The EGFRvIII transcriptome in glioblastoma, a meta-omics analysis.

BACKGROUND: EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being amongst its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signalling compared with wildtype EGFR. METHODS: To better understand the oncogenic role of EGFRvIII, we leveraged four large datasets into one large glioblastoma transcriptome dataset (n=741) alongside 81 whole-genome samples from two datasets. RESULTS: The EGFRvIII/EGFR expression ratios differ strongly between tumours and ranges from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII positive and negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (p=0.007), which may point towards crosstalk between these pathways. EGFRvIII-expressing tumours have an upregulation of 'classical' subtype genes compared to those with EGFR-amplification only (p=3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference towards the 3' end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. CONCLUSIONS: These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumours

The Unstable Distal Radius Fracture-How Do We Define It? A Systematic Review

Background Unstable distal radius fractures are a popular research subject. However, to appreciate the findings of studies that enrolled patients with unstable distal radius fractures, it should be clear how the authors defined an unstable distal radius fracture. Questions In what percentage of studies involving patients with unstable distal radius fractures did the authors define unstable distal radius fracture? What are the most common descriptions of an unstable distal radius fracture? And is there one preferred evidence-based definition for future authors? Methods A systematic search of literature was performed to identify any type of study with the term unstable distal radius fracture. We assessed whether a definition was provided and determined the level of evidence for the most common definitions. Results The search yielded 2,489 citations, of which 479 were included. In 149 studies, it was explicitly stated that patients with unstable distal radius fractures were enrolled. In 54% (81/149) of these studies, the authors defined an unstable distal radius fracture. Overall, we found 143 different definitions. The seven most common definitions were: displacement following adequate reduction; Lafontaine's definition; irreducibility; an AO type C2 fracture; a volarly displaced fracture; Poigenfürst's criteria; and Cooney's criteria. Only Lafontaine's definition originated from a clinical study (level IIIb). Conclusion In only half of the studies involving patients with an unstable distal radius fracture did the authors defined what they considered an unstable distal radius fracture. None of the definitions stood out as the preferred choice. A general consensus definition could help to standardize future researc

Prediction of Distal Radius Fracture Redisplacement: A Validation Study

To externally validate the Edinburgh Wrist Calculator (EWC) in a population of patients with distal radius fractures at risk of loss of threshold alignment. A retrospective cohort study. One academic hospital. All consecutive adult patients with a displaced distal radius fracture with initial dorsal angulation >10 degree and/or an ulnar variance of >3 mm who were treated with closed reduction and cast immobilization between 2009 and 2014. The sensitivity and specificity for diagnosis of loss of threshold alignment within 2 weeks of injury was calculated at the 10%, 40%, and the original 70% probability thresholds. The area under receiver operating characteristic curve was calculated using 2 different thresholds for loss of alignment: Mackenney et al and the Dutch consensus standards. The EWC predicted a greater than 70% chance of redisplacement for only 3 fractures. Redisplacement within 2 weeks occurred in 61 of 99 (62%) fractures according to the thresholds of Mackenney et al and in 18 of 99 (18%) fractures according to the Dutch thresholds. The sensitivity increased and the specificity decreased using a lower probability threshold for redisplacement. The area under the receiver operating characteristic curve of the EWC was poor the Mackenney's thresholds [0.47; 95% confidence interval (CI): 0.36-0.59] and adequate for the Dutch thresholds (0.71; 95% CI: 0.58-0.84). The EWC was a poor predictor of fracture redisplacement greater than threshold in displaced distal radius fractures in our patient populatio

Mason Type I Fractures of the Radial Head

Mason type I fractures are the most common fractures of the radial head. The fractures have a benign character and often result in good, pain-free function. Nevertheless, up to 20% of patients with a Mason type I fracture report loss of extension and residual pain. Currently, there is a lack of consensus concerning diagnosis and treatment of these fractures. The goal of this study was to systematically review incidence, diagnosis, classification, treatment, and outcome of Mason type I radial head fractures in adults and establish an evidence-based treatment guideline. A search of the MEDLINE, EMBASE, and Cochrane databases was conducted for English titles without restrictions on publication date. The authors included titles that addressed Mason type I radial head fractures and covered incidence, diagnostics, treatment, or functional or patient-related outcome. Included were randomized controlled trials; case-control studies; comparative cohort studies; case series with more than 10 patients; and expert opinions. Reference lists were cross-checked for additional titles. The search yielded 1734 studies, of which 95 met the inclusion criteria. Seven studies showed that the elbow extension test has a high sensitivity (88.0-97.6) to rule out Mason type I radial head fractures. If radiography is required, anteroposterior and lateral radiographs suffice. For pain relief, hematoma aspiration seems safe and effective. Mason type I fractures are best treated with 48 hours of rest with a sling, followed with active mobilization. Cast immobilization should be avoided. Mobilization should be encouraged and if needed supported by physical therap

The Minimum Clinically Important Difference of the Patient-rated Wrist Evaluation Score for Patients With Distal Radius Fractures

The Patient-rated Wrist Evaluation (PRWE) is a commonly used instrument in upper extremity surgery and in research. However, to recognize a treatment effect expressed as a change in PRWE, it is important to be aware of the minimum clinically important difference (MCID) and the minimum detectable change (MDC). The MCID of an outcome tool like the PRWE is defined as the smallest change in a score that is likely to be appreciated by a patient as an important change, while the MDC is defined as the smallest amount of change that can be detected by an outcome measure. A numerical change in score that is less than the MCID, even when statistically significant, does not represent a true clinically relevant change. To our knowledge, the MCID and MDC of the PRWE have not been determined in patients with distal radius fractures. We asked: (1) What is the MCID of the PRWE score for patients with distal radius fractures? (2) What is the MDC of the PRWE? Our prospective cohort study included 102 patients with a distal radius fracture and a median age of 59 years (interquartile range [IQR], 48-66 years). All patients completed the PRWE questionnaire during each of two separate visits. At the second visit, patients were asked to indicate the degree of clinical change they appreciated since the previous visit. Accordingly, patients were categorized in two groups: (1) minimally improved or (2) no change. The groups were used to anchor the changes observed in the PRWE score to patients' perspectives of what was clinically important. We determined the MCID using an anchor-based receiver operator characteristic method. In this context, the change in the PRWE score was considered a diagnostic test, and the anchor (minimally improved or no change as noted by the patients from visit to visit) was the gold standard. The optimal receiver operator characteristic cutoff point calculated with the Youden index reflected the value of the MCID. In our study, the MCID of the PRWE was 11.5 points. The area under the curve was 0.54 (95% CI, 0.37-0.70) for the pain subscale and 0.71 (95% CI, 0.57-0.85) for the function subscale. We determined the MDC to be 11.0 points. We determined the MCID of the PRWE score for patients with distal radius fractures using the anchor-based approach and verified that the MDC of the PRWE was sufficiently small to detect our MCID. We recommend using an improvement on the PRWE of more than 11.5 points as the smallest clinically relevant difference when evaluating the effects of treatments and when performing sample-size calculations on studies of distal radius fracture

The Amsterdam Wrist Rules: how much money can they save?

Purpose: To allow physicians to be more selective in their request for a radiograph of the wrist and to potentially reduce costs, the Amsterdam Wrist Rules (AWR) have been developed, externally validated, and recently also implemented. The aim of this study was to conduct an incremental cost analysis and budget impact analysis of the implementation of the AWR at the emergency department (ED) in the Netherlands. Methods: A cost-minimisation analysis to determine the expected cost savings for implementation of the Amsterdam Wrist Rules. The incremental difference in costs before and after implementation of the AWR was based on the reduction in costs for radiographs, the cost savings due to reduction of ED consultation times and the costs of a re-evaluation appointment by a physician. Results: In the Netherlands, implementation of the AWR could potentially result in 6% cost savings per patient with a wrist injury. In addition, implementation of the AWR resulted in €203,510 cost savings annually nationwide. In the sensitivity analysis, an increase in physician compliance to 100% substantially increased the potential total amount of annual cost savings to €610,248, which is 6% of total costs before implementation. Variation in time spent at the ED, a decrease and increase in costs and patients presenting annually at the ED did not change the cost savings substantially. Conclusion: Implementation of the AWR has been shown to reduce direct and indirect costs and can, therefore, result in considerable savings of healthcare consumption and expenditure

The Amsterdam Wrist Rules to reduce the need for radiography after a suspected distal radius fracture: an implementation study

Purpose: While most patients with wrist trauma are routinely referred for radiography, around 50% of these radiographs show no fracture. To avoid unnecessary radiographs, the Amsterdam Wrist Rules (AWR) have previously been developed and validated. The aim of the current study was to evaluate the effect of the implementation of the AWR at the Emergency Department (ED). Methods: In a before-and-after comparative prospective cohort study, all consecutive adult patients with acute wrist trauma presenting at the ED of four hospitals were included. Primary outcome was the number of wrist radiographs before and after implementation of the AWR. Secondary outcomes were the number of clinically relevant missed fractures, the overall length of stay in the ED, physician compliance regarding the AWR, and patient satisfaction and experience with the care received at the ED. Results: A total of 402 patients were included. The absolute reduction in wrist radiographs after implementation was 15% (p < 0.001). One clinically irrelevant fracture was missed. Non-fracture patients without wrist radiography due to the AWR spent 34 min less time in the ED compared with non-fracture patients who had a wrist radiograph (p = 0.015). The physicians adhered to the AWR in 36% of patients. Of all patients who did not receive a radiographic examination of the wrist, 87% were satisfied. Conclusion: Implementation of the AWR safely reduces the amount of wrist radiographs in selected patients and consequently reducing the length of stay in the ED

Functional outcome in patients with unstable distal radius fractures, volar locking plate versus external fixation: a meta-analysis

The aim of this study was to compare bridging external fixation with volar locked plating in patients with unstable distal radial fractures regarding functional outcome. A systematic search was performed in the Cochrane Central Register of Controlled Trials, Medline and EMBASE. All randomized controlled trials that compared bridging external fixation directly with volar locked plating in patients with distal radial fractures were considered. Three reviewers extracted data independently from eligible studies using a data collection form. Studies in which the primary endpoint was measured on the disabilities of the arm shoulder and hand (DASH) score at 3, 6 and 12 months were included in the analysis. To this end, mean scores and standard deviations were extracted. The software package Revman 5 provided by the Cochrane Collaboration was used for data analysis. Three studies involving 174 patients were analyzed. Ninety patients were treated with an (augmented) bridging external fixator and 84 with a volar locking plate. Data were analyzed with the random effects model. The robustness of the results was explored using a sensitivity analysis. Patients treated with a volar locking plate showed significantly lower DASH scores at all times. A difference of 16 (p = 0.006), six (p = 0.008) and eight points (p = 0.06) was found at 3, 6 and 12 months follow-up, respectively. Patients treated with a volar locking plate showed significantly better functional outcome throughout the entire follow-up. However, this difference was only clinically relevant during the early postoperative period (3 months