Central nervous system relapse in high-risk stage 4 neuroblastoma: The HR-NBL1/SIOPEN trial experience.

BACKGROUND: There is rising concern on the impact of new strategies, such as high-dose chemotherapy (HDC) and immunotherapy, on the pattern of relapse in high-risk neuroblastoma (HR-NBL). Our aim is to evaluate the incidence and identify risk factors for first recurrence in the central nervous system (CNS) in HR-NBL. PATIENTS AND METHODS: Data from patients with stage 4V HR-NBL included from February 2002 to June 2015 in the prospective HR-NBL trial of the European International Society of Pediatric Oncology Neuroblastoma Group were analysed. Characteristics at diagnosis, treatment and the pattern of first relapse were studied. CNS imaging at relapse was centrally reviewed. RESULTS: The 1977 included patients had a median age of 3 years (1 day-20 years); 1163 were boys. Among the 1161 first relapses, 53 were in the CNS, with an overall incidence of 2.7%, representing 6.2% of all metastatic relapses. One- and three-year post-relapse overall survival was 25 ± 6% and 8 ± 4%, respectively. Higher risk of CNS recurrence was associated with female sex (hazard ratio [HR] = 2.0 [95% confidence interval {CI}: 1.1-3.5]; P = 0.016), MYCN-amplification (HR = 2.4 [95% CI: 1.2-4.4]; P = 0.008), liver (HR = 2.5 [95% CI: 1.2-5.1]; P = 0.01) or >1 metastatic compartment involvement (HR = 7.1 [95% CI: 1.0-48.4]; P = 0.047) at diagnosis. Neither HDC nor immunotherapy was associated with higher risk of CNS recurrence. Stable incidence of CNS relapse was reported over time. CONCLUSIONS: The risk of CNS recurrence is linked to both patient and disease characteristics, with neither impact of HDC nor immunotherapy. These findings support the current treatment strategy and do not justify a CNS prophylactic treatment.

Cardiac anomaly detection based on time and frequency domain features using tree-based classifiers.

OBJECTIVE: Recent advantages in mHealth-enabled ECG recorders boosted the demand for algorithms, which are able to automatically detect cardiac anomalies with high accuracy. APPROACH: We present a combined method of classical signal analysis and machine learning which has been developed during the Computing in Cardiology Challenge (CinC) 2017. Almost 400 hand-crafted features have been developed to reflect the complex physiology of cardiac arrhythmias and their appearance in single-channel ECG recordings. For the scope of this article, we performed several experiments on the publicly available challenge dataset to improve the classification accuracy. We compared the performance of two tree-based algorithms-gradient boosted trees and random forests-using different parameters for learning. We assessed the influence of five different sets of training annotations on the classifiers performance. Further, we present a new web-based ECG viewer to review and correct the training labels of a signal data set. Moreover, we analysed the feature importance and evaluated the model performance when using only a subset of the features. The primary data source used in the analysis was the dataset of the CinC 2017, consisting of 8528 signals from four classes. Our best results were achieved using a gradient boosted tree model which worked significantly better than random forests. MAIN RESULTS: Official results of the challenge follow-up phase provided by the Challenge organizers on the full hidden test set are 90.8% (Normal), 84.1% (AF), 74.5% (Other), resulting in a mean F1-score of 83.2%, which was only 1.6% behind the challenge winner and 0.2% ahead of the next-best algorithm. Official results were rounded to two decimal places which lead to the equal-second best F1 F -score of 83% with five others. SIGNIFICANCE: The algorithm achieved the second-best score among 80 algorithms of the Challenge follow-up phase equal with five others.

Survey on paediatric tumour boards in Europe: current situation and results from the ExPo-r-Net project

Background: Under the ExPO-r-NeT project (European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment), we aimed to identify paediatric oncology tumour boards in Europe to investigate the kind of technologies and logistics that are in place in different countries and to explore current differences between regions. Methods: A 20-question survey regarding several features of tumor boards was designed. Data collected included infrastructure, organization, and clinical decision-making information from the centres. The survey was distributed to the National Paediatric Haematology and Oncology Societies that forwarded the survey to the sites. For comparative analysis, respondents were grouped into four geographical regions. Results: The questionnaire was distributed amongst 30 countries. Response was obtained from 23 (77%) that altogether have 212 paediatric oncology treating centres. A total of 121 institutions answered (57%). Ninety-one percent of the centres hold multidisciplinary boards; however, international second consultations are performed in 36% and only 15% participate on virtual tumor boards. Videoconferencing facilities and standard operational procedures (SOPs) are available in 49 and 43% of the centres, respectively. There were statistically significant differences between European regions concerning meeting infrastructure and organization/logistics: specific room, projecting equipment, access to medical records, videoconferencing facilities, and existence of SOPs. Conclusion: Paediatric tumor boards are a common feature in Europe. To reduce inequalities and have equal access to healthcare, a virtual network is needed. Important differences on the functioning and access to technology between regions in Europe have been observed and need to be addressed

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Survey on paediatric tumour boards in Europe: current situation and results from the ExPo-r-Net project.

BACKGROUND: Under the ExPO-r-NeT project (European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment), we aimed to identify paediatric oncology tumour boards in Europe to investigate the kind of technologies and logistics that are in place in different countries and to explore current differences between regions. METHODS: A 20-question survey regarding several features of tumor boards was designed. Data collected included infrastructure, organization, and clinical decision-making information from the centres. The survey was distributed to the National Paediatric Haematology and Oncology Societies that forwarded the survey to the sites. For comparative analysis, respondents were grouped into four geographical regions. RESULTS: The questionnaire was distributed amongst 30 countries. Response was obtained from 23 (77%) that altogether have 212 paediatric oncology treating centres. A total of 121 institutions answered (57%). Ninety-one percent of the centres hold multidisciplinary boards; however, international second consultations are performed in 36% and only 15% participate on virtual tumor boards. Videoconferencing facilities and standard operational procedures (SOPs) are available in 49 and 43% of the centres, respectively. There were statistically significant differences between European regions concerning meeting infrastructure and organization/logistics: specific room, projecting equipment, access to medical records, videoconferencing facilities, and existence of SOPs. CONCLUSION: Paediatric tumor boards are a common feature in Europe. To reduce inequalities and have equal access to healthcare, a virtual network is needed. Important differences on the functioning and access to technology between regions in Europe have been observed and need to be addressed.

Unintended Consequences of Wearable Sensor Use in Healthcare. Contribution of the IMIA Wearable Sensors in Healthcare WG.

OBJECTIVES: As wearable sensors take the consumer market by storm, and medical device manufacturers move to make their devices wireless and appropriate for ambulatory use, this revolution brings with it some unintended consequences, which we aim to discuss in this paper. METHODS: We discuss some important unintended consequences, both beneficial and unwanted, which relate to: modifications of behavior; creation and use of big data sets; new security vulnerabilities; and unforeseen challenges faced by regulatory authorities, struggling to keep pace with recent innovations. Where possible, we proposed potential solutions to unwanted consequences. RESULTS: Intelligent and inclusive design processes may mitigate unintended modifications in behavior. For big data, legislating access to and use of these data will be a legal and political challenge in the years ahead, as we trade the health benefits of wearable sensors against the risk to our privacy. The wireless and personal nature of wearable sensors also exposes them to a number of unique security vulnerabilities. Regulation plays an important role in managing these security risks, but also has the dual responsibility of ensuring that wearable devices are fit for purpose. However, the burden of validating the function and security of medical devices is becoming infeasible for regulators, given the many software apps and wearable sensors entering the market each year, which are only a subset of an even larger 'internet of things'. CONCLUSION: Wearable sensors may serve to improve wellbeing, but we must be vigilant against the occurrence of unintended consequences. With collaboration between device manufacturers, regulators, and end-users, we balance the risk of unintended consequences occurring against the incredible benefit that wearable sensors promise to bring to the world.

The impact of adherence on costs and effectiveness of telemedical patient management in heart failure: a systematic review.

OBJECTIVE: This paper analyzes evidence of the impact of patients' adherence to pharmacological and non-pharmacological recommendations on the treatment costs of heart failure (HF) patients. METHODS: A systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Papers were searched using various combinations of the following keywords: 'telemedicine', 'telemonitoring', 'telehealth', 'eHealth', 'remote monitoring', 'adherence', 'compliance', 'cost-effectiveness', 'cost-benefit', 'heart failure', 'healthcare costs', 'hospitalization', and 'drug costs'. We included only papers written in English or German, published between 1998 and 2014, and having one of our search terms in the title. RESULTS: Initially, 73 papers were selected. After a detailed review, these were narrowed done to 9 that reported an association between adherence and/or compliance and costs. However, none established a quantitative relationship between adherence and total healthcare costs. CONCLUSION: A model-based cost-effectiveness analysis that appropriately considers adherence has not been carried out so far, but is needed to fully understand the potential economic benefits of telehealth.

Memorandum on the use of information technology to improve medication safety.

BACKGROUND: Information technology in health care has a clear potential to improve the quality and efficiency of health care, especially in the area of medication processes. On the other hand, existing studies show possible adverse effects on patient safety when IT for medication-related processes is developed, introduced or used inappropriately. OBJECTIVES: To summarize definitions and observations on IT usage in pharmacotherapy and to derive recommendations and future research priorities for decision makers and domain experts. METHODS: This memorandum was developed in a consensus-based iterative process that included workshops and e-mail discussions among 21 experts coordinated by the Drug Information Systems Working Group of the German Society for Medical Informatics, Biometry and Epidemiology (GMDS). RESULTS: The recommendations address, among other things, a stepwise and comprehensive strategy for IT usage in medication processes, the integration of contextual information for alert generation, the involvement of patients, the semantic integration of information resources, usability and adaptability of IT solutions, and the need for their continuous evaluation. CONCLUSION: Information technology can help to improve medication safety. However, challenges remain regarding access to information, quality of information, and measurable benefits.

Near Field Communication-based telemonitoring with integrated ECG recordings.

OBJECTIVES: Telemonitoring of vital signs is an established option in treatment of patients with chronic heart failure (CHF). In order to allow for early detection of atrial fibrillation (AF) which is highly prevalent in the CHF population telemonitoring programs should include electrocardiogram (ECG) signals. It was therefore the aim to extend our current home monitoring system based on mobile phones and Near Field Communication technology (NFC) to enable patients acquiring their ECG signals autonomously in an easy-to-use way. METHODS: We prototypically developed a sensing device for the concurrent acquisition of blood pressure and ECG signals. The design of the device equipped with NFC technology and Bluetooth allowed for intuitive interaction with a mobile phone based patient terminal. This ECG monitoring system was evaluated in the course of a clinical pilot trial to assess the system's technical feasibility, usability and patient's adherence to twice daily usage. RESULTS: 21 patients (4f, 54 ± 14 years) suffering from CHF were included in the study and were asked to transmit two ECG recordings per day via the telemonitoring system autonomously over a monitoring period of seven days. One patient dropped out from the study. 211 data sets were transmitted over a cumulative monitoring period of 140 days (overall adherence rate 82.2%). 55% and 8% of the transmitted ECG signals were sufficient for ventricular and atrial rhythm assessment, respectively. CONCLUSIONS: Although ECG signal quality has to be improved for better AF detection the developed communication design of joining Bluetooth and NFC technology in our telemonitoring system allows for ambulatory ECG acquisition with high adherence rates and system usability in heart failure patients.

An epidemiological modeling and data integration framework.

OBJECTIVES: In this work, a cellular automaton software package for simulating different infectious diseases, storing the simulation results in a data warehouse system and analyzing the obtained results to generate prediction models as well as contingency plans, is proposed. The Brisbane H3N2 flu virus, which has been spreading during the winter season 2009, was used for simulation in the federal state of Tyrol, Austria. METHODS: The simulation-modeling framework consists of an underlying cellular automaton. The cellular automaton model is parameterized by known disease parameters and geographical as well as demographical conditions are included for simulating the spreading. The data generated by simulation are stored in the back room of the data warehouse using the Talend Open Studio software package, and subsequent statistical and data mining tasks are performed using the tool, termed Knowledge Discovery in Database Designer (KD3). RESULTS: The obtained simulation results were used for generating prediction models for all nine federal states of Austria. CONCLUSION: The proposed framework provides a powerful and easy to handle interface for parameterizing and simulating different infectious diseases in order to generate prediction models and improve contingency plans for future events.

Innovative telemonitoring system for cardiology: from science to routine operation.

OBJECTIVE: Results of the Austrian MOBITEL (MOBIle phone based TELemonitoring for heart failure patients) trial indicate that home-based telemonitoring improves outcome of chronic heart failure (CHF) patients and reduces both frequency and duration of hospitalizations. Based on lessons learned, we assessed the weak points to clear the way for routine operations. METHODS: We analyzed the system with respect to recommendations of the ESC Guidelines and experiences gained throughout the trial to identify potential improvements. The following components have been identified: a patient terminal with highest usability, integrated way to document drug-intake and well-being, and automated event detection for worsening of CHF. As a consequence the system was extended by Near Field Communication (NFC) technology and by an event management tool. RESULTS: Usability evaluation with 30 adults (14f, median 51y. IQR[45-65]) showed that 21 (8f) were able to immediately operate the system after reading a step-by-step manual. Eight (6f) needed one time demonstration and one man (80y) failed to operate the blood pressure meter. Routine operation of the revised system started in March 2009. Within 9 months, 15 patients (4f, median 74y. IQR[71-83], all NYHA-III) transmitted 17,149 items. 43 events were detected because of body weight gain of more then 2kg within 2 days. 49 therapy adjustments were documented. Three patients stopped using the system, two (1f) because of non-compliance and one (m, 82y) because of death. Overall, the rate of adherence to daily data transfer was 78%. CONCLUSION: First results confirm the applicability of the revised telemonitoring system in routine operation.

Mobile phone-based surveillance of cardiac patients at home.

We tested the reliability, acceptability and feasibility of a home-monitoring system for cardiac patients. Each participant was equipped with a mobile phone, an automatic blood pressure device and a digital weight scale. In total, 20 patients (14 patients with chronic heart failure, six patients with hypertension; mean age 50 years, standard deviation [SD] 14) were monitored for 90 days each. They were asked to measure their blood pressure, pulse and body weight every day, and to transfer the data together with the dosage of medication to the telemonitoring server using wireless Internet technology in the mobile phone. The physician in charge received email alerts when reported data fell outside pre-defined limits. The patients' compliance with the system was high. During a cumulative monitoring period of 1,735 days, there were 2,040 data transfer sessions, a mean of 102 per patient (SD 43). The mean percentage of successful data transfers was 83% (SD 22). The stability of the telemonitoring system was 98%, meaning that patient data transfer was almost always possible. The accessibility of the secure web server for physicians was above 99%. The web-based home-monitoring system was reliable and easy to handle for both patients and health care professionals. It may be a useful tool for patients with heart failure as well as hypertensive patients.

Initial experiences with a telemedicine framework for remote pacemaker follow-up.

According to international guidelines implanted cardiac pacemakers (PM) have to be checked periodically to ensure that they are working correctly. To spare a significant number of patients the burden of traveling to specialized PM clinics a telemedicine framework has been developed prototypically. A mobile, personal digital assistant (PDA) based PM follow-up unit provides the caregiver at the point-of-care with the necessary infrastructure to perform a basic PM follow-up examination remotely. In case of detected malfunction of the PM the patient is ordered to the hospital for further examination. The system has been evaluated in a clinical pilot trial on 44 patients with a total of 23 different PM models from 8 different manufacturers. The initial results indicate the potential of the concept to work as an efficient, manufacturer independent screening method with the ultimate goal to increase the safety, quality and efficiency of PM therapy.

Automated and manufacturer independent assessment of the battery status of implanted cardiac pacemakers by electrocardiogram analysis.

According to international standards, cardiac pacemakers have to indicate the status of their batteries upon magnet application by specific stimulation patterns. The purpose of this study has been to assess whether this concept can be used as a basis for automated and manufacturer independent examination of the depletion level of pacemakers in the framework of a collaborative telemedical pacemaker follow-up system. A prototype of such a system was developed and tested in a real clinical environment. Electrocardiograms (ECGs) were recorded during magnet application and automatically processed to extract the specific stimulation patterns. The results were used to assign each signal a corresponding pacemaker status: "ok," "replace" or "undefined," based on the expected behavior of the devices as specified by the manufacturer. The outcome of this procedure was compared to the result of an expert examination, resulting in a positive predictive value of 100% for the detection of ECGs indicating pacemaker status "ok." The method can, therefore, be utilized to quickly, safely and manufacturer neutrally classify cases into the categories "ok" and "needs further checking," which - in a telemedical setting - may be used to increase the efficiency of pacemaker follow-up procedures in the future.

Correlation between changes in stroke volume and the paced intracardiac electrogram.

AIM: The aim of this study was to examine the relation between cardiac haemodynamics and parameters extracted from the intracardiac electrogram obtained during pacing, i.e. ventricular evoked response. METHODS AND RESULTS: In the course of routinely scheduled right heart catheterization, intracardiac electrograms and cardiac haemodynamics were monitored simultaneously in ten heart transplant patients (two females, aged 48 +/- 12 (18-59) years), using pacemaker telemetry and Swan-Ganz thermodilution techniques. Different haemodynamic states were induced by pacemaker programming (pacing rate changes) and table tilting (postural changes). Forty different haemodynamic states were assessed, with an average of three (2.4) haemodynamic variations in each patient. Linear regression analysis between relative stroke volume changes and relative changes in the R wave slew rate as extracted from the evoked responses revealed a strong, inverse, and highly significant correlation (r= - 0.93, P<0.0001) between those parameters. Similar results were obtained for pacing rate and postural variations alone, respectively. CONCLUSIONS: The strong correlation between changes in stroke volume and R slew rate indicates that paced intracardiac electrograms reflect changes in the size and geometry of the heart. Telemetrically recorded intracardiac electrograms may thus be used non-invasively to assess key aspects of cardiac haemodynamics.

Non-invasive graft monitoring after heart transplantation: rationale to reduce the number of endomyocardial biopsies.

The endomyocardial biopsy is invasive, reduces quality of life and cannot be repeated daily. Initial studies on noninvasive cardiac graft monitoring have been presented recently. During the heart transplant procedure, we implanted wideband telemetric pacemakers and fractally coated, epimyocardial electrodes. On biopsy days and during each follow-up, intramyocardial electrogram sequences were obtained. The maximum T-slew rate from the ventricular evoked response (VER) was automatically calculated and compared to the biopsy results (n = 331, ISHLT grading). The VER T-slew rate was significantly lower during rejection grade 2 or higher. The negative predictive value to exclude rejection was 98%. Using a single threshold diagnosis model, 74% of the biopsies could have been avoided. Noninvasive cardiac graft monitoring can reduce the need for surveillance biopsies and may offer a tool to optimize immunosuppressive therapy after heart transplantation.