The Value of IgM Memory B-Cells in the Assessment of Splenic Function in Childhood Cancer Survivors at Risk for Splenic Dysfunction: A DCCSS-LATER Study.

Background: Childhood cancer survivors (CCS) who received radiotherapy involving the spleen or total body irradiation (TBI) might be at risk for splenic dysfunction. A comprehensive screening test for examining splenic dysfunction is lacking. Objective: We investigated whether IgM memory B-cells could be used to assess splenic dysfunction in CCS who received a splenectomy, radiotherapy involving the spleen, or TBI. Methods: All CCS were enrolled from the DCCSS-LATER cohort. We analyzed differences in IgM memory B-cells and Howell-Jolly bodies (HJB) in CCS who had a splenectomy (n = 9), received radiotherapy involving the spleen (n = 36), or TBI (n = 15). IgM memory B-cells < 9 cells/µL was defined as abnormal. Results: We observed a higher median number of IgM memory B-cells in CCS who received radiotherapy involving the spleen (31 cells/µL, p=0.06) or TBI (55 cells/µL, p = 0.03) compared to CCS who received splenectomy (20 cells/µL). However, only two CCS had IgM memory B-cells below the lower limit of normal. No difference in IgM memory B-cells was observed between CCS with HJB present and absent (35 cells/µL vs. 44 cells/µL). Conclusion: Although the number of IgM memory B-cells differed between splenectomized CCS and CCS who received radiotherapy involving the spleen or TBI, only two CCS showed abnormal values. Therefore, this assessment cannot be used to screen for splenic dysfunction.

Evaluating the feasibility, effectiveness and costs of implementing person-centred follow-up care for childhood cancer survivors in four European countries: the PanCareFollowUp Care prospective cohort study protocol.

INTRODUCTION: Long-term survival after childhood cancer often comes at the expense of late, adverse health conditions. However, survivorship care is frequently not available for adult survivors in Europe. The PanCareFollowUp Consortium therefore developed the PanCareFollowUp Care Intervention, an innovative person-centred survivorship care model based on experiences in the Netherlands. This paper describes the protocol of the prospective cohort study (Care Study) to evaluate the feasibility and the health economic, clinical and patient-reported outcomes of implementing PanCareFollowUp Care as usual care in four European countries. METHODS AND ANALYSIS: In this prospective, longitudinal cohort study with at least 6 months of follow-up, 800 childhood cancer survivors will receive the PanCareFollowUp Care Intervention across four study sites in Belgium, Czech Republic, Italy and Sweden, representing different healthcare systems. The PanCareFollowUp Care Intervention will be evaluated according to the Reach, Effectiveness, Adoption, Implementation and Maintenance framework. Clinical and research data are collected through questionnaires, a clinic visit for multiple medical assessments and a follow-up call. The primary outcome is empowerment, assessed with the Health Education Impact Questionnaire. A central data centre will perform quality checks, data cleaning and data validation, and provide support in data analysis. Multilevel models will be used for repeated outcome measures, with subgroup analysis, for example, by study site, attained age, sex or diagnosis. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the guidelines of Good Clinical Practice and the Declaration of Helsinki. The study protocol has been reviewed and approved by all relevant ethics committees. The evidence and insights gained by this study will be summarised in a Replication Manual, also including the tools required to implement the PanCareFollowUp Care Intervention in other countries. This Replication Manual will become freely available through PanCare and will be disseminated through policy and press releases. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL8918; https://www.trialregister.nl/trial/8918).

Hypertension in long-term childhood cancer survivors after treatment with potentially nephrotoxic therapy; DCCSS-LATER 2: Renal study.

PURPOSE: To evaluate the prevalence of and risk factors for hypertension in childhood cancer survivors (CCSs) who were treated with potentially nephrotoxic therapies. METHODS: In the Dutch Childhood Cancer Survivor Study LATER cohort part 2 renal study, 1024 CCS ≥5 years after diagnosis, aged ≥18 years at study participation, treated between 1963 and 2001 with nephrectomy, abdominal radiotherapy, total body irradiation (TBI), cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide (≥1 g/m2 per single dose or ≥10 g/m2 total) or haematopoietic stem cell transplantation participated and 500 controls from Lifelines. Hypertension was defined as blood pressure (BP) (mmHg) systolic ≥140 and/or diastolic ≥90 or receiving medication for diagnosed hypertension. At the study visit, the CKD-EPI 2012 equation including creatinine and cystatin C was used to estimate the glomerular filtration rate (GFR). Multivariable regression analyses were used. For ambulatory BP monitoring (ABPM), hypertension was defined as BP daytime: systolic ≥135 and/or diastolic ≥85, night time: systolic ≥120 and/or diastolic ≥70, 24-h: systolic ≥130 and/or diastolic ≥80. Outcomes were masked hypertension (MH), white coat hypertension and abnormal nocturnal dipping (aND). RESULTS: Median age at cancer diagnosis was 4.7 years (interquartile range, IQR 2.4-9.2), at study 32.5 years (IQR 27.7-38.0) and follow-up 25.5 years (IQR 21.4-30.3). The prevalence of hypertension was comparable in CCS (16.3%) and controls (18.2%). In 12% of CCS and 17.8% of controls, hypertension was undiagnosed. A decreased GFR (<60 ml/min/1.73 m2) was associated with hypertension in CCS (OR 3.4, 95% CI 1.4-8.5). Risk factors were abdominal radiotherapy ≥20 Gy and TBI. The ABPM-pilot study (n = 77) showed 7.8% MH, 2.6% white coat hypertension and 20.8% aND. CONCLUSION: The prevalence of hypertension was comparable among CCS who were treated with potentially nephrotoxic therapies compared to controls, some of which were undiagnosed. Risk factors were abdominal radiotherapy ≥20 Gy and TBI. Hypertension and decreased GFR were associated with CCS. ABPM identified MH and a ND.

The European multistakeholder PanCareFollowUp project: novel, person-centred survivorship care to improve care quality, effectiveness, cost-effectiveness and accessibility for cancer survivors and caregivers.

BACKGROUND: The majority of childhood cancer survivors are at risk of treatment-related adverse health outcomes. Survivorship care to mitigate these late effects is endorsed, but it is not available for many adult survivors of childhood cancer in Europe. The PanCareFollowUp project was initiated to improve their health and quality of life (QoL) by facilitating person-centred survivorship care. METHODS: The PanCareFollowUp consortium was established in 2018, consisting of 14 project partners from ten European countries, including survivor representatives. The consortium will develop two PanCareFollowUp Interventions, including a person-centred guideline-based model of care (Care Intervention) and eHealth lifestyle coaching (Lifestyle Intervention). Their development will be informed by several qualitative studies and systematic reviews on barriers and facilitators for implementation and needs and preferences of healthcare providers (HCPs) and survivors. Implementation of the PanCareFollowUp Care Intervention as usual care will be evaluated prospectively among 800 survivors from Belgium, Czech Republic, Italy and Sweden for survivor empowerment, detection of adverse health conditions, satisfaction among survivors and HCPs, cost-effectiveness and feasibility. The feasibility of the PanCareFollowUp Lifestyle Intervention will be evaluated in the Netherlands among 60 survivors. RESULTS: Replication manuals, allowing for replication of the PanCareFollowUp Care and Lifestyle Intervention, will be published and made freely available after the project. Moreover, results of the corresponding studies are expected within the next five years. CONCLUSIONS: The PanCareFollowUp project is a novel European collaboration aiming to improve the health and QoL of all survivors across Europe by developing and prospectively evaluating the person-centred PanCareFollowUp Care and Lifestyle Interventions.

Variations in screening and management practices for subsequent asymptomatic meningiomas in childhood, adolescent and young adult cancer survivors.

INTRODUCTION: Childhood, adolescent and young adult (CAYA) cancer survivors treated with cranial radiotherapy are at risk for developing subsequent meningiomas. There is insufficient evidence concerning the benefits and harms of screening for subsequent meningiomas, and uncertainty about the most appropriate clinical management of asymptomatic meningiomas. Data describing current clinical decision-making is essential to formulate surveillance recommendations. METHODS: We created an online survey to identify the current international clinical practice regarding screening for and management of subsequent asymptomatic meningiomas among CAYA cancer survivors. Fifty-nine physicians from North America and Europe with expertise relevant to meningiomas were invited to participate. RESULTS: Thirty-four physicians (58%) completed the survey. The reported number of CAYA cancer survivors that physicians are willing to screen to detect one meningioma varied widely from 0 to 750 (median 50). Physicians expressed concerns regarding harms from MRI screening, including risks of unnecessary interventions (n = 25, 73%) and overdiagnosis (n = 19, 56%). Growth pattern (n = 33, 97%), location (n = 31, 91%) and size (n = 29, 85%) were endorsed as the most important factors influencing the decision to treat asymptomatic meningiomas. A challenging location (n = 14, 52%), indolent tumor growth pattern (n = 13, 48%), and absence of symptoms (n = 12, 44%) were endorsed as the main reasons to monitor without intervention. CONCLUSIONS: There is international variation in opinions and clinical practice regarding screening for subsequent asymptomatic meningiomas among at risk CAYA cancer survivors. Decision-making regarding interventions of asymptomatic meningiomas are largely driven by clinical characteristics. These valuable insights into current clinical practice will inform surveillance guidelines for CAYA cancer survivors.

Medical assessment of adverse health outcomes in long-term survivors of childhood cancer.

CONTEXT: Improved survival of children with cancer has been accompanied by multiple treatment-related complications. However, most studies in survivors of childhood cancer focused on only 1 late effect. OBJECTIVE: To assess the total burden of adverse health outcomes (clinical or subclinical disorders ["adverse events"]) following childhood cancer in a large cohort of childhood cancer survivors with long-term and complete medical follow-up. DESIGN, SETTING, AND POPULATION: Retrospective cohort study of 1362 five-year survivors of childhood cancer treated in a single institution in the Netherlands between 1966 and 1996. All survivors were invited to a late-effects clinic for medical assessment of adverse events. Adverse events occurring before January 2004 were graded for severity in a standardized manner. MAIN OUTCOME MEASURES: Treatment-specific prevalence of adverse events (according to severity) at end of follow-up and relative risk of high or severe burden of disease (> or =2 severe or > or =1 life-threatening or disabling adverse events) associated with various treatments. RESULTS: Medical follow-up was complete for 94.3% of survivors (median follow-up, 17.0 years). The median attained age at end of follow-up was 24.4 years. Almost 75% of survivors had 1 or more adverse events, and 24.6% had 5 or more adverse events. Furthermore, 40% of survivors had at least 1 severe or life-threatening or disabling adverse event. A high or severe burden of adverse events was observed in 55% of survivors who received radiotherapy only and 15% of survivors treated with chemotherapy only, compared with 25% of survivors who had surgery only (adjusted relative risks, 2.18 [95% confidence interval, 1.62-2.95] and 0.65 [95% confidence interval, 0.46-0.90], respectively). A high or severe burden of adverse events was most often observed in survivors of bone tumors (64%) and least often in survivors of leukemia or Wilms tumor (12% each). CONCLUSIONS: In young adulthood, a substantial proportion of childhood cancer survivors already has a high or severe burden of disease, particularly after radiotherapy. This underscores the need for lifelong risk-stratified medical surveillance of childhood cancer survivors.