Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter

Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction and infiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system. Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalities and diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification. However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involvement with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLH may be lifesaving. Awareness of the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis

Insomnia Symptoms and Daytime Fatigue Co-Occurrence in Adolescent and Young Adult Childhood Cancer Patients in Follow-Up after Treatment:Prevalence and Associated Risk Factors

Simple Summary Insomnia symptoms and daytime fatigue significantly impact physical and psychosocial health. While these are common symptoms in pediatric oncology, relationships between these symptoms remain unclear. This study evaluated the prevalence of insomnia only, daytime fatigue only, the co-occurrence of insomnia and daytime fatigue symptoms, and associated risk factors in adolescent/young adult childhood cancer patients in follow-up after treatment. Results showed that around forty percent had insomnia and daytime fatigue symptoms, which often co-occurred. Risk factors that emerged were: female sex and co-morbidities (all), shorter time after treatment and bedtime gaming (insomnia only), young adulthood (insomnia-fatigue and fatigue only), needing someone else to fall asleep and inconsistent wake times (both insomnia groups), and lower educational level and consistent bedtimes (insomnia-fatigue). Overall, insomnia symptoms and daytime fatigue were common and often co-occurred in this patient population. While current fatigue guidelines do not include insomnia symptoms, healthcare providers should inquire about insomnia as this potentially provides additional options for treatment and prevention. Insomnia symptoms and daytime fatigue commonly occur in pediatric oncology, which significantly impact physical and psychosocial health. This study evaluated the prevalence of insomnia only, daytime fatigue only, the co-occurrence of insomnia-daytime fatigue symptoms, and associated risk factors. Childhood cancer patients (n = 565, 12-26 years old, >= 6 months after treatment) participated in a national, cross-sectional questionnaire study, measuring insomnia symptoms (ISI; Insomnia Severity Index) and daytime fatigue (single item). Prevalence rates of insomnia and/or daytime fatigue subgroups and ISI severity ranges were calculated. Multinomial regression models were applied to assess risk factors. Most patients reported no insomnia symptoms or daytime fatigue (61.8%). In the 38.2% of patients who had symptoms, 48.1% reported insomnia and daytime fatigue, 34.7% insomnia only, and 17.1% daytime fatigue only. Insomnia scores were higher in patients with insomnia-daytime fatigue compared to insomnia only (p < 0.001). Risk factors that emerged were: female sex and co-morbidities (all), shorter time after treatment and bedtime gaming (insomnia only), young adulthood (insomnia-fatigue/fatigue only), needing someone else to fall asleep and inconsistent wake times (both insomnia groups), lower educational level and consistent bedtimes (insomnia-fatigue). Insomnia symptoms and daytime fatigue are common and often co-occur. While current fatigue guidelines do not include insomnia symptoms, healthcare providers should inquire about insomnia as this potentially provides additional options for treatment and prevention

A detailed insight in the high risks of hospitalizations in long-term childhood cancer survivors-A Dutch LATER linkage study

Background Insight in hospitalizations in long-term childhood cancer survivors (CCS) is useful to understand the impact of long-term morbidity. We aimed to investigate hospitalization rates and underlying types of diagnoses in CCS compared to matched controls, and to investigate the determinants. Me

Long-Term Tubular Dysfunction in Childhood Cancer Survivors; DCCSS-LATER 2 Renal Study

Simple Summary We studied survivors of childhood cancer who received cancer treatment that might affect the kidneys and compared them to controls from the general population. We investigated if there was a difference in the occurrence of tubular dysfunction. The tubules are the part of the kidney responsible for reabsorption of needed substances to the blood and the removal of wastes. After around 25 years since their cancer diagnosis, we found that in general there were no differences between survivors and controls, but survivors more often had losses of small proteins in the urine. Yet, some survivors of childhood cancer were found to have an increased risk of tubular dysfunction. Namely, survivors treated with the chemotherapeutic agents ifosfamide, cisplatin or carboplatin. Therefore, these patients should be monitored during their follow-up. The aim of this nationwide cross-sectional cohort study was to determine the prevalence of and risk factors for tubular dysfunction in childhood cancer survivors (CCS). In the DCCSS-LATER 2 Renal study, 1024 CCS (>= 5 years after diagnosis), aged >= 18 years at study, treated between 1963 and 2001 with potentially nephrotoxic therapy (i.e., nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide, or hematopoietic stem cell transplantation) participated, and 500 age- and sex-matched participants from Lifelines acted as controls. Tubular electrolyte loss was defined as low serum levels (magnesium 1.7 mg/mmol was considered as low-molecular weight proteinuria (LMWP). Multivariable risk analyses were performed. After median 25.5 years follow-up, overall prevalence of electrolyte losses in CCS (magnesium 5.6%, potassium 4.5%, phosphate 5.5%) was not higher compared to controls. LMWP was more prevalent (CCS 20.1% versus controls 0.4%). LMWP and magnesium loss were associated with glomerular dysfunction. Ifosfamide was associated with potassium loss, phosphate loss (with cumulative dose > 42 g/m(2)) and LMWP. Cisplatin was associated with magnesium loss and a cumulative dose > 500 mg/m(2) with potassium and phosphate loss. Carboplatin cumulative dose > 2800 mg/m(2) was associated with potassium loss. In conclusion, long-term tubular dysfunction is infrequent. Yet, ifosfamide, cisplatin and carboplatin are risk factors

Prevalence and Risk Factors for Hyposalivation and Xerostomia in Childhood Cancer Survivors Following Different Treatment Modalities-A Dutch Childhood Cancer Survivor Study Late Effects 2 Clinical Study (DCCSS LATER 2)

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

Echocardiography protocol for early detection of cardiac dysfunction in childhood cancer survivors in the multicenter DCCSS LATER 2 CARD study:Design, feasibility, and reproducibility

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

Increased health-related quality of life impairments of male and female survivors of childhood cancer:DCCSS LATER 2 psycho-oncology study

BACKGROUND: The objective of this study was to compare the health-related quality of life (HRQOL) of Dutch adult male and female childhood cancer survivors (CCSs) to general population references and to study medical determinants. METHODS: CCSs from the Dutch Childhood Cancer Survivor Study LATER cohort (1963-2001) part 2, who were 18 years old or older (time since diagnosis ≥ 5 years), were invited to complete the TNO-AZL Questionnaire for Adult Health-Related Quality of Life. Domain scores and proportions of CCSs with impaired HRQOL (score 1.4. In addition, female CCSs were more often impaired in daily activities, pain, and sexuality (ORs, 1.4-1.9) and were less often aggressive (OR, 0.6). CCCs of central nervous system (CNS) tumors, bone tumors, and retinoblastoma and those with cranial, abdominopelvic, or lower extremity radiotherapy were at increased risk of impairment in 1 or more domains. CONCLUSIONS: Dutch adult CCSs, especially females, have impaired HRQOL in several domains; this is most pronounced in cognitive functioning. The vulnerabilities of subgroups at risk, such as CCSs of CNS tumors, were confirmed. Surveillance of HRQOL and multidisciplinary survivor care are recommended. LAY SUMMARY: The health-related quality of life in a Dutch nationwide cohort of 1766 survivors of childhood cancer was studied. Survivors of childhood cancer were found to have lower health-related quality of life in several domains (eg, motor functioning and vitality) in comparison with the general population. They most often reported low cognitive functioning (eg, memory and attention). Females had low health-related quality of life in more domains than males. Survivors of brain tumors had low health-related quality of life in most domains. Monitoring health-related quality of life regularly and collaborating between disciplines in survivor care is recommended

Psychosocial developmental milestones of young adult survivors of childhood cancer

Purpose: The study aimed to compare the psychosocial development of young adult survivors of childhood cancer (YACCS) with a norm group of young adults from the general population. Methods: From 2017 to 2020, 558 YACCS (18–30 years, 51% female, 10.9% CNS cancer) who participated in the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort (diagnosed 1963–2001) part 2 completed the Course of Life Questionnaire (CoLQ), assessing the achievement of milestones. Items were grouped into the scales autonomy, psychosexual, and social development. Differences between YACCS and norm group were examined with ANOVA and Cohen’s d (CoLQ scales) and with logistic regression analysis and odds ratio (OR) (CoLQ items), for the total group and YACCS of CNS cancer. Results: The total group of YACCS did not report a less favorable psychosocial development than the norm group. YACCS of CNS cancer scored lower than the norm group (p < 0.001) on the scales autonomy (d = − 0.36) and psychosexual (d = − 0.46). Additionally, on half of the items of autonomy (0.25 ≤ OR ≤ 0.34), psychosexual (0.30 ≤ OR ≤ 0.48), and social (0.23 ≤ OR ≤ 0.47) development, YACCS of CNS cancer were less likely (p < 0.01) than the norm group to have achieved the milestones. Conclusion: Overall, psychosocial development of YACCS was as favorable as the norm, but YACCS of CNS cancer were at risk of an unfavorable psychosocial development in all domains. Monitoring psychosocial development should be included in the standards of psychosocial care, especially for CNS cancer patients and survivors, to be able to trace delay. Personalized interventions should be offered to improve the psychosocial development in an early stage

Diagnostic tools for early detection of cardiac dysfunction in childhood cancer survivors:Methodological aspects of the Dutch late effects after childhood cancer (LATER) cardiology study

Background: Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure. Objective: To describe the methodology of the Dutch LATER cardiology study (LATER CARD). Methods: The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings. Conclusions: The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure

Adverse late health outcomes among children treated with 3D radiotherapy techniques:Study design of the Dutch pediatric 3D-RT study

Background: Adverse late health outcomes after multimodal treatment for pediatric cancer are diverse and of prime interest. Currently available evidence and survivorship care guidelines are largely based on studies addressing side-effects of two dimensional planned radiotherapy. Aims: The Dutch pediatric 3D-planned radiotherapy (3D-RT) study aims to gain insight in the long-term health outcomes among children who had radiotherapy in the 3D era. Here, we describe the study design, data-collection methods, and baseline cohort characteristics. Methods and Results: The 3D-RT study represents an expansion of the Dutch Childhood Cancer Survivor study (DCCSS) LATER cohort, including pediatric cancer patients diagnosed during 2000–2012, who survived at least 5 years after initial diagnosis and 2 years post external beam radiotherapy. Individual cancer treatment parameters were obtained from medical files. A national infrastructure for uniform collection and archival of digital radiotherapy files (Computed Tomography [CT]-scans, delineations, plan, and dose files) was established. Health outcome information, including subsequent tumors, originated from medical records at the LATER outpatient clinics, and national registry-linkage. With a median follow-up of 10.9 (interquartile range [IQR]: 7.9–14.3) years after childhood cancer diagnosis, 711 eligible survivors were identified. The most common cancer types were Hodgkin lymphoma, medulloblastoma, and nephroblastoma. Most survivors received radiotherapy directed to the head/cranium only, the craniospinal axis, or the abdominopelvic region. Conclusion: The 3D-RT study will provide knowledge on the risk of adverse late health outcomes and radiation-associated dose-effect relationships. This information is valuable to guide follow-up care of childhood cancer survivors and to refine future treatment protocols.</p