There is no evidence-based definition of the temperature limit defining fever (TLDF) in children with neutropenia. Lowering the TLDF is known to increase the number of episodes of fever in ...neutropenia (FN). This study aimed to investigate the influence of a lower versus standard TLDF on diagnostics and therapy.
In a single pediatric cancer center using a high standard TLDF (39°C tympanic-temperature) patients were observed prospectively (NCT01683370). The effect of applying lower TLDFs (range 37.5°C to 38.9°C) versus 39.0°C on these measures was simulated in silicon.
In reality, 45 FN episodes were diagnosed. Of 3391 temperatures measured, 193 were ≥39.0°C, and 937 ≥38.0°C. For persisting fever ≥24 hours, additional blood cultures were taken in 31 (69%) episodes in reality. This number decreased to 22 (49%) when applying 39.0°C, and increased to 33 for 38.0°C (73%; plus 11 episodes; plus 24%). For persisting fever ≥48 hours, i.v.-antibiotics were escalated in 25 (56%) episodes. This number decreased to 15 (33%) when applying 39.0°C, and increased to 26 for 38.0°C (58%; plus 11 episodes; plus 24%). For persisting fever ≥120 hours, i.v.-antifungals were added in 4 (9%) episodes. This number increased to 6 (13%) by virtually applying 39.0°C, and to 11 for 38.0°C (24%; plus 5 episodes; plus 11%). The median length of stay was 5.7 days (range, 0.8 to 43.4). In 43 episodes with hospital discharge beyond 24 hours, applying 38.0°C led to discharge delay by ≥12 hours in 24 episodes (56%; 95% CI, 40 to 71), with a median delay of 13 hours, and a cumulative delay of 68 days.
Applying a low versus standard TLDF led to relevant increases of diagnostics, antimicrobial therapy, and length of stay. The differences between management in reality versus simply applying 39.0° as TLDF reflect the important impact of clinical assessment.
Fusion-positive rhabdomyosarcoma (FP-RMS) is a highly aggressive childhood malignancy which is mainly treated by conventional chemotherapy, surgery and radiation therapy. Since radiotherapy is ...associated with a high burden of late side effects in pediatric patients, addition of radiosensitizers would be beneficial. Here, we thought to assess the role of fenretinide, a potential agent for FP-RMS treatment, as radiosensitizer. Survival of human FP-RMS cells was assessed after combination therapy with fenretinide and ionizing radiation (IR) by cell viability and clonogenicity assays. Indeed, this was found to significantly reduce cell viability compared to single treatments. Mechanistically, this was accompanied by enhanced production of reactive oxygen species, initiation of cell cycle arrest and induction of apoptosis. Interestingly, the combination treatment also triggered a new form of dynamin-dependent macropinocytosis, which was previously described in fenretinide-only treated cells. Our data suggest that fenretinide acts in combination with IR to induce cell death in FP-RMS cells and therefore might represent a novel radiosensitizer for the treatment of this disease.
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.
Introduction
Children with cancer are at an increased risk for various physical and cognitive challenges due to their illness and its treatment. A concerning observation is that young cancer patients ...often lead sedentary or even lying lifestyles, clearly failing to meet the WHO’s recommendation of 60 minutes of moderate-to-vigorous physical activity (PA) daily. This is alarming considering that PA is essential for physical and mental health, e.g., for the development of motor skills and cognitive functions (Bull et al., 2020). However, PA promotion in acute care in Swiss pediatric oncology units is hardly existent. Therefore, the aim of this project is to develop and conduct a physical activity program in a pediatric oncology unit and investigate its effects on cognitive and motor performance.
Methods
Part A of this project involved a qualitative study conducted at the Inselspital Bern’s pediatric oncology unit, aiming to design a tailored PA therapy program. This part included patient interviews and staff surveys. Part B, which is ongoing, focuses on a forthcoming two-arm multicenter crossover-controlled trial. This trial will compare the exercise therapy and PA counseling (intervention group in Bern, n = 40) with standard treatment (control group in Basel, n = 40). Participants will be aged 6-18 years, newly diagnosed with cancer and undergoing cytotoxictreatment for at least six weeks. The 12-week program will consist of thrice-weekly, 45-minute sessions of individualized exercise, aligned with the SK2-guidelines, NAOK, and international Pediatric Oncology Exercise Guidelines (Götte et al., 2022; Wurz et al., 2021). The sessions will focus on motor skills and cognitively challenging PA. In addition, children will receive 4 exercise counseling sessions. To evaluate the study, there will be three measurement points (once at admission, after twelve weeks of intervention and one follow-up after six months). The outcome measures include motor and cognitive performance, physiological and psychosocial functioning.
Results
Initial findings from the qualitative study indicate a strong patient and staff interest in exercise therapy. The study also provided valuable insights for developing and implementing the intervention.
Discussion/conclusion
The results will reveal important insights relevant to research and practice. Adopting a research perspective, the results will shed light on the effects of PA on cognitive performance in acute cancer care. Adopting a more applied perspective, PA has been neglected in Swiss pediatric oncology units so far. Therefore, this study may contribute to proof the effectiveness of PA for childhood cancer patients and thus help implementing it in standard care in the long term.
References
Bull, F. C., Al-Ansari, S. S., Biddle, S., Borodulin, K., Buman, M. P., Cardon, G., Carty, C., Chaput, J.-P., Chastin, S., Chou, R., Dempsey, P. C., DiPietro, L., Ekelund, U., Firth, J., Friedenreich, C. M., Garcia, L., Gichu, M., Jago, R., Katzmarzyk, P. T., Lambert, E., Leitzmann, M., … & Willumsen, J. F. (2020). World Health Organization 2020 guidelines on physical activity and sedentary behaviour. British Journal of Sports Medicine, 54(24), 1451-1462. https://doi.org/10.1136/bjsports-2020-102955
Götte, M., Gauß, G., Dirksen, U., Driever, P. H., Basu, O., Baumann, F. T., Wiskemann, J., Boos, J., & Kesting, S. V. (2022). Multidisciplinary Network ActiveOncoKids guidelines for providing movement and exercise in pediatric oncology: Consensus-based recommendations. Pediatric Blood & Cancer, 69(11), Article e29953. https://doi.org/10.1002/pbc.29953
Wurz, A., McLaughlin, E., Lategan, C., Chamorro Viña, C., Grimshaw, S. L., Hamari, L., Götte, M., Kesting, S., Rossi, F., van der Torre, P., Guilcher, G. M. T., McIntyre, K., & Culos-Reed, S. N. (2021). The international Pediatric Oncology Exercise Guidelines (iPOEG). Translational Behavioral Medicine, 11(10), 1915-1922. https://doi.org/10.1093/tbm/ibab028
Introduction
Increasing physical activity (PA) levels in children and adolescents with cancer holds promise for enhancing outcomes both during treatment and into survivorship (Stout et al., 2017). ...Despite this potential, the promotion of PA within Swiss pediatric oncology units remains largely overlooked. To address this gap, the “KiKli Fit” project has been initiated. This program features personalized training sessions during acute care, accompanied by PA counseling during the transition to the post-acute phase. Importantly, it engages not only the patients but also their families, since they play a crucial role in shaping youth’s PA behavior (Cheung et al., 2021). The PA counseling is designed to enhance motivation, volition, enjoyment, family health-climate, and ultimately, foster an active lifestyle (Schorno et al., 2022). This study aims to outline the theoretical development of the counseling approach and present initial findings from its implementation.
Methods
We plan a two-arm multicenter crossover-controlled trial to investigate the effects of the whole PA program. The trial will compare the PA program (intervention group in Bern, n = 40) with standard treatment (control group in Basel, n = 40). Participants will be aged 6-18, newly diagnosed with cancer and undergoing neurotoxic treatment for at least six weeks. The PA counseling comprises four sessions involving the child or adolescent and their parents. These sessions cover various topics, including parental concerns about their child performing PA, individual preferences in exercise and sports, and ways to be physically active as a whole family. Motivational interviewing techniques are applied across all sessions. The study will start in early 2024. Outcomes will be measured three times (once at admission, after twelve weeks of intervention and for follow-up after six months).
Discussion
The “KiKli Fit”-project is a complex program that aims to promote PA in and after acute care by combining personalized training sessions with PA counseling. The scalability of the PA counseling is a key advantage, allowing it to reach a wide demographic, including those who have completed treatment. Fostering PA in young cancer patients seems to particularly important because it can set a foundation for a healthier lifestyle as they transition into adulthood.
References
Cheung, A. T., Li, W. H. C., Ho, L. L. K., Chan, G. C. F., & Chung, J. O. K. (2021). Parental perspectives on promoting physical activity for their children surviving cancer: A qualitative study. Patient Education and Counseling, 104(7), 1719-1725. https://doi.org/10.1016/j.pec.2020.11.009
Schorno, N., Gut, V., Conzelmann, A., & Schmid, J. (2022). Effectiveness of individual exercise and sport counseling based on motives and goals: A randomized controlled trial. Journal of Sport and Exercise Psychology, 44(2), 103-115. https://doi.org/10.1123/jsep.2021-0018
Stout, N. L., Baima, J., Swisher, A. K., Winters-Stone, K. M., & Welsh, J. (2017). A systematic review of exercise systematic reviews in the cancer literature (2005-2017). PM&R, 9, 347-384. https://doi.org/10.1016/j.pmrj.2017.07.074
Summary
The collectin surfactant protein D (SP‐D) is an important component of the pulmonary innate host defence. Up to now, little is known about the regulation of eosinophil function by SP‐D. ...Various murine models of pulmonary hypersensitivity suggest that SP‐D may be a potent anti‐allergic protein. We investigated the modulation of eosinophil chemotaxis and degranulation by human SP‐D. SP‐D markedly inhibited the chemotaxis of eosinophils triggered by eotaxin, a major tissue‐derived CC‐chemokine, as shown in a modified Boyden chamber assay. In addition, degranulation of ECP in response to Ca2+ ionophore, immobilized IgG and serum from allergic patients was inhibited by SP‐D. In a fixed‐cell enzyme linked immunosorbent assay and in flow cytometry, SP‐D bound to eosinophils. This binding was saturable and was inhibited by the addition of maltose and ethylenediaminetetraacetic acid, suggesting the involvement of the carbohydrate recognition domain of SP‐D. In addition, flow cytometry showed significant interaction of SP‐D with CD32 (FcγII receptor) on eosinophils, which might explain the inhibitory effect of SP‐D on the IgG and serum‐triggered eosinophil cationic protein degranulation of eosinophils. Our data further support the concept of an anti‐inflammatory function of SP‐D in the lung of patients with allergic diseases.
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.
Trial registration.
ClinicalTrials.gov (NCT04914702) on June 7, 2021.
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.
Fever in neutropenia (FN) remains a serious complication of childhood cancer therapy. Clinical decision rules (CDRs) are recommended to help distinguish between children at high and low risk of ...severe infection. The aim of this analysis was to develop new CDRs for three different outcomes and to externally validate published CDRs.
Children undergoing chemotherapy for cancer were observed in a prospective multicenter study. CDRs predicting low from high risk infection regarding three outcomes (bacteremia, serious medical complications (SMC), safety relevant events (SRE)) were developed from multivariable regression models. Their predictive performance was assessed by internal cross-validation. Published CDRs suitable for validation were identified by literature search. Parameters of predictive performance were compared to assess reproducibility.
In 158 patients recruited between April 2016 and August 2018, 360 FN episodes were recorded, including 56 (16%) with bacteremia, 30 (8%) with SMC and 72 (20%) with SRE. The CDRs for bacteremia and SRE used four characteristics (type of malignancy, severely reduced general condition, leucocyte count <0.3 G/L, bone marrow involvement), the CDR for SMC two characteristics (severely reduced general condition and platelet count <50 G/L). Eleven published CDRs were analyzed. Six CDRs showed reproducibility, but only one in both sensitivity and specificity.
This analysis developed CDRs predicting bacteremia, SMC or SRE at presentation with FN. In addition, it identified six published CDRs that show some reproducibility. Validation of CDRs is fundamental to find the best balance between sensitivity and specificity, and will help to further improve management of FN.
Alveolar rhabdomyosarcoma (aRMS) is a highly malicious childhood malignancy characterized by specific chromosomal translocations mostly encoding the oncogenic transcription factor PAX3-FOXO1 and ...therefore also referred to as fusion-positive RMS (FP-RMS). Previously, we have identified fenretinide (retinoic acid p-hydroxyanilide) to affect PAX3-FOXO1 expression levels as well as FP-RMS cell viability. Here, we characterize the mode of action of fenretinide in more detail. First, we demonstrate that fenretinide-induced generation of reactive oxygen species (ROS) depends on complex II of the mitochondrial respiratory chain, since ROS scavenging as well as complexing of iron completely abolished cell death. Second, we co-treated cells with a range of pharmacological inhibitors of specific cell death pathways including z-vad (apoptosis), necrostatin-1 (necroptosis), 3-methyladenine (3-MA) (autophagy), and ferrostatin-1 (ferroptosis) together with fenretinide. Surprisingly, none of these inhibitors was able to prevent cell death. Also genetic depletion of key players in the apoptotic and necroptotic pathway (BAK, BAX, and RIPK1) confirmed the pharmacological data. Interestingly however, electron microscopy of fenretinide-treated cells revealed an excessive accumulation of cytoplasmic vacuoles, which were distinct from autophagosomes. Further flow cytometry and fluorescence microscopy experiments suggested a hyperstimulation of macropinocytosis, leading to an accumulation of enlarged early and late endosomes. Surprisingly, pharmacological inhibition as well as genetic depletion of large dynamin GTPases completely abolished fenretinide-induced vesicle formation and subsequent cell death, suggesting a new form of dynamin-dependent programmed cell death. Taken together, our data identify a new form of cell death mediated through the production of ROS by fenretinide treatment, highlighting the value of this compound for treatment of sarcoma patients including FP-RMS.
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