FAM19A4/miR124-2 methylation analysis as a triage test for HPV-positive women: cross-sectional and longitudinal data from a Dutch screening cohort

Objectives: The aim was to evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening. Methods: We conducted a post hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30–60 years (n = 979). Cross-sectional cervical intraepithelial neoplasia (CIN) 3+ sensitivity, specificity, positive predictive value and negative predictive value as well as cumulative CIN3+ or cervical cancer risks after 9 and 14 years were compared for three baseline triage strategies: (1) cytology, (2) FAM19A4/miR124-2 methylation analysis and (3) combined FAM19A4/miR124-2 methylation with cytology. Results: CIN3+ sensitivity of FAM19A4/miR124-2 methylation analysis was similar to that of cytology (71.3% vs 76.0%, ratio 0.94, 95% CI 0.84 to 1.05), at a lower specificity (78.3% vs 87.0%, ratio 0.90, 95% CI 0.86 to 0.94). Combining FAM19A4/miR124-2 methylation analysis with cytology resulted in a CIN3+ sensitivity of 84.6% (95% CI 78.3 to 90.8) at a specificity of 69.6% (95% CI 66.5 to 72.7). Similar 9- and 14-year CIN3+ risks for baseline cytology-negative women and baseline FAM19A4/miR12

Care after pancreatic resection according to an algorithm for early detection and minimally invasive management of pancreatic fistula versus current practice (PORSCH-trial): design and rationale of a nationwide stepped-wedge cluster-randomized trial

BACKGROUND: Pancreatic resection is a major abdominal operation with 50% risk of postoperative complications. A common complication is pancreatic fistula, which may have severe clinical consequences such as postoperative bleeding, organ failure and death. The objective of this study is to investigate whether implementation of an algorithm for early detection and minimally invasive management of pancreatic fistula may improve outcomes after pancreatic resection. METHODS: This is a nationwide stepped-wedge, cluster-randomized, superiority trial, designed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. During a period of 22 months, all Dutch centers performing pancreatic surgery will cross over in a randomized order from current practice to best practice according to the algorithm. This evidence-based and consensus-based algorithm will provide da

CT angiography and CT perfusion improve prediction of infarct volume in patients with anterior circulation stroke

Introduction: We investigated whether baseline CT angiography (CTA) and CT perfusion (CTP) in acute ischemic stroke could improve prediction of infarct presence and infarct volume on follow-up imaging. Methods: We analyzed 906 patients with suspected anterior circulation stroke from the prospective multicenter Dutch acute stroke study (DUST). All patients underwent baseline non-contrast CT, CTA, and CTP and follow-up non-contrast CT/MRI after 3 days. Multivariable regression models were developed including patient characteristics and non-contrast CT, and subsequently, CTA and CTP measures were added. The increase in area under the curve (AUC) and R2 was assessed to determine the additional value of CTA and CTP. Results: At follow-up, 612 patients (67.5 %) had a detectable infarct on CT/MRI; median infarct volume was 14.8 mL (interquartile range (IQR) 2.8–69.6). Regarding infarct presence, the AUC of 0.82 (95 % confidence interval (CI) 0.79–0.85) for patient characteristics and non-contrast CT was improved with addition of CTA measures (AUC 0.85 (95 % CI 0.82–0.87); p < 0.001) and was even higher after addition of CTP measures (AUC 0.89 (95 % CI 0.87–0.91); p < 0.001) and combined CTA/CTP measures (AUC 0.89 (95 % CI 0.87–0.91); p < 0.001). For infarct volume, adding combined CTA/CTP measures (R2 = 0.58) was superior to patient characteristics and non-contrast CT alone (R2 = 0.44) and to addition of CTA alone (R2 = 0.55) or CTP alone (R2 = 0.54; all p < 0.001). Conclusion: In the acute stage, CTA and CTP have additional value over patient characteristics and non-contrast CT for predicting infarct presence and infarct volume on follow-up imaging. These findings could be applied for patient selection in future trials on ischemic stroke treatment

Prediction of outcome in patients with suspected acute ischaemic stroke with CT perfusion and CT angiography: The Dutch acute stroke trial (DUST) study protocol

Background: Prediction of clinical outcome in the acute stage of ischaemic stroke can be difficult when based on patient characteristics, clinical findings and on non-contrast CT. CT perfusion and CT angiography may provide additional prognostic information and guide treatment in the early stage. We present the study protocol of the Dutch acute Stroke Trial (DUST). The DUST aims to assess the prognostic value of CT perfusion and CT angiography in predicting stroke outcome, in addition to patient characteristics and non-contrast CT. For this purpose, individualised prediction models for clinical outcome after stroke based on the best predictors from patient characteristics and CT imaging will be developed and validated.Methods/design: The DUST is a prospective multi-centre cohort study in 1500 patients with suspected acute ischaemic stroke. All patients undergo non-contrast CT, CT perfusion and CT angiography within 9 hours after onset of the neurological deficits, and, if possible, follow-up imaging after 3 days. The primary outcome is a dichotomised score on the modified Rankin Scale, assessed at 90 days. A score of 0-2 represents good outcome, and a score of 3-6 represents poor outcome. Three logistic regression models will be developed, including patient characteristics and non-contrast CT (model A), with addition of CT angiography (model B), and CT perfusion parameters (model C). Model derivation will be performed in 60% of the study population, and model validation in the remaining 40% of the patients. Additional prognostic value of the models will be determined with the area under the curve (AUC) from the receiver operating characteristic (ROC) curve, calibration plots, assessment of goodness-of-fit, and likelihood ratio tests.Discussion: This study will provide insight in the added prognosti

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1):a multicenter stepped-wedge cluster randomized controlled trial

Background: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. Methods/design: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. Discussion: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. Trial registration: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018

Incidence of Interval Colorectal Cancer After Negative Results From First-Round Fecal Immunochemical Screening Tests, by Cutoff Value and Participant Sex and Age

Background & Aims: We evaluated the incidence of interval cancers between the first and second rounds of colorectal cancer (CRC) screening with the FOB-Gold fecal immunochemical test (FIT), and the effects of different cutoff values and patient sex and age. Methods: We collected data from participants in a population-based

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1): A multicenter stepped-wedge cluster randomized controlled trial

Background: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. Methods/design: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. Discussion: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. Trial registration: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018

No relation between body temperature and arterial recanalization at three days in patients with acute ischaemic stroke

Background: Recanalization of an occluded intracranial artery is influenced by temperature-dependent enzymes, including alteplase. We assessed the relation between body temperature on admission and recanalization. Methods: We included 278 patients with acute ischaemic stroke within nine hours after symptom onset, who had an intracranial arterial occlusion on admission CT angiography, in 13 participating centres. We calculated the relation per every 0.1°Celsius increase in admission body temperature and recanalization at three days. Results: Recanalization occurred in 80% of occluded arteries. There was no relation between body temperature and recanalization at three days after adjustments for age, NIHSS score on admission and treatment with alteplase (adjusted odds ratio per 0.1°Celsius, 0.99; 95% confidence interval, 0.94-1.05; p = 0.70). Results for patients treated or not treated with alteplase were essentially the same. Conclusions: Our findings suggest that in patients with acute ischaemic stroke there is no relation between body temperature on admission and recanalization of an occluded intracranial artery three days later, irrespective of treatment with alteplase

Temporal profile of body temperature in acute ischemic stroke: Relation to infarct size and outcome

Background: High body temperatures after ischemic stroke have been associated with larger infarct size, but the temporal profile of this relation is unknown. We assess the relation between temporal profile of body temperature and infarct size and functional outcome in patients with acute ischemic stroke. Methods: In 419 patients with acute ischemic stroke we assessed the relation between body temperature on admission and during the first 3 days with both infarct size and functional outcome. Infarct size was measured in milliliters on CT or MRI after 3 days. Poor functional outcome was defined as a modified Rankin Scale score ≥3 at 3 months. Results: Body temperature on admission was not associated with infarct size or poor outcome in adjusted analyses. By contrast, each additional 1.0 °C in body temperature on day 1 was associated with 0.31 ml larger infarct size (95% confidence interval (CI) 0.04-0.59), on day 2 with 1.13 ml larger infarct size(95% CI, 0.83-1.43), and on day 3 with 0.80 ml larger infarct size (95% CI, 0.48-1.12), in adjusted linear regression analyses. Higher peak body temperatures on days two and three were also associated with poor outcome (adjusted relative risks per additional 1.0 °C in body temperature, 1.52 (95% CI, 1.17-1.99) and 1.47 (95% CI, 1.22-1.77), respectively). Conclusions: Higher peak body temperatures during the first days after ischemic stroke, rather than on admission, are associated with larger infarct size and poor functional outcome. This suggests that prevention of high temperatures may improve outcome if continued for at least 3 days

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age 65 36 weeks and a birth weight 65 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017