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Purpose: Childhood cancer survivors, in particular those treated with radiation therapy, are at high risk of long-term iatrogenic events. The prediction of risk of such events is mainly based on the knowledge of the radiation dose received to healthy organs and tissues during treatment of childhood cancer diagnosed decades ago. We aimed to set up a standardized organ dose table to help former patients and clinicians in charge of long-term follow-up clinics., Methods and Materials: We performed whole body dosimetric reconstruction for 2646 patients from 12 European countries treated between 1941 and 2006 (median, 1976). Most plannings were 2- or 3-dimensional. A total of 46% of patients were treated using Cobalt 60, and 41%, using a linear accelerator. The median prescribed dose was 27.2 Gy (IQ1-IQ3, 17.6-40.0 Gy). A patient-specific voxel-based anthropomorphic phantom with more than 200 anatomic structures or substructures delineated as a surrogate of each subject's anatomy was used. The radiation therapy was simulated with a treatment planning system based on available treatment information. The radiation dose received by any organ of the body was estimated by extending the treatment planning system dose calculation to the whole body, by type and localization of childhood cancer., Results: The integral dose and normal tissue doses to most of the 23 considered organs increased between the 1950s and 1970s and decreased or plateaued thereafter. Whatever the organ considered, the type of childhood cancer explained most of the variability in organ dose. The country of treatment explained only a small part of the variability., Conclusions: The detailed dose estimates provide very useful information for former patients or clinicians who have only limited knowledge about radiation therapy protocols or techniques, but who know the type and site of childhood cancer, sex, age, and year of treatment. This will allow better prediction of the long-term risk of iatrogenic events and better referral to long-term follow-up clinics., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Quality of life in childhood cancer survivors is largely affected by survivorship care and transition from treatment to long-term follow-up (LTFU). Referring to evidence-based recommendations, we wanted to evaluate LTFU care for survivors through a survey among the Italian Association for Pediatric Hematology-Oncology (AIEOP) centers. The project aimed to evaluate the availability of services in Italy, investigate strengths and weaknesses, analyze improvements of awareness in the field, and identify the gaps that need to be addressed by different centers., Methods: Together with the family representatives, on behalf of AIEOP's Late Effects Working Group, we developed a questionnaire on assisting childhood cancer survivors. All AIEOP centers received one questionnaire including information on local health system organizations; LTFU for childhood cancer survivors; services for adult survivors of childhood cancer; information provided to survivors/caregivers and care plan delivery., Results: Forty-eight AIEOP centers were contacted and 42 replied, with a response rate of 87.5%. The majority of respondents confirmed their interest in assisting patients with a survivorship care plan (95.2%), regardless of a clinic or dedicated staff., Discussion: This is the first overview of LTFU in Italy, which provides detailed results at national levels, prompting consideration of improvements in the last decade. Although there is a high level of interest in survivorship care, many centers lack resources to implement such programs. The identification of these challenges is useful for planning future strategies., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Survival after childhood cancer has significantly improved in recent decades. Nevertheless, an increased incidence of metabolic syndrome and cardiovascular disease among childhood cancer survivors (CCS) has been reported. The aim of this study was to evaluate whether fat-to-lean mass ratio (FLR) is associated with a dysmetabolic profile in CCS., Methods: At least 2 years from completion of therapy, data from CCS aged 10 to 16 years at follow-up and without any concurrent steroid treatment were collected. Body mass index, waist circumference (WC), WC-to-height ratio, laboratory blood tests, and FLR calculated by dual-energy X-ray absorptiometry measurements were considered. Body mass index >85 th percentile and >97 th percentile, WC >90 th percentile, and WC-to-height ratio > 0.5 were chosen as criteria of overweight and obesity, visceral obesity, and increased cardiovascular risk, respectively., Results: We enrolled 205 CCS previously treated for hematologic cancer or solid or central nervous system tumor. The best cutoff of FLR was 0.6. CCS; those with FLR ≥0.6 (43%) were more frequently overweight and obese (P < 0.001), and presented with higher levels of triglycerides (P = 0.011), homeostatic model assessment for insulin resistance (P = 0.001), alanine transaminase (P = 0.004), and trunk fat (P < 0.001) and lower levels of insulin-like growth factor 1 (P < 0.001) and lean mass (P = 0.009). WC >90 th percentile (P = 0.007), insulin-like growth factor 1 (P = 0.002), and trunk fat (P = 0.006) were independent predictors of FLR ≥0.6 in a model including all the previous variables., Conclusions: An increased FLR is suggestive of altered body composition phenotype, allowing identification of CCS at higher risk of metabolic syndrome. Diet and physical activity are needed from commencement of oncological treatments to preserve overall nutritional status and maintain it over the long term., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

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)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Compared to the general population, childhood cancer survivors represent a vulnerable population as they are at increased risk of developing health problems, known as late effects, resulting in excess morbidity and mortality. The Survivorship Passport aims to capture key health data about the survivors and their treatment, as well as personalized recommendations and a care plan with the aim to support long-term survivorship care. The PanCareSurPass (PCSP) project building on the experience gained in an earlier implementation in Giannina Gaslini Institute, Italy, will implement and rigorously assess an integrated, HL7 FHIR based, implementation of the Survivorship Passport. The six implementation countries, namely Austria, Belgium, Germany, Italy, Lithuania, and Spain, are supported by different national or regional digital health infrastructures and Electronic Medical Record (EMR) systems. Semi structured interviews were carried out to explore potential factors affecting implementation, identify use cases, and coded data that can be semi-automatically transferred from the EMR to SurPass. This paper reflects on findings of these interviews and confirms the need for a multidisciplinary and multi-professional approach towards a sustainable and integrated large-scale implementation of the Survivorship Passport across Europe.

Background: Breast cancer is a well-recognised late adverse effect in female childhood cancer survivors (CCSs), especially after chest radiotherapy; information on subsequent male breast cancer (SMBC) is limited. We summarised the existing evidence on SMBC after childhood cancer in a systematic review and investigated the risk of SMBC among males in a Pan-European cohort., Methods: We searched Medline/PubMed for cohort studies and case reports/series that assessed SMBC after childhood cancer (≤21 years). Furthermore, we analysed data on SMBC in the PanCareSurFup cohort, reporting standardised incidence ratios (SIRs), absolute excess risks (AERs), and 5- and 10-year survival rates., Results: The systematic review included 38 of 7080 potentially eligible articles. Cohort-specific SMBC frequencies were 0-0.40% (31 studies). SMBC occurred after a follow-up ranging from 24.0 to 42.0 years. Nine case reports/series described 11 SMBC cases, occurring 11.0-42.5 years after primary childhood cancer. In the PanCareSurFup cohort (16 SMBC/37,738 males; 0.04%), we observed a 22.3-fold increased risk of SMBC relative to the general male population (95% CI 12.7-36.2; absolute excess risk/100,000 person-years: 2.3, 95% CI 1.3-3.7). The five- and ten-year survival rates after SMBC diagnosis were 60.3% (95% CI 35.6%-85.0%) and 43.0% (95% CI 16.1%-69.9%), respectively. Clear evidence of risk factors did not emerge from these comprehensive efforts., Conclusions: Compared to the general population, male CCSs have an elevated risk of developing subsequent breast cancer, although the absolute risk is low. Health care providers should be aware of this rare yet serious late effect; male CCSs with symptoms potentially related to SMBC warrant careful examination., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Long-term follow-up (LTFU) care for childhood, adolescent, and young adult (CAYA) cancer survivors is essential to preserve health and quality of life (QoL). Evidence-based guidelines are needed to inform optimal surveillance strategies, but many topics are yet to be addressed by the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). Therefore, the PanCareFollowUp Recommendations Working Group collaborated with stakeholders to develop European harmonised recommendations in anticipation of evidence-based IGHG guidelines., Methods: The PanCareFollowUp Recommendations Working Group, consisting of 23 late effects specialists, researchers, and survivor representatives from nine countries, collaborated in the first Europe-wide effort to provide unified recommendations in anticipation of evidence-based guidelines. A pragmatic methodology was used to define recommendations for topics where no evidence-based IGHG recommendations exist. The objective was to describe the surveillance requirements for high-quality care while balancing the different infrastructures and resources across European health care systems. The process included two face-to-face meetings and an external consultation round involving 18 experts from 14 countries., Results: Twenty-five harmonised recommendations for LTFU care were developed collaboratively and address topics requiring awareness only (n = 6), awareness, history and/or physical examination (n = 9), or additional surveillance tests (n = 10)., Conclusions: The PanCareFollowUp Recommendations, representing a unique agreement across European stakeholders, emphasise awareness among survivors and health care providers in addition to tailored clinical evaluation and/or surveillance tests. They include existing IGHG guidelines and additional recommendations developed by a pragmatic methodology and will be used in the Horizon 2020-funded PanCareFollowUp project to improve health and QoL of CAYA cancer survivors., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While considerable efforts and progress in our understanding of the long-term toxicities of surgery, radiation and chemotherapy in children with cancer have been made over the last 5 decades, there continues to be a wide gap in our knowledge of the long-term health impact of most novel targeted and immunotherapy agents. To address this gap, ACCELERATE, a multi-stakeholder collaboration of clinical and translational academics, regulators from the EMA and FDA, patient/family advocates and members spanning small biotechnology through to large pharmaceutical companies have initiated the development of an international long-term follow-up data registry to collect this important information prospectively. Providing critical safety data on the long-term use of these approved and investigational therapies in children will support the regulatory requirements and labeling information. It will also provide the necessary insight to help guide physicians and families on the appropriateness of a targeted or immune therapy for their child and inform survivorship planning., (© 2021 Wiley Periodicals LLC.)

Study Question: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors?, Summary Answer: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively., What Is Known Already: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce., Study Design, Size, Duration: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study., Participants/materials, Setting, Methods: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites., Main Results and the Role of Chance: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively., Limitations, Reasons for Caution: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results., Wider Implications of the Findings: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired., Study Funding/competing Interest(s): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests., Trial Registration Number: n/a., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Male patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19., (© 2020 Wiley Periodicals LLC.)

Introduction: Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry., Materials and Methods: CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs)., Results: Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86-88) and at 45 years was 81% (95% CI: 77-84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7-12), corresponding to an AER of 48 (95% CI: 45-51). Mortality decreased by 60% for survivors treated most recently (1990-1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death., Conclusions: This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF., Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public., Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case-control studies of subsequent malignancies and cardiac disease in 5-year survivors., Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Currently, there are between 300,000 and 500,000 childhood cancer survivors (CCSs) in Europe. A significant proportion is at high risk, and at least 60% of them develop adverse health-related outcomes that can appear several years after treatment completion. Many survivors are unaware of their personal risk, and there seems to be a general lack of information among healthcare providers about pathophysiology and natural history of treatment-related complications. This can generate incorrect or delayed diagnosis and treatments., Method: The Survivorship Passport (SurPass) consists of electronic documents, which summarise the clinical history of the childhood or adolescent cancer survivor. It was developed by paediatric oncologists of the PanCare and SIOPE networks and IT experts of Cineca, together with parents, patients, and survivors' organisations within the European Union-funded European Network for Cancer research in Children and Adolescents. It consists of a template of a web-based, simply written document, translatable in all European languages, to be given to each CCS. The SurPass provides a summary of each survivor's clinical history, with detailed information about the original cancer and of treatments received, together with personalised follow-up and screening recommendations based on guidelines published by the International Guidelines Harmonization Group and PanCareSurFup., Results: The SurPass data schema contains a maximum of 168 variables and uses internationally approved nomenclature, except for radiotherapy fields, where a new classification was defined by radiotherapy experts. The survivor-specific screening recommendations are mainly based on treatment received and are automatically suggested, thanks to built-in algorithms. These may be adapted and further individualised by the treating physician in case of special disease and survivor circumstances. The SurPass was tested at the Istituto Giannina Gaslini, Italy, and received positive feedback. It is now being integrated at the institutional, regional and national level., Conclusions: The SurPass is potentially an essential tool for improved and more harmonised follow-up of CCS. It also has the potential to be a useful tool for empowering CCSs to be responsible for their own well-being and preventing adverse events whenever possible. With sufficient commitment on the European level, this solution should increase the capacity to respond more effectively to the needs of European CCS., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The number of persons who have successfully completed treatment for a cancer diagnosed during childhood and who have entered adulthood is increasing over time, and former patients will become aging citizens., Methods: Ten years ago, an expert panel met in Erice, Italy, to produce a set of principles concerning the cure and care of survivors of childhood and adolescent cancer. The result was the Erice Statement (Haupt et al. Eur J Cancer 43(12):1778-80, 2007) that was translated into nine languages. Ten years on, it was timely to review, and possibly revise, the Erice Statement in view of the changes in paediatric oncology and the number and results of international follow-up studies conducted during the intervening years., Results: The long-term goal of the cure and care of a child with cancer is that he/she becomes a resilient and autonomous adult with optimal health-related quality of life, accepted in society at the same level as his/her age peers. "Cure" refers to cure from the original cancer, regardless of any potential for, or presence of, remaining disabilities or side effects of treatment. The care of a child with cancer should include complete and honest information for parents and the child., Conclusions and Implication for Cancer Survivors: Some members of the previous expert panel, as well as new invited experts, met again in Erice to review the Erice Statement, producing a revised version including update and integration of each of the ten points. In addition, a declaration has been prepared, by the Childhood Cancer International Survivors Network in Dublin on October 2016 (see Annex 1).

Childhood cancer survivors face risks from a variety of late effects, including cardiac events, second cancers, and late mortality. The aim of the pan-European PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup) Consortium was to collect data on incidence and risk factors for these late effects among childhood cancer survivors in Europe. This paper describes the methodology of the data collection for the overall PanCareSurFup cohort and the outcome-related cohorts. In PanCareSurFup 13 data providers from 12 countries delivered data to the data centre in Mainz. Data providers used a single variable list that covered all three outcomes. After validity and plausibility checks data was provided to the outcome-specific working groups. In total, we collected data on 115,596 patients diagnosed with cancer from 1940 to 2011, of whom 83,333 had survived 5 years or more. Due to the eligibility criteria and other requirements different numbers of survivors were eligible for the analysis of each of the outcomes. Thus, 1014 patients with at least one cardiac event were identified from a cohort of 39,152 5-year survivors; for second cancers 3995 survivors developed at least one second cancer from a cohort of 71,494 individuals, and from the late mortality cohort of 79,441 who had survived at least 5 years, 9247 died subsequently. Through the close cooperation of many European countries and the establishment of one central data collection and harmonising centre, the project succeeded in generating the largest cohort of children with cancer to date.

Purpose/objectives: To test the content validity of a 16-item version of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20). 
., Research Approach: Cross-sectional, prospective, qualitative design. 
., Setting: Six outpatient oncology clinics within the University of Michigan Health System's comprehensive cancer center in Ann Arbor. 
., Participants: 25 adults with multiple myeloma or breast, gynecologic, gastrointestinal, or head and neck malignancies experiencing peripheral neuropathy caused by neurotoxic chemotherapy. 
., Methodologic Approach: Cognitive interviewing methodology was used to evaluate the content validity of a 16-item version of the QLQ-CIPN20 instrument.
., Findings: Minor changes were made to three questions to enhance readability. Twelve questions were revised to define unfamiliar terminology, clarify the location of neuropathy, and emphasize important aspects. One question was deleted because of clinical and conceptual redundancy with other items, as well as concerns regarding generalizability and social desirability. 
., Interpretation: Cognitive interviewing methodology revealed inconsistencies between patients' understanding and researchers' intent, along with points that required clarification to avoid misunderstanding. 
., Implications for Nursing: Patients' interpretations of the instrument's items were inconsistent with the intended meanings of the questions. One item was dropped and others were revised, resulting in greater consistency in how patients, clinicians, and researchers interpreted the items' meanings and improving the instrument's content validity. Following additional revision and psychometric testing, the QLQ-CIPN20 could evolve into a gold-standard CIPN patient-reported outcome measure.

Background and Aim: Childhood cancer survivors are at high risk of long-term adverse effects of cancer and its treatment, including cardiac events. The pan-European PanCareSurFup study determined the incidence and risk factors for cardiac events among childhood cancer survivors. The aim of this article is to describe the methodology of the cardiac cohort and nested case-control study within PanCareSurFup., Methods: Eight data providers in Europe participating in PanCareSurFup identified and validated symptomatic cardiac events in their cohorts of childhood cancer survivors. Data on symptomatic heart failure, ischemia, pericarditis, valvular disease and arrhythmia were collected and graded according to the Criteria for Adverse Events. Detailed treatment data, data on potential confounders, lifestyle related risk factors and general health problems were collected., Results: The PanCareSurFup cardiac cohort consisted of 59,915 5-year childhood cancer survivors with malignancies diagnosed between 1940 and 2009 and classified according to the International Classification of Childhood Cancer 3. Different strategies were used to identify cardiac events such as record linkage to population/ hospital or regional based databases, and patient- and general practitioner-based questionnaires., Conclusion: The cardiac study of the European collaborative research project PanCareSurFup will provide the largest cohort of 5-year childhood cancer survivors with systematically ascertained and validated data on symptomatic cardiac events. The result of this study can provide information to minimize the burden of cardiac events in childhood cancer survivors by tailoring the follow-up of childhood cancer survivors at high risk of cardiac adverse events, transferring this knowledge into evidence-based clinical practice guidelines and providing a platform for future research studies in childhood cancer patients. ., Competing Interests: The authors have declared that no competing interests exist.

Survival after childhood cancer has improved substantially over recent decades. Although cancer in childhood is rare increasingly effective treatments have led to a growing number of long-term survivors. It is estimated that there are between 300,000 and 500,000 childhood cancer survivors in Europe. Such good survival prospects raise important questions relating to late effects of treatment for cancer. Research has shown that the majority will suffer adverse health outcomes and premature mortality compared with the general population. While chronic health conditions are common among childhood cancer survivors, each specific type of late effect is very rare. Long-term effects must be considered particularly when addressing complex multimodality treatments, and taking into account the interaction between aspects of treatment and genotype. The PanCare Network was set up across Europe in order to effectively answer many of these questions and thereby improve the care and quality of life of survivors. The need for a structured long-term follow-up system after childhood cancer has been recognised for some time and strategies for implementation have been developed, first nationally and then trans-nationally, across Europe. Since its first meeting in Lund in 2008, the goal of the PanCare Network has been to coordinate and implement these strategies to ensure that every European survivor of childhood and adolescent cancer receives optimal long-term care. This paper will outline the structure and work of the PanCare Network, including the results of several European surveys, the start of two EU-funded projects and interactions with relevant stakeholders and related projects., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia - PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers.

Background: Monotherapy is recommended as the first choice for initial empirical therapy of febrile neutropenia, but local epidemiological and antibiotic susceptibility data are now considered pivotal to design a correct management strategy., Aim: To evaluate the proportion of Gram-negative rods isolated in bloodstream infections in children with cancer resistant to antibiotics recommended for this indication., Materials & Methods: The in vitro susceptibility to ceftazidime, piperacillin-tazobactam, meropenem and amikacin of Gram-negatives isolated in bacteremic episodes in children with cancer followed at the Istituto "Giannina Gaslini", Genoa, Italy in the period of 2001-2013 was retrospectively analyzed using the definitions recommended by EUCAST in 2014. Data were analyzed for any single drug and to the combination of amikacin with each β-lactam. The combination was considered effective in absence of concomitant resistance to both drugs, and not evaluated by means of in vitro analysis of antibiotic combinations (e.g., checkerboard)., Results: A total of 263 strains were evaluated: 27% were resistant to piperacillin-tazobactam, 23% to ceftazidime, 12% to meropenem and 13% to amikacin. Concomitant resistance to β-lactam and amikacin was detected in 6% of strains for piperacillin-tazobactam, 5% for ceftazidime and 5% for meropenem. During the study period there was a nonsignificant increase in the proportions of strains resistant to β-lactams indicated for monotherapy, and also increase in the resistance to combined therapies., Conclusion: in an era of increasing resistance to antibiotics guideline-recommended monotherapy could be not appropriate for initial empirical therapy of febrile neutropenia. Strict local survey on etiology and antibiotic susceptibility is mandatory for a correct management of this complication in cancer patients.

Background: Fertility is impaired in many survivors of childhood cancer following treatment. Preservation of fertility after cancer has become a central survivorship concern. Nevertheless, several doctors, patients, and families do not discuss fertility and recommendations for fertility preservation in pediatrics are still lacking. Recommendations based on scientific evidence are needed and before their development we wanted to assess the practice patterns of fertility preservation in Europe., Procedures: On behalf of the PanCare network, we sent a questionnaire to pediatric onco-hematology institutions across Europe. The survey consisted of 21 questions assessing their usual practices around fertility preservation., Results: One hundred ninety-eight institutional representatives across Europe received the survey and 68 (response rate 34.3%) responded. Pre-treatment fertility counseling was offered by 64 institutions. Counseling was done by a pediatric onco-hematologist in 52% (33/64) and in 32% (20/64) by a team. The majority of institutions (53%) lacked recommendations for fertility preservation. All 64 centers offered sperm banking; eight offered testicular tissue cryopreservation for pre-pubertal males. For females, the possibility of preserving ovarian tissue was offered by 40 institutions., Conclusions: There is a high level of interest in fertility preservation among European centers responding to our survey. However, while most recommended sperm cryopreservation, many also recommended technologies whose efficacy has not been shown. There is an urgent need for evidence-based European recommendations for fertility preservation to help survivors deal with the stressful topic of fertility., (© 2014 Wiley Periodicals, Inc.)

Background: In the last decades, several diagnostic and therapeutic strategies have been implemented for management of invasive fungal diseases (IFD) in patients with cancer or receiving allogeneic hemopoietic stem cell transplant. Few data are available on their impact on mortality in children., Methods: All IFD episodes diagnosed at tertiary care center during a 30-year period between 1983 and 2012 were analyzed for 90-day mortality and risk factors. Diagnoses were coded according to international (European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group) criteria. Four treatment eras (1983-1990, 1991-1999, 2000-2005 and 2006-2012) were defined according to availability of diagnostic technologies, new antifungal drugs and use of a diagnostic-driven approach without empiric antifungal therapy., Results: A total of 198 IFD were diagnosed in 191 patients; 71.2% were proven/probable infections; 39.9% were caused by yeasts and 31.3% by molds. Within 90 days from IFD diagnosis, 58 (30.4%) patients died for a 28.3% cumulative probability of death. A multivariable analysis showed that the highest risk of death was associated with alternative donor-hemopoietic stem cell transplant [hazard ratio (HR): 3.96] and mold etiology (HR: 1.34). The risk of death significantly decreased across the treatment eras, with almost a 3-fold reduced risk for patients diagnosed during the 2006-2012 period (HR: 0.24). Also if the variable year of diagnosis was considered as continuous, the hazard of death significantly decreased by 5% per year (HR: 0.95)., Conclusions: New management strategies resulted in a better prognosis of IFD in children with cancer or hemopoietic stem cell transplant. A diagnostic-driven approach was not associated with an increase in mortality.

Introduction: Fever is an important complication in neutropenic patients and standard of care calls for empirical broad-spectrum antibiotics, followed by 'empirical' antifungal therapy in persisting fever. Emergence of infections due to resistant bacteria, especially Gram-negatives, and usefulness of empirical antifungal therapy represent the major concerns in this field., Areas Covered: Clinical trials registered in 5 international databases were referred for randomized clinical trials (RCTs) of empirical antibacterial therapy or empirical antifungal therapy in neutropenic cancer patients. The majority of RCTs compared antibiotics without major differences in the spectrum of activity, especially in the wake of the present epidemiology with an increase of infections and mortality due to resistant Gram-negatives; oral therapy and home care were analyzed in 3 RCTs. As regards empirical antifungal therapy, 1 ongoing study is comparing 'standard' empirical treatment vs diagnostic-driven approach., Expert Opinion: In an era of increasing antibiotic resistance the comparison of different strategies more than that of different drugs will probably represent the future in studies in this field. The next future will tell us if a diagnostic-driven approach is safe for fungal infections, or if we should continue to treat them only on the basis of the persistence of febrile neutropenia.

Background: Febrile neutropenia (FN) is a possible complication of antineoplastic chemotherapy. Aim of the study was to estimate the risk of developing fever at the beginning of any neutropenic period based on the previous history of FN., Procedure: The conditional frailty model was used to estimate the risk of developing fever during neutropenia separately for children with acute leukaemia/non-Hodgkin lymphoma (AL/NHL), or solid tumour (ST). The total number of previous FN episodes (PFNE), age, gender, type of tumour, calendar year of granulocytopenic period, phase of treatment, and granulocyte count were included in the model., Results: A total of 901 granulocytopenic periods was observed in 223 children: 306 in 66 AL/NHL and 595 in 157 ST. Fever developed in 328 cases: 125 in 53 AL/NHL and 203 in 92 ST. The PFNE variable was not significantly associated to the risk of fever [hazard ratio (HR) of 0.87, 95% confidence interval (CI) of 0.62-1.22 in children with AL/NHL, and HR of 0.98, 95% CI of 0.70-1.37 in those with ST]. The hazard of FN was significantly affected by the phase of treatment in AL/NHL (P<0.01), and by the level of neutropenia at onset in ST (P<0.01)., Conclusions: Previous history of FN does not increase the risk of further febrile episodes in any new subsequent granulocytopenic period. The aggressiveness of chemotherapy and the level of neutropenia at onset are the most important risk factors in children with AL/NHL and with ST respectively.

Goals of Work: To describe the course of hepatitis C in a cohort of 105 survivors after childhood cancer., Patients and Methods: Data on chemo/radiotherapy, clinical status, serial alanine aminotransferase (ALT) evaluation, and virological parameters after the end of treatment were collected for each patient. Liver biopsies, when performed, were centrally evaluated by a pathologist., Main Results: All patients were alive at the end of follow-up and did not show hepatic insufficiency. ALT evaluation along the entire follow-up showed a moderate (87%) or a remarkable (13%) cytolytic pattern. Young age at diagnosis, hematopoietic stem cell transplantation, and duration of infection significantly correlate with a worse hepatic activity. Type of tumor and chemo and/or radiotherapy regimens did not influence the pattern of hepatic cytolysis. Liver biopsy, centrally reviewed in 30% of the cohort, showed one case of cirrhosis and mild fibrosis in 71% of the group. Higher degrees of fibrosis did not seem to be related to any exposition to chemo/radiotherapy but correlated significantly with the more remarkable cytolytic course., Conclusions: The outcome of hepatitis C in our patients is comparable to the one described in European cohorts of adult cancer survivors and perinatally infected subjects. Nevertheless, progression to high degrees of hepatic damage has to be monitored by a careful follow-up.

Purpose: Mechanical complications in tunneled indwelling central venous catheters (CVCs) often involve a risk of displacement. Fixation procedures are, therefore, of primary importance. We prospectively evaluated the incidence of CVC-related mechanical and infectious complications observed in devices fixated with the Sri Paran technique., Methods: All CVCs inserted in children with cancer at our Institution from October 2005 to January 2007 were prospectively monitored for device-related mechanical and infectious complications. The Sri Paran fixation technique was used in all cases. The complication rate per 1,000 days was calculated as 1,000 times the number of complications divided by the total number of catheter days., Results: Ninety-five CVCs were positioned in 84 children. The overall length of observation ranged between 41 and 482 days for a total of 18,618 catheter days. Mechanical complications occurred in 5% of the devices (specific rate 0.27); infections were observed in 6% of the devices (specific rate 0.32). No complications were observed during the first 30 days after CVC insertion., Conclusions: The results, we obtained with the Sri Paran technique are extremely encouraging. Yet, randomized studies are required to prove these preliminary data.

The objective of this study was to assess the efficacy of an injection of 100 microg/kg of pegfilgrastim in haematopoietic recovery and mobilization in children following 32 courses of chemotherapy. End points were duration of neutropaenia, myeloid recovery and PBMC collection. Neutropaenia lasted a mean of 4.7 days (+/-2.13 days). Myeloid recovery occurred at a median of 10 days (inter quartile range (IQR) 8-11). Febrile neutropaenia complicated 13 courses (40.6%). Mobilization was observed in 20 out of 26 assessable courses (76.9%). The rise in CD34+ cells occurred at a median of 6 days (IQR 4-7) after PEG and remained >20 per microl for 6 days (IQR 4-8), with a median value of 80 per microl (IQR 48-170.5). The median CD34+ cell peak was 165 per microl (IQR 82.5-331), 9 days (range 6-14) after PEG. PBMC were collected on average at day +5 (+4 to +9) after PEG. In 93.3% of collections, at least 3 x 10(6) per kg CD34+ cells were collected through a single apheresis. Myeloid recovery occurred in all cases within 15 days, without concomitant thrombocytopaenia. The incidence of primary febrile episodes is in line with data in the literature and with our own historical experience. A long-lasting period of circulating CD34+ cells allowed for more accurate scheduling of apheresis.

We describe the survival patterns of 10,791 Italian children (age 0-14) diagnosed with cancer during 1989-1998 and who were included in the hospital-based registry of the Italian Association of Paediatric Haematology and Oncology. Five-year cumulative survival percentages were 76% for lymphoproliferative disorders and 68% for solid tumours. Survival rates in 1994-1998 significantly improved for acute lymphocytic leukaemia (ALL), acute non-lymphocytic leukaemia, Hodgkin's lymphoma and Wilms' tumour. Gender and age were determinants of survival for some specific types of cancer. Girls with ALL and neuroblastoma exhibited a significant advantage (hazard ratio HR 0.72, 0.62-0.83) and disadvantage (HR 0.73, 0.59-0.90) over boys, respectively. Children with a Wilms' tumour diagnosed above age 3 had a worse prognosis than younger children (HR 2.3, 1.4-4.1). The persisting gender-related difference in survival rate for ALL requires understanding as to whether it is attributable to delays in the adoption of more recent therapeutic protocols, while the corresponding findings for Wilms' tumour and neuroblastoma deserve further biological interpretation.

Background: The purpose of our study was to evaluate the incidence and clinical characteristics of febrile episodes during neutropenia following chemotherapy in children with cancer., Patients and Methods: A prospective, 3-year single-center observational study of periods of neutropenia was performed. Epidemiology and clinical diagnoses of febrile episodes occurring during the neutropenic periods were evaluated, taking into consideration different categories of anticancer treatment based on the type of tumor and phase of therapy., Results: A total of 703 febrile episodes were observed during 614 (34%) of 1792 neutropenic periods (34%), for a total of 28,001 days at risk, accounting for a rate of 0.76 episodes per 30 days at risk. The highest proportions of neutropenic periods with primary febrile episodes were observed after autologous hemopoietic stem cell transplantation (58%), aggressive treatment for acute leukemia or non-Hodgkin lymphoma (48%), and allogeneic hemopoietic stem cell transplantation (44%); the lowest proportion (9%) was observed during maintenance chemotherapy for acute leukemia (P<.001). The most frequent clinical diagnosis was fever of unknown origin (in 79% of cases), followed by bacteremia (10%); invasive mycosis was diagnosed in only 2% of cases., Conclusions: The overall incidence of febrile neutropenia and severe infectious complications in children with cancer is low, with differences according to the aggressiveness of chemotherapy. This fact must be considered when designing clinical trials on the management of infectious complications in children with cancer.

The number of subjects that have successfully completed treatment for a cancer diagnosed during childhood and are entering adulthood is increasing over time. Members of the International Berlin-Frankfurt-Munster (I-BFM) Early and Late Toxicity Educational Committee (ELTEC) invited 45 paediatric cancer experts (representing oncologists, psychologists, nurses, epidemiologists, parents, and survivors) from 13 European countries (with five additional experts from North America) to Erice, Sicily (from October 27 to 29, 2006) to discuss the circumstances in which the word 'cure' should be used when speaking about children with cancer, and when and why continuing follow-up and care may be required. The objective of the gathering was to generate from the personal and professional experience of the participants an overview statement of the group's philosophy of cure and care of survivors of childhood cancer. The ten points reflect what the group considers essential in the survivors' cure and care.

Background: Data on epidemiology and survival after fungal infections in patients with cancer are primarily based on studies in adults, whereas few data are available on children., Methods: A prospective, multicenter, 2-year surveillance of fungal infections in children receiving antineoplastic treatment was performed in 15 Italian centers. For each case, defined by means of EORTC-IFIG/NIAID-MSG, information was collected on age, phase of treatment, presence of neutropenia or lymphocytopenia, administration of antifungal drugs and survival., Results: Ninety-six episodes (42 proven [19 fungemias, 23 deep tissue infections], 17 probable and 37 possible invasive mycoses) were reported. Most of them (73%) followed aggressive chemotherapy, 21% allogeneic hematopoietic stem cell transplantation and only 6% moderately aggressive treatment. Neutropenia was present in 77% of the episodes, and it had a longer duration before deep tissue mycosis as compared with fungemia (P = 0.020). Lymphocytopenia was present in 75% of the episodes observed in nonneutropenic patients. As compared with children with fungemia, patients with probable invasive mycoses had a 25.7-fold increased risk of death, whereas it was 7.7-fold greater in children with possible invasive mycoses and 5-fold higher in those with proven deep tissue infection (P = 0.004). The risk of death was also 3.8-fold higher in patients already receiving antifungals at the time of diagnosis of infection as compared with those not receiving antimycotic drugs., Conclusions: In children with cancer, aggressive antineoplastic treatment, severe and longlasting neutropenia and lymphocytopenia are associated with fungal infections. These features as the clinical pictures are similar to those reported in adults, but in children, the overall and the infection-specific (fungemia or mycosis with deep tissue infection) mortalities are lower.

Aims: To evaluate cardiopulmonary exercise tolerance in a large cohort of apparently healthy paediatric cancer survivors in order to determine their participation in sporting activities., Methods: A total of 84 young (<21 years) asymptomatic childhood cancer survivors, who had been exposed to anthracyclines (mean dose 212 mg/m2) and/or chest irradiation (median dose 2000 cGy), with normal left ventricular systolic function at rest (fractional shortening >29%), and 79 healthy controls were studied. Exercise testing was performed on a treadmill ergometer. Gas exchange analysis and derived variables were measured on a breath-by-breath basis. Pulmonary functional evaluation was performed before exercise. Echocardiographic evaluation at rest was performed within one month before the exercise test., Results: There were no differences in exercise responses between patients and controls. In boys <13 years, mean VO2 max was slightly but significantly lower than in controls. This finding was thought to be a result of decreased physical fitness as all the other exercise parameters were similar to those in the controls., Conclusions: Results show that apparently healthy survivors of paediatric cancer can take part in dynamic sporting activities if they exhibit a normal response to cardiopulmonary exercise testing, while those that exhibit a reduced VO2 max should be re-evaluated after an aerobic training programme, and should undergo tailored dynamic physical activity if the VO2 max does not normalise.

Objective: To evaluate the role of active follow-up for the detection of relapses occurring after completion of therapy in children with cancer., Methods: The clinical records of all children who had a cancer relapse more than 3 months after the end of therapies in the period 1985-2000 were reviewed. Relapses were defined "diagnosed at a scheduled visit" or "at an unscheduled visit" based upon how the visit that lead to the suspected diagnosis was scheduled. Information was collected on how the first suspicion of relapse was made. Survival after relapse was calculated, by type of visit and tumor type., Results: Among 739 children who completed therapy for a malignant tumor in first complete remission (CR), 101 relapses [74 after solid tumors (ST), 27 after leukemia/lymphoma (L)] occurred after a median time of 12 months (range 3-87). Fifty-one (50.5%) first relapses were diagnosed during a visit scheduled because of symptoms (36 ST, 15 L), and 50 relapses (49.5%) at a regularly scheduled visit (38 ST, 12 L). Overall, 75% of relapses were first suspected on clinical basis, 16% via imaging, and only 9% via lab tests. Survival more than 10 years from first relapse was 25.7% (SE: 0.05%), with no significant differences between relapses diagnosed at a scheduled visit (20.5%), or at an unscheduled visit (32.1%; P = 0.826). Children with L had a better overall survival (OS, 70.6%) as compared to those with ST (9.2%, P < 0.001), probably because of a more extensive use of stem cell transplantation (SCT) as part of the salvage regimens., Conclusions: Scheduled follow-up programs failed to detect relapses in 50% of cases presented here. Survival after relapse is not affected by whether relapse was detected at a scheduled or an unscheduled visit., ((c) 2005 Wiley-Liss, Inc.)

Aim of the Study: To evaluate the possible link between malfunctioning events and catheter related infections in indwelling central venous devices in children with cancer., Patients and Methods: Prospective observation of 418 devices inserted in 2 Italian tertiary care pediatric cancer centers. The presence of a relationship was identified if a malfunctioning event was followed by a catheter related infection within 10 days, or vice versa., Results: The 418 catheters were followed for a period of 107,012 days. Among the malfunctioning events 2 out of 141 (1%) were followed by a catheter related infection while among infectious episodes 3 out of 93 (3%) were followed by a malfunctioning event., Conclusions: Malfunctioning events followed by catheter related infections and catheter related infections followed by malfunctioning are both rare events in children with cancer.

The long-term evolution of hepatitis C virus (HCV) infection in oncologic and/or transplanted patients is still unknown. Patients treated for cancer are different from the general HCV-infected population because of the immunosuppression and the hepatotoxic treatments, which act as co-factors of liver damage. Recently it was observed that antimetabolites play a role in accelerating the process of hepatic fibrosis. The aims of this retrospective study were to describe the clinical course of chronic hepatitis C acquired during anticancer treatment in a group of patients referred to a single center, and to correlate the course of hepatic disease to the type of treatment they received. Among the 17 children who underwent very long follow-up (range 10-18.5 years), the authors identified a group with more active hepatic cytolysis through the serial observation of mean ALT values, HCV RNA determination, and histologic data when available. During follow-up, none of them developed hepatic failure, cirrhosis, or hepatocarcinoma. No single risk factor, such as exposure to antimetabolites, alkylating agents, or other chemotherapy, radiotherapy to the abdomen, exposure to other hepatotoxic drugs, appearance of vaso-occlusive disease, acute and/or chronic graft-versus-host disease, or length of immunosuppression, correlated with a worse course of hepatitis. No definitive conclusions can be drawn. However, multivariate analysis of hepatic risk factors in larger cohorts of patients will be able to provide us with more precise information about the clinical outcome of chronic hepatitis in survivors.

The proportion of ciprofloxacin-resistant Gram-negative bacteria isolated from the blood of children with cancer (not receiving prophylaxis) was 10% in a paediatric hospital (Genoa) where the use of quinolones was highly restricted, compared with 41% in a department of haematology (Rome) where leukaemic adults, who received fluoroquinolone prophylaxis, were also treated (p < 0.0001). Moreover, simultaneous resistance to ciprofloxacin and ceftazidime, amikacin or imipenem-cilastatin was 11% in Genoa compared with 37% in Rome (p < 0.001). Ciprofloxacin resistance was more frequent in children who shared an environment with adults who were receiving ciprofloxacin prophylaxis.

Background: The use of indwelling central venous catheters (CVCs) has become commonplace in the management of children undergoing anticancer treatment. Several types of CVC are available, while information on complications observed in children is scarce. We describe the experience of two tertiary care centers in Italy that prospectively followed up three types of CVC used at both institutions over a 30-month period., Patients and Methods: Between January 2000 and May 2002, double-lumen (DL) or single-lumen (SL) Hickman-Broviac (HB) catheters, and single-lumen pressure-activated safety valve (PASV) catheters were used and prospectively evaluated. Four types of possible complication were defined a priori: mechanical, thrombotic, malfunctioning and infectious., Results: Four hundred and eighteen CVCs (180 SL-HB, 162 DL-HB and 76 PASV) were inserted in 368 children, for a total of 107 012 catheter days at risk of complication. At least one complication occurred while using 169 of the devices (40%): 46% of the DL-HB, 46% of the PASV and 33% of the SL-HB (P=0.02) catheters. Subjects with hematological malignancies or non-malignant diseases had significantly more complications than those with solid tumors (P <0.0001). Overall, 234 complications were documented: 93 infectious [complication rate per 1000 catheter days at risk (CR)=0.87], 84 malfunctioning (CR=0.78), 48 mechanical (CR=0.45) and nine thrombotic (CR=0.08). SL-HB had statistically fewer infectious complications, while PASV had more mechanical complications. In a multivariate regression model, the most significant risk factors for having a CVC complication were hematological disease [relative risk (RR)=3.0; 95% confidence interval (CI) 1.8-4.8] and age <6 years at CVC insertion (RR=2.5; 95% CI 1.5-4.1). As for the type of CVC, compared with SL-HB, the DL-HB catheter had a statistically significant two-fold increased risk of any complication (RR=2.1; 95% CI 1.2-3.6), while the PASV catheter had a borderline RR of 1.8 (95% CI 1.0-3.6). Analysis by tumor type showed a higher risk of any kind of complication in patients with solid malignancies who had received a DL-HB catheter as compared with an SL-HB catheter (RR=7.2; 95% CI 2.8-18.7)., Conclusions: CVCs may cause complications in up to 40% of patients, with type of CVC, underlying disease and patient age being the three main factors that affect the incidence of CVC-related complications. SL-HB catheters have the best performance.

The use of indwelling central venous catheters (CVCs) has become essential for managing children undergoing cancer treatment. Various types of CVCs are available, but reports on complications observed in pediatric series are scarce. We describe our experience concerning early mechanical complications at our institute by providing a prospective evaluation of three types of CVCs that were inserted over a 39-month period. Between January 1, 2000, and March 31, 2003, double-lumen (DL) or single-lumen (SL) Hickman-Broviac (HB) and single-lumen pressure-activated safety-valved (PASV) catheters were inserted and prospectively evaluated. Five groups of possible mechanical complications were defined a priori: dislodgement, migration, rupture, accidental removal, and blockage. We took into consideration complications occurring only within the first 30 days of insertion. A total of 272 CVCs (118 PASV, 57 DL-HB, and 97 SL-HB) were inserted in 232 children. A total of 29 early mechanical complications (10.7% of all CVCs) were diagnosed: 15.2% of the PASV, 10.5% of the DL-HB, and 4.1% of the SL-HB. Elective removal of the catheter due to complications was required in eight patients. SL-HB catheters had fewer complications, while the complication rate and the number of devices that were removed were significantly higher in patients with PASV catheters. We conclude that catheter type correlates with the risk of early mechanical complications and removal.

Background and Objectives: Giannina Gaslini Children's Hospital (GGCH) is a tertiary care hospital with an average of 100 new cancer diagnoses made each year. In April 2000, following preliminary analysis of the potential benefits, and the results of a questionnaire filled in by the parents attending the out-patient clinic, a Home Care (HC) program was started., Design and Methods: Children in stable, non-critical, clinical conditions requiring i.v. therapy, parenteral nutrition, transfusional support, blood examinations, and central venous catheter use training management, as well as terminally ill children needing palliative and support therapy were considered eligible for the program., Results: After one year of activity, 45 children, aged 1 month-19 years (median 3 years), requiring i.v. therapy and blood tests in 32 cases, central venous catheter use training in 5, and palliative care in 8, were treated at home. The median duration of assistance for each child was 19 days (range 1-172). An average of 4 patients per week were assisted for a total of 1,364 days. A total of 881 accesses at home replaced 551 and 330 out-patient and in-patient days of hospitalization, respectively. The average cost per patient given home care (2,936 E, range 150-20,700) resulted to be significantly lower than the average cost per patient hospitalized to undergo the same procedures (9,785E, range 350-96,750)., Interpretation and Conclusions: The opportunity to reduce the frequency and duration of hospitalization represents an incalculable advantage for these children and their families. This report shows that home care is a feasible kind of assistance for children suffering from cancer, and reduces costs as well.

We carried out a retrospective study on the infection rate--in episodes per 100 person months at risk (p/m/r)--of septicaemia and invasive mycoses in children with solid tumours treated at a single institution between 1985 and 1996. Among 982 patients, accounting for 8108 p/m/r, 257 infectious episodes were documented, for an infection rate of 3.2. The infection rate for "intensive" treatment was greater than that for "less intensive" treatments, 3.7 compared with 0.5, respectively; P<0.001. 58% of infectious episodes were associated with neutropenia, 22% were megatherapy-related, and 39% were related to central venous catheter (CVC), while in 13% of the episodes no risk factor was identified. Of the episodes, single organism Gram-positive bacteraemias accounted for 62%, single organism Gram-negative for 23%, multiple organism bacteraemias for 7%, invasive mycoses for 4%, and isolated fungaemias for 4%. The infection rate for Gram-positive organisms decreased significantly over time (-5.9% per year; P<0.01), but increased for the Gram-negative organisms (+3.4% per year; P=0.4). This study demonstrates that the risk of bacteraemia increases in parallel with the treatment intensity, and that a considerable number of children with solid tumours develop bacteraemia in the absence of an identifiable risk factor.

The first cohort of subjects treated for cancer during childhood is now entering adulthood, and it is necessary to determine whether treatment has been sufficient to completely eradicate the neoplastic clone, and whether the cancer itself or treatment-related toxicity may have increased the risk of premature death. For these reasons, long-term survival and causes of death were evaluated in a cohort of subjects treated for childhood cancer who reached the elective end of therapy in continuous remission and were registered until 1992 in the Italian Registry of off-therapy subjects (OTR). The vital status of OTR subjects was ascertained in 1996 by a postal survey through census bureaux; for deceased subjects, the cause of death was defined and compared with the expected rates in the general population. At follow-up, out of 6402 eligible and evaluable subjects, 890 were found to have died; the estimated overall survival at 20 years was 80.7% (95% CI 79.3-82.1). Most of the patients (84.6%) died due to recurrence of the primary cancer, usually within the first 5 years after the OT. The cumulative incidence of death due to recurrence of the primary tumor was greater among subjects treated for solid tumor than among those treated for leukemia/lymphoma (p = 0.0001); in contrast, OT subjects after leukemia and lymphoma were more likely to die due to of medical complications of therapy (p < 0.02). Second cancers were the second most frequent cause of death, with a 12-fold risk compared with the general population; the figures were similar in the 2 cancer groups. Compared with the general population, OT subjects were 32 times more likely than same-age subjects to die. The SMR decreased to 6.1 when only non-cancer deaths were considered. Deaths due to external or avoidable causes occurred among survivors at a rate similar to that of the general population., (Copyright 2000 Wiley-Liss, Inc.)