affect direct measures of the hospital disease burden. We aim to tackle this issue and estimate RSV-associated respiratory hospital admissions through time series modelling of hospital admissions. Methods: The number of RSV hospital admissions in Denmark, England, Finland, the Netherlands, and Spain were estimated with attribution analyses, using age-specific respiratory tract infection (RTI) admissions combined with virological data, both from routinely collected healthcare data. Analyses covered the years 2016–2023. Findings: The attributed incidence of RSV per 100,000 children 0–2 months ranged from 1715 in Denmark to 3842 in England. In older adults, substantial differences in the incidence of ICD-10 coded RSV hospitalisations were found, while the attributed RSV incidence was more comparable, ranging from approximately 100 per 100,000 in adults 65–74 years to 200 per 100,000 persons 75–84 years and 500 per 100,000 persons 85 years and older. Interpretation: RSV-attributed time series exhibit a high degree of synchronicity between participating countries, suggesting that this method for attribution addresses the known issues with underdiagnosis and misclassification. In the older age groups, a substantial proportion of RTI hospitalisations is attributed to RSV, underscoring the relevance of RSV as a cause of severe respiratory infections. Funding: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 101034339. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA
Long-term exposure therapy outcome in phobia and the link with behavioral and neural indices of extinction learning
Full text linkExtinction learning is regarded as a core mechanism underlying exposure therapy. Under this assumption, studies have looked at the predictive value of the extinction learning paradigm for exposure therapy outcomes. However, predicting factors of long-term exposure therapy success have not been established. Participants with a specific phobia (SP) for spiders were included in a double-blind randomized controlled trial. Participants were randomly assigned to receive exposure therapy (n = 25, 24 females) or an active control intervention, progressive muscle relaxation (PMR; n = 18, 15 females). Symptom levels were measured with the Fear of Spiders questionnaire (FSQ) at baseline (T0), after the intervention (T1), and at six- (T2) and twelve (T3) months follow-up. At baseline, participants completed a three-day fMRI fear conditioning, extinction learning, and extinction recall paradigm. Indices of extinction were defined as self-reported threat expectancy and fear, and neural activation during stimulus presentations and threat omission in the ventromedial prefrontal cortex and nucleus accumbens, based on prior data. Mixed model analysis revealed that the exposure therapy group had an overall stronger decrease in phobic symptoms over time than the PMR group (β = 10.95, p < .001). However, none of the indices of extinction learning were predictive for FSQ scores after exposure therapy at the longest follow-up measurement (T3). In sum, the current results show the long-term effectiveness of a single session of exposure therapy for reducing a specific fear of spiders but no baseline characteristics were identified that predicted individual differences in exposure therapy success after one year
Systematic review of 99 extremity bone malignancy survival prediction models
Full text linkBACKGROUND: Various prediction models have been developed for extremity metastasis and sarcoma. This systematic review aims to evaluate extremity metastasis and sarcoma models using the utility prediction model (UPM) evaluation framework. METHODS: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and systematically searched PubMed, Embase, and Cochrane to identify articles presenting original prediction models with 1-year survival outcome for extremity metastasis and 5-year survival outcome for sarcoma. Identified models were assessed using the UPM score (0-16), categorized as excellent (12-16), good (7-11), fair (3-6), or poor (0-2). A total of 5 extremity metastasis and 94 sarcoma models met inclusion criteria and were analyzed for design, validation, and performance. RESULTS: We assessed 5 models for extremity metastasis and 94 models for sarcoma. Only 4 out of 99 (4%) models achieved excellence, 1 from extremity metastasis and 3 from sarcoma. The majority were rated good (62%; 61/99), followed by fair (31%, 31/99) and poor (3%, 3/99). CONCLUSIONS: Most predictive models for extremity metastasis and sarcoma fall short of UPM excellence. Suboptimal study design, limited external validation, and the infrequent availability of web-based calculators are main drawbacks. LEVEL OF EVIDENCE: This study is classified as Level 2a evidence according to the Oxford 2011 Levels of Evidence. Trial registration This study was registered in PROSEPRO (CRD42022373391, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=373391 )
Adjuvant Pembrolizumab in Stage II Melanoma: Outcomes by Primary Tumor Location in the Randomized, Double-Blind, Phase III KEYNOTE-716 Trial
No full textBackground: Previous results from the KEYNOTE-716 trial demonstrated significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) with adjuvant pembrolizumab versus placebo in patients with resected stage IIB or IIC melanoma. We present a post hoc analysis of efficacy according to primary tumor location. Methods: KEYNOTE-716 (NCT03553836) is a randomized, multicenter, double-blind, phase III study. Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma (sentinel node-negative) were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. This post hoc analysis evaluated RFS and DMFS by primary tumor location of the head/neck, trunk, or extremities. Results: Overall, 976 patients were assigned to pembrolizumab (n = 487) or placebo (n = 489). Median follow-up was 39.4 months (range 26.0–51.4). The hazard ratios {HRs (95% confidence interval [CI])} for RFS were 0.60 (0.38–0.93) for the head/neck subgroup, 0.57 (0.38–0.84) for the trunk subgroup, and 0.69 (0.47–1.02) for the extremities subgroup. The HRs (95% CI) for DMFS were 0.65 (0.37–1.14) for the head/neck subgroup, 0.59 (0.38–0.92) for the trunk subgroup, and 0.53 (0.31–0.90) for the extremities subgroup. Conclusion: RFS and DMFS consistently favored adjuvant pembrolizumab over placebo in most subgroups analyzed in this post hoc analysis from the KEYNOTE-716 trial. These results support the benefit of adjuvant pembrolizumab on RFS and DMFS in patients with resected high-risk stage II melanoma, irrespective of primary tumor location
Clinical Relevance of ATRX/DAXX Gene Mutations and ALT in Functioning Pancreatic Neuroendocrine Tumors
Full text linkFunctioning pancreatic neuroendocrine tumors (PanNETs) represent a subset of PanNETs that cause symptoms due to hormonal activity. Insulinoma is the most common functioning PanNET type. Mutations in the alpha thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes result in genomic instability. ATRX/DAXX mutations and associated alternative lengthening of telomeres (ALT) are common in non-functioning PanNETs and associated with aggressive tumor behavior. Recent reports have shown that ATRX/DAXX mutations and ALT are also present in functioning PanNETs. In this review, we summarize the literature addressing ATRX/DAXX mutations and ALT in functioning PanNETs and discuss the clinical relevance with regard to distinguishing aggressive and indolent functioning tumors. ATRX/DAXX gene mutations and/or ALT have been reported in insulinoma, glucagonoma, gastrinoma, VIPoma and calcitoninoma. In insulinoma, the presence of ATRX/DAXX mutations and ALT are associated with aggressive behavior and could therefore be used as prognostic biomarkers. Although ATRX/DAXX mutation and ALT assessment may currently not be the standard of care in routine diagnostic pathology practice, the use of DAXX/ATRX immunohistochemistry at least can be encouraged not only for non-functioning but also for functioning PanNETs
Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib
Full text linkObjectives: Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic areas outside human immunodeficiency virus (HIV) therapy. Data on the PK of the booster cobicistat and its effect on CYP3A-substrates outside of HIV therapy are lacking. This study aimed to describe the PK of once- and twice-daily cobicistat regimens in healthy volunteers and patients with rheumatoid arthritis, cancer, or HIV infection and to investigate the interplay between cobicistat and the anticancer drug olaparib. Methods: Cobicistat levels from 683 samples from 66 subjects in four clinical trials were included in the analysis. For olaparib, 261 samples from 12 subjects from one trial were included. Population PK analysis was performed by nonlinear mixed-effects modelling. Results: Both cobicistat and olaparib PK were adequately described by a well-stirred liver model with one central compartment and Erlang type absorption. Cobicistat PK was similar across patient populations and dosing regimens. Cobicistat increased olaparib prehepatic bioavailability 1.65-fold (RSE 6%) and decreased intrinsic clearance 0.34-fold (RSE 6.5%). A correlation between olaparib PK and cobicistat exposure could not be identified. The interindividual variability in olaparib clearance was lower with cobicistat than without cobicistat. Conclusions: The developed pharmacokinetic models adequately described cobicistat and olaparib plasma concentrations. PK boosting with cobicistat at 150 mg twice daily led to an increase in olaparib bioavailability and decrease in clearance. This effect was not correlated with cobicistat exposure, which may reflect saturation of the boosting effect of cobicistat at this dose. Trial Registration Numbers (date of registration): NCT02565888 (30-09-2015), NCT00825929 (19-01-2009), Netherlands Trial Register NL7766 (18-12-2018), NCT05078671 (22-09-2021)