With increasing life expectancy, upper extremity (UE) function becomes more and more important in boys with Duchenne muscular dystrophy (DMD). Knowledge of UE function in these children is, however, ...limited. The aim of this study was to gain insight into the changing patterns of UE function during the course of DMD. A Web-based questionnaire on UE function, covering all domains of the International Classification of Functioning Disability and Health, was distributed worldwide. Primary domains of the questionnaire were: participant characteristics, UE pain and stiffness, UE activities, and social participation. Data were described per disease stage and analyzed using descriptive analysis. A total of 213 boys/men with DMD (1–35 years) were included in this study. UE pain, stiffness, and activity limitations increased with disease stage. UE activity limitations already occurred in the early ambulatory stage. Compared to the healthy population, social participation was restricted in DMD patients and about 70 % of the respondents experienced UE limitations when performing social activities. Despite the existence of UE impairments, only 9 % of the respondents used supportive aids. Functional capacities and activities of the UE are limited already in the early ambulatory stage of patients with DMD affecting their social participation. Therefore, clinicians should pay attention to UE limitations before DMD patients lose their capacity to walk. Effective and adequate aids as well as attention for pain and stiffness in the therapeutic management could help to reduce UE activity limitations and related restrictions in social participation.
Paediatric rhabdomyosarcoma (RMS) is a soft tissue malignancy of mesenchymal origin that is thought to arise as a consequence of derailed myogenic differentiation. Despite intensive treatment ...regimens, the prognosis for high-risk patients remains dismal. The cellular differentiation states underlying RMS and how these relate to patient outcomes remain largely elusive. Here, we use single-cell mRNA sequencing to generate a transcriptomic atlas of RMS. Analysis of the RMS tumour niche reveals evidence of an immunosuppressive microenvironment. We also identify a putative interaction between NECTIN3 and TIGIT, specific to the more aggressive fusion-positive (FP) RMS subtype, as a potential cause of tumour-induced T-cell dysfunction. In malignant RMS cells, we define transcriptional programs reflective of normal myogenic differentiation and show that these cellular differentiation states are predictive of patient outcomes in both FP RMS and the less aggressive fusion-negative subtype. Our study reveals the potential of therapies targeting the immune microenvironment of RMS and suggests that assessing tumour differentiation states may enable a more refined risk stratification.
We have completed a multicenter, randomized controlled phase III clinical trial in Stages II and III colon cancer patients with active specific immunotherapy (ASI) using autologous tumor cells with ...an immunomodulating adjuvant bacillus Callmette-Guérin (BCG) vaccine (OncoVAX
®) in an adjuvant setting. In this study, patients were randomized to receive either OncoVAX
® therapy or no therapy after surgical resection of the primary tumor and stratified by stage of disease. Since the biologic essence of the effective tumor immunotherapy is the presence in the vaccine of a minimum number of viable, metabolically active, autologous tumor cells, the processing of the vaccine product, occurred within 48
h after surgery.
Analysis of prognostic benefit in the pivotal phase III trial, with a 5.8 year median follow-up, showed that a beneficial effect of OncoVAX
® is statistically significant for all endpoints including recurrence-free interval, overall survival, and recurrence-free survival in Stage II colon cancer patients. Surgery alone cures approximately 65% of Stage II (Dukes B
2, B
3) colon cancer patients. In the remaining patients, OncoVAX
® in an adjuvant setting, significantly prolongs recurrence-free interval (57.1% relative risk reduction) and significantly improves 5-year overall survival and recurrence-free survival. No statistically significant prognostic benefits were achieved in Stage III (Duke's C
1–C
3) patients.
A health economics assessment was performed on these results in Stage II colon cancer patients using disease-free survival and overall survival (for the entire intent-to-treat population). Cost-effectiveness, cost-utility and sensitivity analysis were applied with, cost of life years, recurrence-free life years and quality adjusted life years (QALYs) as the primary endpoints to this analysis. The perspective of the economic analysis was the current direct medical cost established by the health care providers. The introduction of new technologies often leads to additional costs. This report verified that the use of OncoVAX
® for patients with Stage II colon cancer not only has significant prognostic benefit and positive clinical outcomes, but also showed that OncoVAX
® therapy yields impressive health economics benefits.
Aims/hypothesis
The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) ...butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes.
Methods
We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the ‘oral sodium butyrate capsules first’ or ‘oral placebo capsules first’ study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers.
Results
All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work.
Conclusions/interpretation
Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes.
Trial registration
Netherlands Trial Register: NL4832 (
www.trialregister.nl
).
Data availability
Raw sequencing data are available in the European Nucleotide Archive repository (
https://www.ebi.ac.uk/ena/browse
) under study PRJEB30292.
Funding
The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.
Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research ...designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients.
Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future.
Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing.
Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Background
The coagulopathy in cirrhosis is associated with thrombosis and bleeding.
Objectives
To gain better insights into the coagulopathy in patients with cirrhosis, we evaluated plasma ...thrombin generation and whole blood clot formation in a cross‐sectional study.
Methods
Blood was collected from 73 patients with all‐cause cirrhosis (Child‐Pugh‐A n = 52, B n = 15, C n = 6) and 20 healthy controls. Activity of the coagulation pathways was measured with assays for factor (F) VIIa and FIXa‐antithrombin and FXa‐antithrombin complexes, respectively. Thrombin generation by calibrated automated thrombography was determined in platelet‐poor plasma using a 1 or 5 pm tissue factor trigger with/without thrombomodulin. ROTEM measurements were performed in whole blood triggered with 35 pm tissue factor without/with 175 ng mL−1 tissue plasminogen activator (the latter refered to as ‘tPA‐ROTEM’).
Results
We observed an increased generation of FVIIa and a moderately elevated amount of FIXa (in complex with antithrombin) without apparent increase in FX activation in patients with cirrhosis. In accordance with this prothrombotic state, markers of thrombin generation potential were also increased upon increasing severity of cirrhosis. In the whole blood clotting assay we observed delayed clot formation and decreased clot strength associated with increased severity of cirrhosis. No significant differences were found for tPA‐ROTEM parameters of clot degradation.
Conclusion
These results indicate that cirrhosis patients have an overall procoagulant plasma milieu but a decreased whole blood clot formation capacity with an apparently unaltered resistance to clot lysis.
•MR-guided radiotherapy for rectal cancer on a 1.5T MR-linac is feasible.•An online adaptive workflow takes about 48 min each fraction.•Treatment of rectal cancer on the 1.5T MR-linac is well ...tolerated by patients.•This workflow holds promise for margin reduction.
Daily online adaptation of the clinical target volume (CTV) using MR-guided radiotherapy enables margin reduction of the planning target volume (PTV). This study describes the implementation and initial experience of MR-guided radiotherapy on the 1.5T MR-linac and evaluates treatment time, patient compliance, and target coverage, including an initial assessment of margin reduction.
Patients were treated on a 1.5T MR-linac (7MV, FFF). At each fraction a 3D T2 weighted (T2w) MR-sequence was acquired on which the CTV was adapted after a deformable registration of the contours from the pre-planning CT scan. Based on the new contours a full online replanning was done after which a new 3D T2w MR-sequence was acquired for position verification. A 5 field Intensity Modulated Radiotherapy (IMRT) plan was delivered.
Forty-three patients with rectal cancer were treated with 25 Gy in 5 fractions of which 18 with reduced margins. In total, 204 of 215 fractions were delivered on the MR-linac all of which obtained a clinically acceptable treatment plan. Median in-room time per fraction was 48 min (interquartile range 8). No fractions were canceled or interrupted because of patient intolerance. CTV coverage after margin reduction was good on all post-treatment scans but one due to passing gas.
MR-guided radiotherapy using daily full online recontouring and replanning on a 1.5T MR-linac for rectal cancer is feasible and currently takes about 48 min per fraction.
Please cite this paper as: Ravelli A, Jager K, de Groot M, Erwich J, Rijninks‐van Driel G, Tromp M, Eskes M, Abu‐Hanna A, Mol B. Travel time from home to hospital and adverse perinatal outcomes in ...women at term in the Netherlands. BJOG 2011;118:457–465.
Objective To study the effect of travel time, at the start or during labour, from home to hospital on mortality and adverse outcomes in pregnant women at term in primary and secondary care.
Design Population‐based cohort study from 2000 up to and including 2006.
Setting The Netherlands Perinatal Registry.
Population A total of 751 926 singleton term hospital births.
Methods We assessed the impact of travel time by car, calculated from the postal code of the woman’s residence to the 99 maternity units, on neonatal outcome. Logistic regression modelling with adjustments for gestational age, maternal age, parity, ethnicity, socio‐economic status, urbanisation, tertiary care centres and volume of the hospital was used.
Main outcome measures Mortality (intrapartum, and early and late neonatal mortality) and adverse neonatal outcomes (mortality, Apgar <4 and/or admission to a neonatal intensive care unit).
Results The mortality was 1.5 per 1000 births, and adverse outcomes occurred in 6.0 per 1000 births. There was a positive relationship between longer travel time (≥20 minutes) and total mortality (OR 1.17, 95% CI 1.002–1.36), neonatal mortality within 24 hours (OR 1.51, 95% CI 1.13–2.02) and with adverse outcomes (OR 1.27, 95% CI 1.17–1.38). In addition to travel time, both delivery at 37 weeks of gestation (OR 2.23, 95% CI 1.81–2.73) or 41 weeks of gestation (OR 1.52, 95% CI 1.29–1.80) increased the risk of mortality.
Conclusions A travel time from home to hospital of 20 minutes or more by car is associated with an increased risk of mortality and adverse outcomes in women at term in the Netherlands. These findings should be considered in plans for the centralisation of obstetric care.
Caloric restriction (CR) extends lifespan in mammals, yet the mechanisms underlying its beneficial effects remain unknown. The manner in which CR has been implemented in longevity experiments is ...variable, with both timing and frequency of meals constrained by work schedules. It is commonplace to find that nocturnal rodents are fed during the daytime and meals are spaced out, introducing prolonged fasting intervals. Since implementation of feeding paradigms over the lifetime is logistically difficult, automation is critical, but existing systems are expensive and not amenable to scale. We have developed a system that controls duration, amount, and timing of food availability and records feeding and voluntary wheel-running activity in mice. Using this system, mice were exposed to temporal or caloric restriction protocols. Mice under CR self-imposed a temporal component by consolidating food intake and unexpectedly increasing wheel-running activity during the rest phase, revealing previously unrecognized relationships among feeding, metabolism, and behavior.
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•Automated feeder system enables long-term control and measurement of food access•Calorically restricted mice rapidly eat within 2 hr despite 24 hr food availability•Calorically restricted mice increase their locomotor activity during the rest phase•Daytime feeding prevents body weight loss under 30% caloric restriction in mice
Acosta-Rodríguez et al. developed an automated feeding system that controls amount, duration, and timing of food availability and also records feeding and voluntary wheel-running activity in mice. They discover that calorie-restricted mice self-imposed a temporal component by consolidating food intake and unexpectedly increasing wheel-running activity during the rest phase.
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