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The article examines the incidence and outcomes of hypertension at diagnosis in children with kidney tumors, providing insights from a substantial national retrospective cohort. It reports that 55 percent of children with a kidney tumor were hypertensive at diagnosis, with most having grade one hypertension. It is noted that there were no significant differences in hypertension occurrence based on gender or tumor subtypes.

Introduction: Vincristine is an integral component of treatment for children with cancer. Its main dose‐limiting side effect is vincristine‐induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of 1‐hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short‐term outcomes (median follow‐up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1‐hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow‐up 20 months), which includes treatment outcome as a secondary objective (follow‐up 3 years). Methods: VIPN was measured 1–7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric‐modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed. Results: Forty‐five participants per randomization group were included. There was no significant effect of 1‐hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one‐hour group (rate ratio 0.52, 95% confidence interval 0.33–0.80, p = 0.003). Four patients in the one‐hour group and one patient in the push group relapsed. Two patients in the one‐hour group died. Conclusion: 1‐hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1‐hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile. Vincristine is an integral component of treatment for children with cancer. Its main dose‐limiting side effect is vincristine‐induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of one‐hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. We found that in patients receiving concurrent azoles, one‐hour infusion may be less toxic. [ABSTRACT FROM AUTHOR]

Simple Summary: Children treated for hemato-oncological diseases are at risk of muscle deterioration, such as loss of muscle mass and muscle weakness, with consequent impaired physical functioning. An easy screening tool will facilitate the early identification of children at risk and will support clinical decision making. We investigated the accuracy of an easy screening tool: the pediatric SARC-F (PED-SARC-F), for identifying functional sarcopenia in pediatric hemato-oncology patients. Functional sarcopenia indicates low muscle strength combined with low physical performance. We showed that the PED-SARC-F has a 90% accuracy in identifying pediatric hemato-oncology patients with functional sarcopenia. A PED-SARC-F cut-off point of ≥5 had the highest specificity (91%) and limits unnecessary assessments in patients who are not at risk of sarcopenia. This tool can be used to identify children that need a physiotherapy assessment and further interventions to prevent physical deterioration during and shortly after treatment for a hemato-oncology disease. Sarcopenia in pediatric hemato-oncology patients is undesirable because of the consequences it may have for treatment continuation and outcome, physical abilities and participation in daily life. An easy-to-use screening tool for sarcopenia will facilitate the identification of children at risk who need interventions to prevent serious physical deterioration. In the elderly, the use of the SARC-F score as a case-finding tool for sarcopenia is recommended. The aim of this cross-sectional study was to investigate the accuracy of the pediatric SARC-F (PED-SARC-F) for identifying sarcopenia in pediatric hemato-oncology patients, including the determination of a cut-off point for clinical use. Patients 3–20 years of age, under active treatment or within 12 months after treatment cessation were eligible. Patients had a physiotherapy assessment including a PED-SARC-F (0–10) and measurements of muscle strength (handheld dynamometry), physical performance (various tests) and/or muscle mass (bio-impedance analysis), as part of the standard of care. Spearman's correlation coefficient (rs) between the PED-SARC-F and physiotherapy outcomes were calculated. Structural sarcopenia was defined as low appendicular skeletal muscle mass (ASMM) in combination with low muscle strength and/or low physical performance. Functional sarcopenia indicated low muscle strength combined with low physical performance. Multiple logistic regression models were estimated to study the associations between the PED-SARC-F and structural/functional sarcopenia. To evaluate which cut-off point provides the most accurate classification, the area under the receiver operating characteristic curve (AUCs), sensitivity and specificity per point were calculated. In total, 215 assessments were included, 62% were performed in boys and the median age was 12.9 years (interquartile range: 8.5–15.8). The PED-SARC-F scores correlated moderately with the measurements of muscle strength (rs = −0.37 to −0.47, p < 0.001) and physical performance (rs = −0.45 to −0.66, p < 0.001), and weakly with ASMM (rs = −0.27, p < 0.001). The PED-SARC-F had an AUC of 0.90 (95% confidence interval (CI) = 0.84–0.95) for functional sarcopenia and 0.79 (95% CI = 0.68–0.90) for structural sarcopenia. A cut-off point of ≥5 had the highest specificity of 96% and a sensitivity of 74%. In conclusion, we adapted the SARC-F to a pediatric version, confirmed its excellent diagnostic accuracy for identifying functional sarcopenia and defined a clinically useful cut-off point in pediatric hemato-oncology patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Vincristine is a type of chemotherapy that is often used in the treatment of children with cancer. The main side effect of vincristine is nerve damage. Patients experience symptoms such as tingling, pain or muscle weakness. Some children are more sensitive to vincristine than others, which may depend on variations in genes and in the breakdown of vincristine by the body. In this study, we investigated the effect of variations in genes on nerve damage due to vincristine and breakdown of vincristine by the body. We found that nine variations in seven genes were associated with nerve damage due to vincristine, whereas three variations in three genes were associated with the breakdown of vincristine by the body. It is important that future studies try to replicate these findings. Our findings help us towards the goal of tailoring vincristine treatment to each child, with optimal therapeutic effect while limiting nerve damage. Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and pharmacokinetics (PK). In this study, we identify and replicate genetic variants associated with VCR PK and VIPN. Patient samples from a randomized clinical trial studying the effect of administration duration of VCR on VIPN in 90 patients were used. PK sampling was conducted on between one and five occasions at multiple time points. A linear two-compartment model with first-order elimination was used, and targeted next-generation DNA sequencing was performed. Genotype–trait associations were analyzed using mixed-effect models or logistic regression analysis for repeated measures, or Poisson regression analysis in which the highest VIPN score per patient was included. Nine single-nucleotide polymorphisms (SNPs) in seven genes (NDRG1, GARS, FIG4, FGD4, SEPTIN9, CEP72, and ETAA1) were associated with VIPN. Furthermore, three SNPs in three genes (MTNR1B, RAB7A and SNU13) were associated with PK of VCR. In conclusion, PK of VCR and VIPN are influenced by SNPs; upfront identification of those that lead to an altered susceptibility to VIPN or VCR exposure could help individualize VCR treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Salivary gland dysfunction is an underestimated late effect in childhood cancer survivors (CCS). The objective of this cross-sectional study, part of the multidisciplinary multicenter Dutch Childhood Cancer Survivor Study Late Effects 2 (DCCSS LATER 2), was to assess the prevalence of and risk factors for hyposalivation and xerostomia in CCS with a long-term follow-up exceeding 15 years. From February 2016 until March 2020, 292 CCS were included. The prevalence of hyposalivation was 32% and the prevalence of xerostomia was 9.4%. Hyposalivation and xerostomia did not correlate significantly. Risk factors for hyposalivation were female gender and a higher dose of radiotherapy (>12 Gy) to the salivary glands. Screening for hyposalivation during long-term follow-up in CCS is recommended in order to provide optimal oral supportive care aimed to improve oral health. Background: Limited data are available on the risk factors of salivary gland dysfunction in long-term childhood cancer survivors (CCS). The objective of this cross-sectional study, part of the multidisciplinary multicenter Dutch CCS Study Late Effects 2 (DCCSS LATER 2), was to assess the prevalence of and risk factors for hyposalivation and xerostomia in CCS. Methods: From February 2016 until March 2020, 292 CCS were included. Data with regard to gender, age at study, diagnosis, age at diagnosis, and treatment characteristics were collected, as well as the unstimulated (UWS) and stimulated whole salivary flow rate (SWS). Xerostomia was assessed with the Xerostomia Inventory (XI) questionnaire. Multivariable Poisson regression analyses were used to evaluate the association between potential risk factors and the occurrence of hyposalivation. Results: The minimum time between diagnosis and study enrollment was 15 years. The prevalence of hyposalivation was 32% and the prevalence of xerostomia was 9.4%. Hyposalivation and xerostomia were not significantly correlated. Risk factors for hyposalivation were female gender and a higher dose of radiotherapy (>12 Gy) to the salivary gland region. Conclusion: Considering the importance of saliva for oral health, screening for hyposalivation in CCS is suggested in order to provide optimal oral supportive care aimed to improve oral health. [ABSTRACT FROM AUTHOR]

This multi-center cohort-study examined late mortality among 6,165 Dutch five-year childhood cancer survivors diagnosed 1963–2001. Clinical details and cause of death were based on medical records. Mortality was 12-fold that of the general population, with 51.3 additional deaths per 10,000 person-years (21.9 yrs median follow-up). Cumulative mortality 15 yrs post-diagnosis was 6.9%, predominantly from late recurrences; thereafter the absolute contribution of other health outcomes increased. Cumulative all-cause and recurrence-related mortality were highest for Central Nervous System and bone tumor survivors. All-cause, but not subsequent tumor and circulatory disease-related cumulative mortality, was highest for patients diagnosed 1963–1979 vs. later (p-trend <0.001). [ABSTRACT FROM AUTHOR]

Background: Some children with central nervous system (CNS) and solid tumors are at risk to develop ototoxicity during treatment. Up to now, several risk factors have been identified that may contribute to ototoxicity, such as platinum derivates, cranial irradiation, and brain surgery. Comedication, like antibiotics and diuretics, is known to enhance ototoxicity, but their independent influence has not been investigated in childhood cancer patients. Recommendations for hearing loss screening are missing or vary highly across treatment protocols. Additionally, adherence to existing screening guidelines is not always optimal. Currently, knowledge is lacking on the prevalence of ototoxicity. Objective: The aim of the Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND) is to determine the feasibility of audiological testing and to determine the prevalence and determinants of ototoxicity during treatment for childhood cancer in a national cohort of patients with solid and CNS tumors. Methods: The SOUND study is a prospective cohort study in the national childhood cancer center in the Netherlands. The study aims to include all children aged 0 to 19 years with a newly diagnosed CNS or solid tumor. Part of these patients will get audiological examination as part of their standard of care (stratum 1). Patients in which audiological examination is not the standard of care will be invited for inclusion in stratum 2. Age-dependent audiological assessments will be pursued before the start of treatment and within 3 months after the end of treatment. Apart from hearing loss, we will investigate the feasibility to screen patients for tinnitus and vertigo prevalence after cancer treatment. This study will also determine the independent contribution of antibiotics and diuretics on ototoxicity. Results: This study was approved by the Medical Research Ethics Committee Utrecht (Identifier 20-417/M). Currently, we are in the process of recruitment for this study. Conclusions: The SOUND study will raise awareness about the presence of ototoxicity during the treatment of children with CNS or solid tumors. It will give insight into the prevalence and independent clinical and cotreatment-related determinants of ototoxicity. This is important for the identification of future high-risk patients. Thereby, the study will provide a basis for the selection of patients who will benefit from innovative otoprotective intervention trials during childhood cancer treatment that are currently being prepared. Trial Registration: Netherlands Trial Register NL8881; https://www.trialregister.nl/trial/8881 International Registered Report Identifier (IRRID): DERR1-10.2196/34297 [ABSTRACT FROM AUTHOR]

Purpose: Vincristine (VCR) is a chemotherapeutic agent used in the treatment of pediatric oncology patients, but its main toxicity is VCR‐induced peripheral neuropathy (VIPN). However, whether VIPN has an effect on health‐related quality of life (HR‐QoL) in children during treatment is unknown. Therefore, the aim of our study was to investigate the association between VIPN and HR‐QoL in children starting treatment for cancer. Methods: Measurements of VIPN were performed using two tools: Common Terminology Criteria for Adverse Events (CTCAE) and pediatric‐modified Total Neuropathy Score (ped‐mTNS). Assessment of HR‐QoL was done with self‐ and proxy assessment of the Cancer and Generic module of the Pediatric Cancer Quality of Life Inventory™ (PedsQL). Results: In total, N = 86 children were included. HR‐QoL of children with VIPN (n = 67%, 76%) was significantly lower in comparison with children without VIPN: estimated Total score of PedsQL Generic (proxy) 84.57; β = −8.96 and 95% confidence interval (CI) −14.48 to −3.43; p = 0.002, estimated PedsQL Generic Total score (self‐reported): 85.16, β = −8.38 (95% CI: −13.76 to −3.00); p = 0.003. Similar results were found in the Pain and Hurt domain of the PedsQL Cancer (pain: estimated score [proxy]: 85.28, β = −9.94 [95%CI: −16.44 to −3.45], p = 0.003; hurt: estimated score [self‐report] 97.57, β = −19.15 [95%CI: −26.82 to −11.48], p < 0.001). Conclusion: VIPN results in a significant reduction of HR‐QoL in children under treatment for a malignancy, which means that VIPN is important for the well‐being of pediatric oncology patients. Therefore, this study underlines the importance of optimizing treatment with VCR, thereby aiming to reduce VIPN while maintaining efficacy. [ABSTRACT FROM AUTHOR]

Background: Cardiotoxicity is a well‐known side effect after anthracyclines and chest radiotherapy in childhood cancer survivors (CCS). The DCCSS LATER 2 CARD (cardiology) study includes evaluation of echocardiographic measurements for early identification of CCS at highest risk of developing heart failure. This paper describes the design, feasibility, and reproducibility of the echocardiography protocol. Methods: Echocardiograms from CCS and sibling controls were prospectively obtained at the participating centers and centrally analyzed. We describe the image acquisition, measurement protocol, and software‐specific considerations for myocardial strain analyses. We report the feasibility of the primary outcomes of systolic and diastolic function, as well as reproducibility analyses in 30 subjects. Results: We obtained 1,679 echocardiograms. Biplane ejection fraction (LVEF) measurement was feasible in 91% and 96% of CCS and siblings, respectively, global longitudinal strain (GLS) in 80% and 91%, global circumferential strain (GCS) in 86% and 89%, and ≥2 diastolic function parameters in 99% and 100%, right ventricle free wall strain (RVFWS) in 57% and 65%, and left atrial reservoir strain (LASr) in 72% and 79%. Intra‐class correlation coefficients for inter‐observer variability were 0.85 for LVEF, 0.76 for GLS, 0.70 for GCS, 0.89 for RVFWS and 0.89 for LASr. Intra‐class correlation coefficients for intra‐observer variability were 0.87 for LVEF, 0.82 for GLS, 0.82 for GCS, 0.85 for RVFWS and 0.79 for LASr. Conclusion: The DCCSS LATER 2 CARD study includes a protocolized echocardiogram, with feasible and reproducible primary outcome measurements. This ensures high‐quality outcome data for prevalence estimates and for reliable comparison of cardiac function parameters. [ABSTRACT FROM AUTHOR]

Study Question: Do children conceived by ART have an increased risk of cancer?Summary Answer: Overall, ART-conceived children do not appear to have an increased risk of cancer.What Is Known Already: Despite the increasing use of ART, i.e. IVF or ICSI worldwide, information about possible long-term health risks for children conceived by these techniques is scarce.Study Design, Size, Duration: A nationwide historical cohort study with prospective follow-up (median 21 years), including all live-born offspring from women treated with subfertility treatments between 1980 and 2001.Participants/materials, Setting, Methods: All offspring of a nationwide cohort of subfertile women (OMEGA study) treated in one of the 12 Dutch IVF clinics or two fertility clinics. Of 47 690 live-born children, 24 269 were ART-conceived, 13 761 naturally conceived and 9660 were conceived naturally or through fertility drugs, but not by ART. Information on the conception method of each child and potential confounders were collected through the mothers' questionnaires and medical records. Cancer incidence was ascertained through linkage with The Netherlands Cancer Registry from 1 January 1989 until 1 November 2016. Cancer risk in ART-conceived children was compared with risks in naturally conceived children from subfertile women (hazard ratios [HRs]) and with the general population (standardized incidence ratios [SIRs]).Main Results and the Role Of Chance: The median follow-up was 21 years (interquartile range (IQR): 17-25) and was shorter in ART-conceived children (20 years, IQR: 17-23) compared with naturally conceived children (24 years, IQR: 20-30). In total, 231 cancers were observed. Overall cancer risk was not increased in ART-conceived children, neither compared with naturally conceived children from subfertile women (HR: 1.00, 95% CI 0.72-1.38) nor compared with the general population (SIR = 1.11, 95% CI: 0.90-1.36). From 18 years of age onwards, the HR of cancer in ART-conceived versus naturally conceived individuals was 1.25 (95% CI: 0.73-2.13). Slightly but non-significantly increased risks were observed in children conceived by ICSI or cryopreservation (HR = 1.52, 95% CI: 0.81-2.85; 1.80, 95% CI: 0.65-4.95, respectively). Risks of lymphoblastic leukemia (HR = 2.44, 95% CI: 0.81-7.37) and melanoma (HR = 1.86, 95% CI: 0.66-5.27) were non-significantly increased for ART-conceived compared with naturally conceived children.Limitations, Reasons For Caution: Despite the large size and long follow-up of the cohort, the number of cancers was rather small for subgroup analyses as cancer in children and young adults is rare.Wider Implications Of the Findings: Overall, ART-conceived children do not appear to have an increased cancer risk after a median follow-up of 21 years. This large study provides important results, enabling physicians to better inform couples considering ART about the long-term safety of ART for their children. However, larger studies with prolonged follow-up are needed to investigate cancer risk in adults and in children conceived by ICSI and/or from cryopreserved embryos.Study Funding/competing Interest(s): This work was supported by The Dutch Cancer Society (NKI 2006-3631) which funded the OMEGA-women's cohort and Children Cancer Free (KIKA;147) which funded the OMEGA-offspring cohort. We declare no competing interests. [ABSTRACT FROM AUTHOR]

Background and purpose: To assess intra- and inter-fraction motion uncertainties, due to displacements of the tumor bed (TB) and organs at risk (OAR), as well as intra- and inter-fraction patient set-up uncertainties, due to positioning variations, during image-guided radiation therapy (IGRT) in children with Wilms' tumor. Material and methods: Four-dimensional computed tomography (4D-CT) and daily pre- and post-treatment cone-beam CT (CBCT)-scans of 15 patients (average 4, range 1-8 years) undergoing flank irradiation after nephrectomy were analyzed. TB (marked by four surgical clips) and OAR motion uncertainties were quantified by displacements of the center of mass in all orthogonal directions. Translational and rotational bone off-sets were recorded for patient set-up uncertainties assessment in all orthogonal directions. The average results, systematic and random errors were computed. Results: Average intra- and inter-fraction motion uncertainties were ≤1.1 mm (range: [-6.9;7.9] mm) for the TB and ≤3.2 mm (range: [-9.1;9.6] mm) for the OAR. Average intra- and inter-fraction patient set-up uncertainties were ≤0.1 mm (range: [-3.3;4.8] mm) and ≤0.9° (range: [0.0;2.8°]). Both motion and patient set-up uncertainties were larger for the cranio-caudal direction. Calculated systematic and random errors were ≤2.4 mm for the motion uncertainties and ≤0.8 mm/0.7° for the patient set-up uncertainties. Conclusions: Average motion and patient set-up uncertainties during radiotherapy treatment were found to be limited. However, uncertainties were larger for the cranio-caudal direction and outliers were found in all orthogonal directions. When having available 4D-CT and CBCT information, the use of patient-specific and anisotropic safety margin expansions is advised for both target volume and OAR. [ABSTRACT FROM AUTHOR]

Objective: The Psychosocial Assessment Tool (PAT) was developed to screen for psychosocial risk in families of a child diagnosed with cancer. The current study is the first describing the cross-cultural adaptation, reliability, validity, and usability of the PAT in an European country (Dutch translation).Methods: A total of 117 families (response rate 59%) of newly diagnosed children with cancer completed the PAT2.0 and validation measures.Results: Acceptable reliability was obtained for the PAT total score (α = .72) and majority of subscales (0.50-0.82). Two subscales showed inadequate internal consistency (Social Support α = .19; Family Beliefs α = .20). Validity and usability were adequate. Of the families, 66% scored low (Universal), 29% medium (Targeted), and 5% high (Clinical) risk.Conclusions: This study confirms the cross-cultural applicability, reliability, and validity of the PAT total score. Reliability left room for improvement on subscale level. Future research should indicate whether the PAT can be used to provide cost-effective care. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this Task Force was to review the use of dual-energy X-ray absorptiometry (DXA) in children and adolescents with underlying chronic diseases that pose risk factors for compromised bone health, such as inflammation, glucocorticoid therapy, or decreased mobility. The Task Force systematically analyzed more than 270 studies, with an emphasis on those published in the interval since the original 2007 Position Statements. Important developments over this period included prospective cohort studies demonstrating that DXA measures of areal bone mineral density (aBMD) predicted incident fractures and the development of robust reference data and strategies to adjust for bone size in children with growth impairment. In this report, we summarize the current literature on the relationship between DXA-based aBMD and both fracture (vertebral and non-vertebral) outcomes and non-fracture risk factors (e.g., disease characteristics, ambulatory status, and glucocorticoid exposure) in children with chronic illnesses. Most publications described the aBMD profile of children with underlying diseases, as well as the cross-sectional or longitudinal relationship between aBMD and clinically relevant non-fracture outcomes. Studies that addressed the relationship between aBMD and prevalent or incident fractures in children with chronic illnesses are now emerging. In view of these updated data, this report provides guidelines for the use of DXA-based aBMD in this setting. The initial recommendation that DXA is part of a comprehensive skeletal healthy assessment in patients with increased risk of fracture is unchanged. Although the prior guidelines recommended DXA assessment in children with chronic diseases at the time of clinical presentation with ongoing monitoring, this revised Position Statement focuses on the performance of DXA when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture and when the DXA results will influence that management. [Copyright &y& Elsevier]

Gooskens SL, Braakman E, van den Boom AL, So-Osman C, de Winter F, Pieters R, van den Heuvel-Eibrink MM. Peripheral stem cell harvest using regular chemotherapy schedules in childhood cancer. Abstract: Prediction of the best moment for the harvest of PBSCs after standard chemotherapy followed by filgrastim in children with cancer is difficult. We retrospectively analyzed the moment of harvesting of 152 procedures in 94 patients. The start of apheresis was guided by WBC count and CD34+ cell measurement in peripheral blood. We defined the first day of filgrastim administration, after completion of mobilizing chemotherapy, as day 1. Median time to harvest in different subgroups is as follows: neuroblastoma 11 days (range, 6-29 days), Ewing's sarcoma nine days (range, 7-15 days), brain tumor 10 days (range, 7-15 days), relapsed Wilms' tumor 16 days (range, 9-20 days), and extracranial GCT seven days (range, 6-14 days). Patients harvested after cyclophosphamide priming (time to harvest within a range of 8-9 days) were analyzed as a separate group. The optimal moment for harvesting in different types of tumors was highly variable, although most consistent in patients diagnosed with Ewing's sarcoma or brain tumors and after cyclophosphamide priming. [ABSTRACT FROM AUTHOR]

Simple Summary: Survival of children with Wilms tumor is excellent. However, treatment-related complications may occur, requiring treatment at the pediatric intensive care unit (PICU). The aim of our retrospective study was to assess the frequency, clinical characteristics, and outcome of 175 children with Wilms tumor requiring treatment at the PICU in the Netherlands. Thirty-three patients (almost 20%) required unplanned PICU admission during their disease course. Younger age at diagnosis, intensive chemotherapy regimens, and bilateral tumor surgery were risk factors for these unplanned PICU admissions. Three children required renal replacement therapy, two of which continued dialysis after PICU discharge. Two children died during their PICU stay. During follow up, hypertension and renal dysfunction were frequently observed, which justifies special attention for kidney function and blood pressure monitoring during and after treatment of these children. Survival rates are excellent for children with Wilms tumor (WT), yet tumor and treatment-related complications may require pediatric intensive care unit (PICU) admission. We assessed the frequency, clinical characteristics, and outcome of children with WT requiring PICU admissions in a multicenter, retrospective study in the Netherlands. Admission reasons of unplanned PICU admissions were described in relation to treatment phase. Unplanned PICU admissions were compared to a control group of no or planned PICU admissions, with regard to patient characteristics and short and long term outcomes. In a multicenter cohort of 175 children with an underlying WT, 50 unplanned PICU admissions were registered in 33 patients. Reasons for admission were diverse and varied per treatment phase. Younger age at diagnosis, intensive chemotherapy regimens, and bilateral tumor surgery were observed in children with unplanned PICU admission versus the other WT patients. Three children required renal replacement therapy, two of which continued dialysis after PICU discharge (both with bilateral disease). Two children died during their PICU stay. During follow-up, hypertension and chronic kidney disease (18.2 vs. 4.2% and 15.2 vs. 0.7%) were more frequently observed in unplanned PICU admitted patients compared to the other patients. No significant differences in cardiac morbidity, relapse, or progression were observed. Almost 20% of children with WT required unplanned PICU admission, with young age and treatment intensity as potential risk factors. Hypertension and renal impairment were frequently observed in these patients, warranting special attention at presentation and during treatment and follow-up. [ABSTRACT FROM AUTHOR]

Background. Several longitudinal studies have shown contradictory results regarding the change in bone status in children with acute lymphoblastic leukaemia (ALL) using dual-energy X-ray absorptiometry as the bone assessment technique. Objective. To determine whether a more recently developed bone assessment technique which does not use radiation, tibial ultrasonometry, can be used for the detection of short-term changes. Patients and methods. From January 1997 to February 2001, 37 patients (25 boys, 12 girls, mean age 9.0 years, range 3.0–16.8 years) were included in a longitudinal study to assess changes in bone status induced by the disease itself and/or treatment. Of these 37 patients, 35 had a measurement at the start of therapy (t0), 26 at 6 months (t6), 24 at 12 months (t12), 11 at 24 months (t24) and 9 at 36 months (t36). For assessment of bone mass, the tibial ultrasound (US) device SoundScan Compact was used, which measures the speed of sound (SOS) along the cortex of the tibia over a fixed length of 5 cm at the mid-tibial point. Results. The SOS standard deviation (SD) scores were significantly lower at t6, t12, t24 and t36 than at baseline (t0). The biggest change was found between t0 and t6. During follow-up, no significant correlation was found between changes from baseline of height SD scores and SOS SD scores, indicating that tibial ultrasonometry was not measuring growth. After ending therapy (t36), no further growth retardation was found. Conclusions. Short-term changes of SOS SD scores in children with ALL can be detected by tibial ultrasonometry. Tibial ultrasonometry measures a change in bone status, not growth. [ABSTRACT FROM AUTHOR]

Simple Summary: We studied children with cancer who receive vincristine chemotherapy as a one-hour infusion and compared them to children who received vincristine as a push injection. We investigated if there was a difference in the development of vincristine induced peripheral neuropathy, the most common side effect of vincristine. We found that in general there were no differences between the two groups (one-hour group versus push group). However, in children using both vincristine and azole antifungals, we noticed that children who received vincristine as a one-hour infusion experienced less severe vincristine induced peripheral neuropathy compared to children who received vincristine as a push injection. Therefore, in children who require both azole antifungal medication as well as vincristine it might be beneficial to administer the vincristine as a one-hour infusion instead of a push injection. However, this finding needs to be confirmed in other studies as well. Vincristine (VCR) is a frequently used chemotherapeutic agent. However, it can lead to VCR-induced peripheral neuropathy (VIPN). In this study we investigated if one-hour infusions of VCR instead of push-injections reduces VIPN in pediatric oncology patients. We conducted a multicenter randomized controlled trial in which participants received all VCR administrations through push injections or one-hour infusions. VIPN was measured at baseline and 1–5 times during treatment using Common Terminology Criteria of Adverse Events (CTCAE) and pediatric-modified Total Neuropathy Score. Moreover, data on co-medication, such as azole antifungals, were collected. Overall, results showed no effect of administration duration on total CTCAE score or ped-mTNS score. However, total CTCAE score was significantly lower in patients receiving one-hour infusions concurrently treated with azole antifungal therapy (β = -1.58; p = 0.04). In conclusion, generally VCR administration through one-hour infusions does not lead to less VIPN compared to VCR push injections in pediatric oncology patients. However, one-hour infusions lead to less severe VIPN compared to push-injections when azole therapy is administered concurrently with VCR. These results indicate that in children treated with VCR and requiring concurrent azole therapy, one-hour infusions might be beneficial over push injections, although larger trials are needed to confirm this association. [ABSTRACT FROM AUTHOR]

Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1–5 occasions (1–8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (Cmax) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V2), and Cmax were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V2, and Cmax, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN. [ABSTRACT FROM AUTHOR]

Pediatric renal cell carcinoma (RCC) is a rare type of kidney cancer, most commonly occurring in teenagers and young adolescents. Few relatively large series of pediatric RCC have been reported. Knowledge of clinical characteristics, outcome and treatment strategies are often based on the more frequently occurring adult types of RCC. However, published pediatric data suggest that clinical, molecular and histological characteristics of pediatric RCC differ from adult RCC. This paper summarizes reported series consisting of ≥10 RCC pediatric patients in order to create an up-to-date overview of the clinical and histopathological characteristics, treatment and outcome of pediatric RCC patients. [ABSTRACT FROM AUTHOR]

Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. To assess which genes and pathways are implicated in tumor drug resistance, we correlated ex vivo drug response data to genome-wide gene expression profiles of 73 primary pediatric AML samples obtained at initial diagnosis. Ex vivo response of primary AML blasts towards cytarabine (Ara C), daunorubicin (DNR), etoposide (VP16), and cladribine (2-CdA) was associated with the expression of 101, 345, 206, and 599 genes, respectively (p < 0.001, FDR 0.004–0.416). Microarray based expression of multiple genes was technically validated using qRT-PCR for a selection of genes. Moreover, expression levels of BRE, HIF1A, and CLEC7A were confirmed to be significantly (p < 0.05) associated with ex vivo drug response in an independent set of 48 primary pediatric AML patients. We present unique data that addresses transcriptomic analyses of the mechanisms underlying ex vivo drug response of primary tumor samples. Our data suggest that distinct gene expression profiles are associated with ex vivo drug response, and may confer a priori drug resistance in leukemic cells. The described associations represent a fundament for the development of interventions to overcome drug resistance in AML, and maximize the benefits of current chemotherapy for sensitive patients. [ABSTRACT FROM AUTHOR]

Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding. Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3–18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect. The median age was 5.5 years (range 3.0–18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect -2.05 (95% confidence interval (CI) -6.00–1.90). Also, no benefit from hydrocortisone compared to placebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL. Hydrocortisone, when compared to placebo, had no additional effect in reducing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hydrocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems. Netherlands Trial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017–002738–22 (https://eudract.ema.europa.eu/). • 66% of paediatric ALL patients experience dexamethasone-induced behavioural problems. • Previous research showed that hydrocortisone may improve these problems. • Compared to placebo, hydrocortisone had no additional beneficial effect in this study. • Placebo and nocebo effects may play an important role in behavioural side-effects. [ABSTRACT FROM AUTHOR]

This population-based study is the first to provide a detailed analysis of trends in incidence and survival of children and adolescents diagnosed with renal malignancies in the Netherlands. Data on all renal malignancies diagnosed in paediatric patients (0–18 years) between 1990 and 2014 [N = 648, 92% Wilms tumour (WT)] were extracted from the Netherlands Cancer Registry. Five-year overall survival (OS) was estimated using the actuarial method. Time trends in incidence were assessed by calculating average annual percentage change. A parametric survival model was used to compare the multivariable-adjusted risk of dying from WT between two diagnostic periods. The incidence was 8 per million person-years and was constant over time (average annual percentage change -0.8%, p = 0.29). Patients with WT had a favourable outcome in both time periods; 5-year OS was 88% in 1990–2001 and 91% in 2002–2014. Multivariable analysis showed that the risk of dying from WT was not significantly decreased in the latest period (hazard ratio, 95% CI: 0.7, 0.4–1.3). Five-year OS decreased with increasing disease stage, ranging from 95 to 100% for stage I-II and about 80% for stage III–IV to 74% for bilateral disease. Five-year OS were 81% for renal cell carcinoma, 77% for clear cell sarcoma of the kidney and 20% for malignant rhabdoid tumour of the kidney. Incidence of paediatric renal malignancies in the Netherlands has been stable since the 1990s. Five-year OS of WT reached 91% and was similar to findings for other developed countries. Contrary to the excellent outcome for WT, the outcome of malignant rhabdoid tumour of the kidney remained inferior. • The incidence of paediatric renal tumours in the Netherlands was stable between 1990 and 2014. • 5-year OS of Wilms tumour reached 91% and was similar to rates in other developed countries. • 5-year OS were 81% for renal cell carcinoma, 77% for clear cell sarcoma of the kidney and 20% for malignant rhabdoid tumour of the kidney. • Particular attention should be paid to adverse prognostic subgroups, especially malignant rhabdoid tumour of the kidney. [ABSTRACT FROM AUTHOR]

Abstract Aims Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies. Methods PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning. Results PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors. Conclusions The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being. Highlights • PanCareLIFE is a large pan-European study on late effects after childhood cancer. • Studies of hearing loss, fertility impairment and quality of life are included. • Clinical and genetic methods with new guidelines will lead to improved health. [ABSTRACT FROM AUTHOR]

Context: Although a large percentage of children with advanced-stage cancer die at home, remarkably little information is available regarding the experience of general practitioners (GPs) with respect to providing home-based palliative care to children with incurable cancer.Objectives: The objective of this study was to explore the perspectives of GPs who care for children with advanced-stage cancer in a home-based setting.Methods: In this cross-sectional study, 144 GPs who provided home-based palliative care to 150 children with incurable cancer from 2001 through 2010 were invited to complete a questionnaire addressing their perspectives regarding: 1) symptom management, 2) collaboration with other health care professionals, 3) the child's death and care after death, and 4) impact of having provided palliative care, scored on distress thermometer (range 0-10).Results: A total of 112 GPs (78%) responded, and 91 GPs completed the questionnaire for 93 patients. The median interval between the child's death and completing the questionnaire was seven years. The most prevalent symptoms reported in the patients were fatigue (67%) and pain (61%). Difficulties with communicating with (14%), coordinating with (11%), collaborating with (11%), and contacting (2%) fellow members of the multidisciplinary treatment team were rare. Hectic (7%) and shocking (5%) situations and panic (2%) around the child's death were rare. GPs reported feelings of sadness (61%) and/or powerlessness (43%) around the time of the patient's death, and they rated their own distress level as relatively high during the terminal phase (median score 6, range 0-9.5). The majority of GPs (94%) reported that they ultimately came to terms with the child's death.Conclusion: In general, GPs appear to be satisfied with the quality of home-based palliative care that they provide pediatric patients with incurable cancer. Communication among health care professionals is generally positive and is considered important. Finally, although the death of a pediatric patient has a profound impact on the GP, the majority of GPs eventually come to terms with the child's death. [ABSTRACT FROM AUTHOR]

Abstract: Context: Approximately 25% of children diagnosed with cancer eventually die. Losing a child puts parents at increased risk for developing psychological problems. Objectives: To explore parents' perceptions of the interaction with health care professionals (communication, continuity of care, and parental involvement) and symptom management during the pediatric palliative phase, and to investigate the influence on long-term grief in parents who lost a child to cancer. Methods: A total of 89 parents of 57 children who died of cancer between 2000 and 2004 participated in this retrospective cross-sectional study by completing a set of questionnaires measuring grief (Inventory of Traumatic Grief), parents' perceptions of the interaction with health care professionals (communication, continuity of care, and parental involvement), and symptom management during the palliative phase. Care was assessed on a five point Likert scale (1=disagree and 5=agree). Results: Parents highly rated communication (4.6±0.6), continuity of care (4.3±0.6), and parental involvement (4.6±0.7) during the palliative phase. Parents' most often reported physical and psychological symptoms of their child during the palliative phase were fatigue (75%), pain (74%), anxiety to be alone (52%), and anger (48%). Higher ratings of parents on communication (β=−9.08, P =0.03) and continuity of care (β=−11.74, P =0.01) were associated with lower levels of long-term parental grief. The severity of the child's dyspnea (β=2.96, P =0.05), anxiety to be alone (β=4.52, P <0.01), anxiety about the future (β=5.02, P <0.01), anger (β=4.90, P <0.01), and uncontrolled pain (β=6.60, P <0.01) were associated with higher levels of long-term parental grief. Multivariate models combining the interaction with health care professionals and symptom management showed a significant influence of both aspects on long-term parental grief. Conclusion: Both interaction with health care professionals, especially communication and continuity of care, and symptom management in children dying of cancer are associated with long-term parental grief levels. [Copyright &y& Elsevier]

Abstract: Purpose: To determine the prognosis of children with stage II and III of low or intermediate risk histology (SIOP classification) in unilateral localised Wilms tumour (WT) after neoadjuvant chemotherapy according to the trial and study of the International Society of Paediatric Oncology, SIOP 93-01. Patients and methods: Patients with unilateral localised WT and stage II or III with low (LR) or intermediate risk (IR) histology between 6months and 18years of age, were selected from the total sample of patients registered in the SIOP 93-01 study between June 1993 and December 2001. All patients received 4weeks of actinomycin-D/vincristine before surgery. Postoperative chemotherapy consisted of actinomycin-D, vincristine and epirubicin/doxorubicin for 27weeks. Flank or whole abdomen irradiation was given for stage III. Event-free survival (EFS) and overall survival (OS) were analysed for various subgroups. Results: Of 1476 registered patients 594 (40%) met the inclusion criteria for this analysis. Four hundred and two (67%) had stage II disease and 563 (95%) had intermediate risk histology. Median tumour volume was 439ml at diagnosis and 163ml after preoperative chemotherapy. With a median follow-up of 8years, 5-year EFS was 90% (95% confidence interval [95% CI]: 87–92%) and OS 95% (95% CI: 93–97%). Patients with stage III, blastemal type histology and a large volume at surgery had a worse outcome. Conclusion: Treatment for stage II and III LR or IR WT is successful in a neoadjuvant setting as advised by the SIOP. Stage, tumour volume and blastemal type histology are the most important prognostic factors. [Copyright &y& Elsevier]