Vital signs in pediatric oncology patients assessed by continuous recording with a wearable device, NCT04134429.

Pediatric patients with cancer are at high risk for severe infections. Changes in vital signs, triggered by infections, may be detected earlier by continuous recording with a wearable device than with discrete measurements. This prospective, observational single-center feasibility study consecutively recruited pediatric patients undergoing chemotherapy for cancer. The WD Everion® was used for 14 days in each of the 20 patients on study to continuously record vital signs. Nine different vital signs and health indicators derived from them, plus six quality scores. This resulted in 274 study days (6576 hours) with 85'854 measuring points, which are a total of 772'686 measurements of vital signs and health indicators, plus 515'124 quality scores. Additionally, non-WD data like side effects, acceptability of the WD and effort for investigators were collected. In this manuscript, we present the methods of acquisition and explanations to the complete data set, which have been made publically available on open access and which can be used to study feasibility of continuous multi-parameter recording of vital signs by a WD

Predicting fever in neutropenia with safety-relevant events in children undergoing chemotherapy for cancer: The prospective multicenter SPOG 2015 FN Definition Study

BACKGROUND Fever in neutropenia (FN) remains a frequent complication in pediatric patients undergoing chemotherapy for cancer. Preventive strategies, like primary antibiotic prophylaxis, need to be evidence-based. PROCEDURE Data on pediatric patients with any malignancy from the prospective multicenter SPOG 2015 FN Definition Study (NCT02324231) were analyzed. A score predicting the risk to develop FN with safety-relevant events (SRE; bacteremia, severe sepsis, intensive care unit admission, death) was developed using multivariate mixed Poisson regression. Its predictive performance was assessed by internal cross-validation and compared with the performance of published rules. RESULTS In 238 patients, 318 FN episodes were recorded, including 53 (17%) with bacteremia and 68 (21%) with SRE. The risk-prediction score used three variables: chemotherapy intensity, defined according to the expected duration of severe neutropenia, time since diagnosis, and type of malignancy. Its cross-validated performance, assessed by the time needed to cover (TNC) one event, exceeded the performance of published rules. A clinically useful score threshold of ≥11 resulted in 2.3% time at risk and 4.1 months TNC. Using external information on efficacy and timing of intermittent antibiotic prophylaxis, 4.3 months of prophylaxis were needed to prevent one FN with bacteremia, and 5.2 months to prevent one FN with SRE, using a threshold of ≥11. CONCLUSIONS This score, based on three routinely accessible characteristics, accurately identifies pediatric patients at risk to develop FN with SRE during chemotherapy. The score can help to design clinical decision rules on targeted primary antibiotic prophylaxis and corresponding efficacy studies

Time to antibiotics is unrelated to outcome in pediatric patients with fever in neutropenia presenting without severe disease during chemotherapy for cancer.

Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49-180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted

Time to antibiotics is unrelated to outcome in pediatric patients with fever in neutropenia presenting without severe disease during chemotherapy for cancer

Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49-180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted

Continuous recording of vital signs with a wearable device in pediatric patients undergoing chemotherapy for cancer-an operational feasibility study.

PURPOSE Pediatric patients with cancer are at high risk for severe infections. Infections can trigger changes of vital signs long before clinical symptoms arise. Continuous recording may detect such changes earlier than discrete measurements. We aimed to assess the feasibility of continuous recording of vital signs by a wearable device (WD) in pediatric patients undergoing chemotherapy for cancer. METHODS In this prospective, observational single-center study, pediatric patients under chemotherapy wore the Everion® WD for 14 days. The predefined patient-specific goal was heart rate recorded in good quality during ≥18/24 h per day, on ≥7 consecutive days. The predefined criterion to claim feasibility was ≥15/20 patients fulfilling this patient-specific goal. RESULTS Twenty patients were included (median age, 6 years; range, 2-16). Six patients aged 3-16 years fulfilled the patient-specific goal. Quality of heart rate recording was good during 3992 of 6576 (61%) hours studied and poor during 300 (5%) hours, and no data was recorded during 2284 (35%) hours. Eighteen of 20 participants indicated that this WD is acceptable to measure vital signs in children under chemotherapy. CONCLUSION The predefined feasibility criterion was not fulfilled. This was mainly due to important compliance problems and independent of the WD itself. However, continuous recording of vital signs was possible across a very wide age range in pediatric patients undergoing chemotherapy for cancer. We recommend to study feasibility in the Everion® again, plus in further WDs, applying measures to enhance compliance. TRIAL REGISTRATION ClinicalTrials.gov (NCT04134429) on October 22, 2019

Continuous timely monitoring of core temperature with two wearable devices in pediatric patients undergoing chemotherapy for cancer - a comparison study.

PURPOSE Pediatric patients with cancer often develop chemotherapy-induced fever in neutropenia (FN), requiring emergency broad-spectrum antibiotics. Continuous temperature monitoring can lead to earlier FN detection and therapy with improved outcomes. We aimed to compare the feasibility of continuous core temperature monitoring with timely data availability between two wearable devices (WDs) in pediatric oncology patients undergoing chemotherapy. METHODS In this prospective observational two-center study, 20 patients (median age: 8 years) undergoing chemotherapy simultaneously wore two WDs (CORE®, Everion®) for 14 days. The predefined goal was core temperature recorded in sufficient quality and available within ≤ 30 min during ≥ 18/24 h for ≥ 7/14 days in more than 15 patients. RESULTS More patients reached the goal with CORE® (n = 13) versus Everion® (n = 3) (difference, 50% p < 0.001). After correcting for the transmission bottleneck caused by two WDs transmitting via one gateway, these numbers increased (n = 15 versus n = 14; difference, 5%; p = 0.69). CORE® measurements corresponded better to ear temperatures (n = 528; mean bias, - 0.07 °C; mean absolute difference, 0.35 °C) than Everion® measurements (n = 532; - 1.06 °C; 1.10 °C). Acceptance rates for the WDs were 95% for CORE® and 89% for Everion®. CONCLUSION The CORE® fulfilled the predefined feasibility criterion (15 of 20 patients) after correction for transmission bottleneck, and the Everion® nearly fulfilled it. Continuous core temperature recording of good quality and with timely data availability was feasible from preschool to adolescent patients undergoing chemotherapy for cancer. These results encourage the design of randomized controlled trials on continuously monitored core temperature in pediatric patients. CLINICALTRIALS gov (NCT04914702) on June 7, 2021

39·0°C versus 38·5°C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: a multicentre, cluster-randomised, multiple-crossover, non-inferiority trial.

BACKGROUND Fever in neutropenia is the most frequent complication of chemotherapy for cancer. The temperature limit defining fever used clinically varies. A higher limit can avoid unnecessary diagnoses in patients spontaneously recovering from fever. This trial primarily aimed to determine if a limit of 39·0°C ear temperature is non-inferior to 38·5°C regarding safety. METHODS This cluster-randomised, multiple crossover, non-blinded, non-inferiority trial was done in six Swiss Paediatric Oncology Group centres (clusters) in Switzerland. Patients (aged 1 to <18 years) with any malignancy and treated with myelosuppressive chemotherapy expected to last 2 months or more were repeatedly randomly assigned (1:1), at the cluster level, to either monthly 39·0°C or 38·5°C ear temperature limits for diagnosis of fever in neutropenia. Diagnosis below the randomised limit was allowed for clinical reasons. Such a diagnosis implied emergency hospitalisation, examinations (including blood culture), as-needed antipyretics, and empirical intravenous broad-spectrum antibiotics. The primary outcome was the rate of fever in neutropenia with safety relevant events (SRE) per chemotherapy year; we also assessed efficacy in terms of rate of fever in neutropenia. The non-inferiority margin was 1·33 for safety, and for effiacy, the superiority margin was 1·00. This trial is registered at ClinicalTrials.gov, number NCT02324231. FINDINGS 269 patients were recruited between April 28, 2016, to Aug 27, 2018, until the trial was stopped for success after the second interim analysis. Patients were repeatedly randomly assigned, with 1210 (48%) of 2547 randomisation periods and 92 (47%) of 195 chemotherapy years randomised to 39·0°C. SREs were diagnosed in 72 (20%) of 360 fever in neutropenia episodes (zero deaths, 16 intensive care unit admissions, 22 cases of severe sepsis, and 56 cases of bacteraemia). In 92 chemotherapy years randomised to the 39·0°C fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year). In 103 chemotherapy years randomised to 38·5°C, 209 episodes were diagnosed (2·03 per year), including 50 (24%) with SRE (0·49 per year). The mixed Poisson regression rate ratio (RR) of fever in neutropenia with SRE in 39·0°C versus 38·5°C was 0·56 (95% upper confidence bound 0·72). The corresponding RR of fever in neutropenia was 0·83 (95% upper confidence bound 0·98). INTERPRETATION In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature was safe and seemed efficacious. For Switzerland and comparable settings, 39·0°C can be recommended as new evidence-based standard fever limit except for patients with acute myeloid leukaemia or haematopoietic stem cell transplantation. FUNDING Swiss Cancer League (KLS-3645-02-2015)

Deep learning-enabled diagnosis of liver adenocarcinoma.

BACKGROUND & AIMS Diagnosis of adenocarcinoma in the liver is a frequent scenario in routine pathology and has a critical impact on clinical decision-making. However, rendering a correct diagnosis can be challenging and often requires the integration of clinical, radiological, and immunohistochemical information. We present a deep learning model (HEPNET) to distinguish intrahepatic cholangiocarcinoma (iCCA) from colorectal liver metastasis (CRM) as the most frequent primary and secondary forms of liver adenocarcinoma with clinical-grade accuracy using hematoxylin and eosin-stained whole-slide images. METHODS HEPNET was trained on 714 589 image tiles from 456 patients who were randomly selected in a stratified manner from a pool of 571 patients who underwent surgical resection or biopsy at Heidelberg University Hospital. Model performance was evaluated on a hold-out internal test set comprising 115 patients and externally validated on 159 patients recruited at Mainz University Hospital. RESULTS On the hold-out internal test set, HEPNET achieved an area under the receiver operating characteristic curve (AUROC) of 0.994 (95% CI 0.989-1.000) and an accuracy of 96.522% (95% CI 94.521-98.694%) at the patient level. Validation on the external test set yielded an AUROC of 0.997 (95% CI 0.995-1.000), corresponding to an accuracy of 98.113% (95% CI 96.907-100.000%). HEPNET surpassed the performance of six pathology experts with different levels of experience in a reader study of 50 patients (P=.0005), boosted the performance of resident pathologists to the level of senior pathologists, and reduced potential downstream analyses. CONCLUSION Here, we provide a ready-to-use tool with a clinical-grade performance that may facilitate routine pathology by rendering a definitive diagnosis and guiding ancillary testing. The incorporation of HEPNET into pathology laboratories may optimize the diagnostic workflow, complemented by test-related labor and cost savings