Redisplacement of reduced distal radius fractures in adults: does the type of casting play a role? The CAST study, a multicentre cluster randomized controlled trial.

Aims: It is not clear which type of casting provides the best initial treatment in adults with a distal radial fracture. Given that between 32% and 64% of adequately reduced fractures redisplace during immobilization in a cast, preventing redisplacement and a disabling malunion or secondary surgery is an aim of treatment. In this study, we investigated whether circumferential casting leads to fewer the redisplacement of fewer fractures and better one-year outcomes compared with plaster splinting. Methods: In a pragmatic, open-label, multicentre, two-period cluster-randomized superiority trial, we compared these two types of casting. Recruitment took place in ten hospitals. Eligible patients aged ≥ 18 years with a displaced distal radial fracture, which was acceptably aligned after closed reduction, were included. The primary outcome measure was the rate of redisplacement within five weeks of immobilization. Secondary outcomes were the rate of complaints relating to the cast, clinical outcomes at three months, patient-reported outcome measures (PROMs) (using the numerical rating scale (NRS), the abbreviated version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH), and Patient-Rated Wrist/Hand Evaluation (PRWHE) scores), and adverse events such as the development of compartment syndrome during one year of follow-up. We used multivariable mixed-effects logistic regression for the analysis of the primary outcome measure. Results: The study included 420 patients. There was no significant difference between the rate of redisplacement of the fracture between the groups: 47% (n = 88) for those treated with a plaster splint and 49% (n = 90) for those treated with a circumferential cast (odds ratio 1.05 (95% confidence interval (CI) 0.65 to 1.70); p = 0.854). Patients treated in a plaster splint reported significantly more pain than those treated with a circumferential cast, during the first week of treatment (estimated mean NRS 4.7 (95% CI 4.3 to 5.1) vs 4.1 (95% CI 3.7 to 4.4); p = 0.014). The rate of complaints relating to the cast, clinical outcomes and PROMs did not differ significantly between the groups (p > 0.05). Compartment syndrome did not occur. Conclusion: Circumferential casting did not result in a significantly different rate of redisplacement of the fracture compared with the use of a plaster splint. There were comparable outcomes in both groups.

Association between stringency of lockdown measures and emergency department visits during the COVID-19 pandemic: A Dutch multicentre study.

INTRODUCTION: The COVID-19 outbreak disrupted regular health care, including the Emergency Department (ED), and resulted in insufficient ICU capacity. Lockdown measures were taken to prevent disease spread and hospital overcrowding. Little is known about the relationship of stringency of lockdown measures on ED utilization. OBJECTIVE: This study aimed to compare the frequency and characteristics of ED visits during the COVID-19 outbreak in 2020 to 2019, and their relation to stringency of lockdown measures. MATERIAL AND METHODS: A retrospective multicentre study among five Dutch hospitals was performed. The primary outcome was the absolute number of ED visits (year 2018 and 2019 compared to 2020). Secondary outcomes were age, sex, triage category, way of transportation, referral, disposition, and treating medical specialty. The relation between stringency of lockdown measures, measured with the Oxford Stringency Index (OSI) and number and characteristics of ED visits was analysed. RESULTS: The total number of ED visits in the five hospitals in 2019 was 165,894, whereas the total number of visits in 2020 was 135,762, which was a decrease of 18.2% (range per hospital: 10.5%-30.7%). The reduction in ED visits was greater during periods of high stringency lockdown measures, as indicated by OSI. CONCLUSION: The number of ED visits in the Netherlands has significantly dropped during the first year of the COVID-19 pandemic, with a clear association between decreasing ED visits and increasing lockdown measures. The OSI could be used as an indicator in the management of ED visits during a future pandemic.

Patient satisfaction, needs, and preferences concerning information dispensation at the emergency department: a cross-sectional observational study.

BACKGROUND: Patient satisfaction is an important indicator of emergency care quality and has been associated with information dispensation at the emergency department (ED). Optimal information dispensation could improve patient experience and expectations. Knowing what kind of information patients want to receive and the preferred way of information dispensation are essential to optimize information delivery at the ED. The purpose of this cross-sectional observational study was to evaluate patient satisfaction concerning information dispensation (including general, medical, and practical information), the need for additional information, and preferences with regard to the way of information dispensation at the ED of a teaching hospital in the Netherlands. RESULTS: Four hundred twenty-three patients (patients ≥ 18 years with Glasgow Coma Scale 15) were enrolled (response rate 79%). The median patient satisfaction score concerning the overall information dispensation at the ED was 7.5 on a rating scale 0-10. Shorter length of ED stay was associated with higher patient satisfaction in multivariate analysis (P < 0.001). The majority of respondents were satisfied regarding medical (n = 328; 78%) and general information (n = 233; 55%). Patients were less satisfied regarding practical information (n = 180; 43%). Respondents who indicated that they received general, medical and practical information were significantly more often satisfied compared to patients who did not receive this information (P < 0.001). Two thirds (n = 260; 62%) requested more general information. Half of the respondents (n = 202; 48%) requested more practical information and a third (n = 152; 36%) requested more medical information. The preferred way for receiving information was orally (n = 189; 44.7%) or by leaflets (n = 108; 25.5%). CONCLUSION: The majority of respondents were satisfied concerning information dispensation at the ED, especially regarding medical information. Respondents requested more general and practical information and preferred to receive the information orally or by leaflets.

Effect of written and video discharge instructions on parental recall of information about analgesics in children: a pre/post-implementation study.

OBJECTIVE: The aim of this study was to determine whether written and video instructions improved the recall of how to use analgesics correctly in parents of children discharged following assessment in the emergency department (ED). METHODS: This was a prospective pre- and post-implementation study set in the EDs of a tertiary teaching hospital and an urban general hospital in the Netherlands. The participants were parents/carers of children under 12-years-old who had been assessed in and subsequently discharged from the ED. The pre-implementation phase involved 165 participants; the post-phase involved 174 participants. In the post-implementation phase, written instructions about correct analgesic use in children and a link to an online video were provided at discharge. Endpoints were measured using a questionnaire designed to ascertain participants' recall of how to use analgesics correctly and their patterns of use, completed 3-5 days following discharge of their child from the ED. Additionally, participants were asked about re-attending healthcare services and their satisfaction with and preferences for information about analgesic use. RESULTS: Recall of the correct use of analgesics was significantly higher in participants in the post-implementation phase compared to the pre-implementation phase [difference 29%; 95% confidence interval (CI) 19-39%]. In the post-implementation phase, participants represented to healthcare services less frequently (difference -6%; 95% CI -13-0%). Patterns of use of analgesics varied between the pre- and post-phases, with significantly more participants giving analgesics at home (difference 11%; 95% CI 1-20%). Participants in the post-implementation phase were significantly more (highly) satisfied about the analgesic advice they received compared to parents in the pre-implementation phase (difference -13; 95% CI -23% to -3%). Verbal (93%) or written instructions (83%) were the most popular choices for discharge instructions. CONCLUSION: In our study, we observed that the recall of the correct use of analgesics was increased in participants who had been given written instructions at discharge.

Changes of ferritin and CRP levels in melanoma patients treated with adjuvant interferon-α (EORTC 18952) and prognostic value on treatment outcome.

Adjuvant therapy with interferon-α (IFN) only benefits a small subgroup of melanoma patients and a predictive marker selecting responders does not exist. IFN induces increased ferritin and decreased C-reactive protein (CRP) levels; however, an association with treatment effect was not studied. Serum was collected from patients participating in the European Organization for Research and Treatment of Cancer 18 952 trial comparing adjuvant treatment with IFN to observation. Serial ferritin and CRP levels were determined using enzyme-linked immunosorbent assays, before treatment and up to 24 months. Ferritin levels are influenced by sex and age; therefore ratios of serial ferritin and CRP values with corresponding pretreatment values were calculated. Cox regression model and landmark method at end of induction and 6 months were used to evaluate the association between ferritin, CRP and distant metastasis-free survival (DMFS). Baseline ferritin levels were comparable in the two treatment groups (P=0.92). However, ferritin ratios were significantly higher in IFN-treated patients (N=96) compared with untreated patients (N=21) at end of induction (mean: 2.88 vs. 0.75; P=0.0003) and at 6 months (mean: 3.18 vs. 1.02; P=0.009). In the IFN arm, higher ferritin ratios at end of induction and at 6 months were not associated with improved outcome (respectively, P=0.66 and 0.86). Concerning CRP ratios, no differences between the treatment groups, neither an association with DMFS, were observed. Administration of IFN in melanoma patients induced increase in ferritin levels but not in CRP levels. Ferritin and CRP ratios have no prognostic value regarding DMFS.

Immunologic functions as prognostic indicators in melanoma.

Outcome in melanoma patients with advanced disease is poor and systemic treatment seems to benefit only a subset of patients. Predictive markers identifying these patients are currently not available. Early studies showed an association of immune-related side effects such as vitiligo and autoimmune thyroiditis with response to IL-2 or IFNα treatment. However, conflicting data have been reported as well, mentioning the effect of a higher rate of immune-related toxicities during prolonged administration of the drug in responders. The review discusses the prognostic significance of autoimmunity during various forms of immunotherapy and stresses the importance of correcting for guarantee-time bias. In addition, other immune-related factors which have been associated with melanoma prognosis such as, CRP, white blood cell count, absolute lymphocyte count and human leukocyte antigen will be reviewed as well. A better understanding of the immune system and the host-tumor interactions should ultimately lead to more effective treatment. A major challenge expected to be addressed in future is proving ways to uncouple tumor immunity from autoimmunity.

Autoimmunity and treatment outcome in melanoma.

PURPOSE OF REVIEW: Only a subset of melanoma patients with advanced disease seems to benefit from immunotherapy. Predictive markers identifying these patients are unfortunately not available. Whether immune-related side effects could serve as predictors for treatment response or just resemble unwanted side effects from immunotherapy will be outlined in this review. RECENT FINDINGS: Early studies suggested an association of immune-related side effects such as vitiligo and autoimmune thyroiditis with response in patients receiving IL-2 or IFNα. However, conflicting data have been reported as well, mentioning the effect of a higher rate of immune-related toxicities during prolonged administration of the drug in responders/survivors. This type of bias is also known as guarantee-time bias. Recently, a clearly significant and clinically relevant prolongation of survival was demonstrated in patients with metastatic melanoma treated with ipilimumab. Immune-related adverse events were associated with response to ipilimumab, however, at the cost of considerable toxicity. SUMMARY: Evidence for an association of immune-related toxicities and response in patients receiving IL-2 or IFNα is weak, considering guarantee-time bias. On the contrary, this association for patients receiving anti-cytotoxic T-lymphocyte antigen-4 therapy (ipilimumab) appears much stronger. Importantly, can we uncouple tumor immunity from autoimmunity in order to optimize immunotherapy in melanoma?

Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus observation: prognostic significance of autoantibodies--EORTC 18991.

PURPOSE: Conflicting data have been reported concerning the prognostic value of autoimmune antibodies in patients with melanoma treated with adjuvant interferon alfa-2b (IFN). We evaluated the prognostic significance of autoantibodies in the European Organisation for Research and Treatment of Cancer 18991 trial, comparing long-term administration of pegylated IFN (PEG-IFN) with observation. PATIENTS AND METHODS: Anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined by enzyme-linked immunosorbent assays in 296 patients before random assignment and every 6 months after random assignment for up to 5 years. Prognostic impact of autoantibodies on recurrence-free survival (RFS) was assessed using the following three Cox models: a model that considered autoantibody appearance as a time-independent variable (model 1); a model that considered a patient to be autoantibody positive from the first positive test (model 2); and a model in which the most recent autoantibody test was used to define the status of the patient (model 3). RESULTS: Patients who were autoantibody negative at baseline were analyzed (n = 220). Occurrence of autoantibodies during follow-up was higher in the PEG-IFN-treated patients (18% in the observation arm v 52% in the PEG-IFN arm). Autoantibody appearance was of prognostic importance by using model 1 (hazard ratio [HR] = 0.56; 95% CI, 0.36 to 0.87; P = .01). However, when guarantee-time bias was taken into account using model 2 (HR = 1.19; 95% CI, 0.75 to 1.88; P = .46) or method 3 (HR = 1.14; 95% CI, 0.71 to 1.83; P = .59), significance was lost. Results were similar when treatment groups were analyzed separately. CONCLUSION: Appearance of autoimmune antibodies is neither a prognostic nor a predictive factor for improved outcome in patients with melanoma treated with PEG-IFN.

Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis?

The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population.

Serum concentrations of pegylated interferon alpha-2b in patients with resected stage III melanoma receiving adjuvant pegylated interferon alpha-2b in a randomized phase III trial (EORTC 18991).

PURPOSE: The EORTC 18991 trial assessed the effect of long-term adjuvant pegylated interferon (Peg-IFN) alpha-2b administered weekly in patients with lymph node-positive melanoma. Serum concentrations were analyzed to determine exposure to Peg-IFN alpha-2b. METHODS: After surgery, patients were randomized to receive Peg-IFN alpha-2b or to observation only. The treatment group received 6 microg/kg/week Peg-IFN alpha-2b subcutaneously for 8 weeks, followed by a maintenance dose of 3 microg/kg/week for up to 5 years. Blood samples were collected between months 3 and 60. RESULTS: A total of 208 Peg-IFN alpha-2b concentrations from 48 patients were available. Serum trough concentrations increased in a dose-related manner. Mean dose-normalized serum concentrations and intersubject variability over the 5-year study period in patients with melanoma were similar to those observed in patients with chronic hepatitis. CONCLUSION: Data suggest that the exposure to Peg-IFN alpha-2b was sustained during long-term adjuvant treatment with Peg-IFN alpha-2b in patients with melanoma, consistent with the EORTC 18991 trial's conclusion of a significant, sustained, and relapse-free survival benefit.

Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon.

BACKGROUND: Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b was reported to be associated with improved prognosis. We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two randomized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients. METHODS: Serum levels of anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer (EORTC) 18952 and Nordic IFN trials, respectively, immediately before and up to 3 years after random assignment. The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline (125 from the EORTC 18952 trial and 230 from the Nordic IFN trial): 1) a model that considered appearance of autoantibodies as a time-independent variable, 2) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained, and 3) a model in which the status of the patient was defined by the most recent autoantibody test. All statistical tests were two-sided. RESULTS: When treated as a time-independent variable (model 1), appearance of autoantibodies was associated with improved relapse-free interval in both trials (EORTC 18952, hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.25 to 0.68, P < .001; and Nordic IFN, HR = 0.51, 95% CI = 0.34 to 0.76, P < .001). However, on correction for guarantee-time bias, the association was weaker and not statistically significant (model 2: EORTC 18952, HR = 0.81, 95% CI = 0.46 to 1.40, P = .44; and Nordic IFN, HR = 0.85, 95% CI = 0.55 to 1.30, P = .45; model 3: EORTC 18952, HR = 1.05, 95% CI = 0.59 to 1.87, P = .88; and Nordic IFN, HR = 0.78, 95% CI = 0.49 to 1.24, P = .30). CONCLUSIONS: In two randomized trials of IFN for the treatment of melanoma patients, appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias.