TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity

Healthcare professionals' perceived barriers and facilitators of health behavior support provision: A qualitative study.

BACKGROUND: Childhood cancer survivors (CCSs) have an increased risk of developing chronic health conditions. Evidence suggests that poor health behaviors further increase health risks. Healthcare professionals (HCPs) involved in survivorship care have a key role in providing health behavior support (HBS) but can feel limited in their ability to do so. This study aims to explore European HCPs perceived facilitators and barriers to providing HBS to CCSs. METHODS: Five focus groups with 30 HCPs from survivorship care clinics across Europe were conducted. Topic guides were informed by the Theoretical Domains Framework (TDF) to capture domains that may influence provision of HBS. Focus groups were analyzed with thematic analysis. Transcripts were inductively coded, after which axial coding was applied to organize codes into categories. Finally, categories were mapped onto the TDF domains. RESULTS: Nine TDF domains were identified in the data. The most commonly reported TDF domains were "Knowledge", "Skills", and "Environmental context and resources". HCPs indicated that their lack of knowledge of the association between late effects and health behaviors, besides time restrictions, were barriers to HBS. Facilitators for HBS included possession of skills needed to pass on health behavior information, good clinic organization, and an established network of HCPs. CONCLUSIONS: This study identified education and training of HCPs as key opportunities to improve HBS. Survivorship care clinics should work towards establishing well-integrated structured care with internal and external networks including HBS being part of routine care. Proper understanding of facilitators and barriers should lead to better survivorship care for CCSs

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)

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

Platin treatment and hearing loss: initial audiological results from PanCareLIFE

Background: Cisplatin and carboplatin are widely used in paediatric cancer treatment. Cisplatin especially can have long-term side effects, including sensorineural hearing loss. The aim of this study is to define the risk factors for platin-related ototoxicity.Materials and Methods: As part of the PanCareLIFE consortium, we gathered audiological data from 13 pan-European clinics. Eligible patients were 20 dB HL at any frequency).A total of 2,696 patients with 10,320 audiograms from various stages of cancer treatment were obtained. Audiometric data were quality-checked and classified (Münster and SIOP classifications) and 736 patients with sufficient data were phenotyped. A logistic regression investigated the likelihood of developing a hearing loss >=Münster 2b (thresholds >40 dB HL at >=4 kHz) after treatment given age, gender, cisplatin dose and cranial irradiation.Results: 48.2% of 1,385 patients with a post-treatment audiogram had clinically-relevant hearing loss (defined as >=Münster 2b) after platin treatment.Children 15 years (odds ratio 2.7, 95% CI 1.5-4.9, p=0.0006). Patients with a cumulative cisplatin dose >450 mg/m2 were more likely to develop hearing loss than those treated with carboplatin alone (OR 12.5, 95% CI 6.8-23.0, p=3.7x10-16). Treatment with cranial irradiation was more likely to lead to hearing loss than without (OR 4.5, 95% CI 3.0-6.7, p=7.2x10-13).Discussion: This is the first study of platin ototoxicity with such a large sample size. The results support tendencies found in previous studies with smaller groups. The high risk groups identified here must be monitored regularly for ototoxicity. Further detailed analyses into audiological changes and possible pharmacogenetic confounders are planned.Conclusion: 48% of patients treated with cisplatin develop clinically-relevant hearing loss. Age <5 years old, higher cumulative cisplatin doses and cranial irradiation present especially high risks.Acknowledgement: This work was supported by the PanCareLIFE consortium that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030

The PanCareFollowUp Care Intervention: a European harmonised approach to person-centred guideline-based survivorship care after childhood, adolescent and young adult cancer.

ABSTRACT: Background Long-term follow-up (LTFU) care, although endorsed, is not available for the majority of adult survivors of childhood, adolescence and young adult (CAYA) cancer. Barriers to implementation include lack of time, knowledge, personnel and funding. Sustainable solutions are urgently needed to address the needs of CAYA cancer survivors to improve the quality of life and reduce the burden of late effects on survivors, health care systems and society. The European Union-funded PanCareFollowUp project, initiated by the Pan-European Network for Care of Survivors after Childhood and Adolescent Cancer, was established to facilitate the implementation of person-centred survivorship care across Europe. Patients and methods The PanCareFollowUp Care Intervention was co-developed with survivors as part of the PanCareFollowUp project. It is a person-centred approach to survivorship care, supported by guidelines and with flexibility to adapt to local health care settings. The Care Intervention consists of three steps: (1) previsit completion of a Survivor Questionnaire (by the survivor) and Treatment Summary (by the health care provider [HCP]), (2) a clinic visit including shared decision-making, and (3) a follow-up call to finalise the individualised Survivorship Care Plan. Results We developed the key components of the PanCareFollowUp Care Intervention: a PanCareFollowUp Survivor Questionnaire, Treatment Summary template, Survivorship Care Plan template, and educational materials for HCPs and survivors. Wide implementation of the PanCareFollowUp Care Intervention will be supported with a freely distributed Replication Manual on completion of the PanCareFollowUp project. Conclusions The PanCareFollowUp Care Intervention will support the implementation of person-centred, guideline-based LTFU care in different health care settings across Europe to improve survivors' health and well-being

Confirmation of genetic risk markers of platinum-induced ototoxicity

Background: Platinum compounds such as cisplatin or carboplatin are potent antineoplastic agents widely used for a variety of cancer types. Unfortunately, their use leads to dose-limiting side effects such as ototoxicity. Our study aimed at investigating the predictive value of 11 candidate genetic markers in a large non-selected pediatric population of cancer survivors who had been treated with cisplatin and/or carboplatin.Materials and Methods: As a part of the PanCareLIFE study, the ototoxicity study included 2,696 survivors from 7 European countries treated with cisplatin and/or carboplatin for childhood cancer, resulting in the largest clinical European cohort assembled for this late-effect study. Hearing loss was audiologically classified using the Münster Classification. Three groups were defined, i.e., no hearing loss, minor hearing loss, and clinically relevant hearing loss. Patients were genotyped for single nucleotide polymorphisms (SNPs) in 7 candidate genes. Genetic association analyses were performed considering non-genetic covariates.Results: 900 patients were included in the final genetic analysis. Multinomial logistic regression was performed to model the relationship between the predictors and membership in the hearing loss group. The model explained 25% of the variance in hearing loss and correctly classified 58% of cases. Significant unique contributions were made by SLC22A2 rs316019 (P=0.017), age at the start of platinum treatment (P=1.46x10-17), cranial radiation (P=5.42x10-6), and the cumulative dose of cisplatin (P=5.86x10-19). Addition of the rs316019 genetic marker to the non-genetic risk factors (age, dose, cranial radiation) improved the area under the ROC curve only marginally (0.731 vs. 0.730).Discussion: Our study confirmed one potential genetic marker, rs316019 in SLC22A2. Its predictive value, however, is low.Conclusion: Due to the heterogeneity of results from genetic association studies performed so far, the evidence seems not yet sufficient to recommend screening for specific markers. Advances in the understanding of the pathophysiologic mechanisms of cisplatin-induced ototoxicity, as well as future genome-wide association studies, may help identify suitable genetic markers.Acknowledgement: This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030