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Objectives: In our study, we aimed to characterise adult childhood cancer survivors (ACCS), assess their health issues, gauge health-related quality of life (HRQOL) and evaluate visit satisfaction., Design: Prospective cohort study using data from clinical visits and questionnaires., Setting: Interdisciplinary follow-up programme for ACCS based on the long-term follow-up (LTFU) guidelines of the Children's Oncology Group and overseen by internists in two Swiss hospitals., Participants: ACCS attending our LTFU clinics between April 2017 and January 2022 were eligible., Interventions: We documented medical history, current health status and assessed HRQOL using Short Form-36 V.2, comparing it with Swiss general population (SGP) norms (T mean=50, SD=10; age stratified). 3 months post visit, a feedback questionnaire was distributed., Main Results: Among 102 ACCS (mean age: 32 years (range: 18-62 years), 68% women), 43 had no prior follow-up (36 ACCS>28 years, 7 ACCS≤28 years). A notable 94% had health issues, affecting an average of 6.1 (SD=3.3) organ systems. HRQOL was lower in ACCS>28 years than the SGP>28 years (physical: 44.8 (SD=11.65) vs 49.3 (SD=10.29), p=0.016; mental: 44.4 (SD=13.78) vs 50.53 (SD=9.92), p=0.004). Older ACCS (>28 years) reported inferior physical (44.8 vs 50.1 (SD=9.30), p=0.017) and mental HRQOL (44.4 vs 50.3 (SD=7.20), p=0.009) than younger ACCS. The majority of respondents reported high levels of satisfaction with the consultation, exceeding 90%., Conclusion: ACCS attending LTFU clinics face diverse health issues impacting multiple organ systems and exhibit lower HRQOL compared with the SGP. Thus, internist-led LTFU clinics are crucial for optimising follow-up care., Competing Interests: Competing interests: A-EM is a specialist for porphyria and received financial support via an unrestricted research grant from Clinuvel Pharmaceuticals and for a porphyria nurse from Alnylam Pharmaceuticals. Both are paid into the ‘Stiftung für wissenschaftliche Forschung, Stadtspital Triemli’ and are not related to this scientific work. JDL is supported by grants from the Swiss National Science Foundation (SNF 160072 and 185592) as well as by the Swiss Personalised Health Network (SPHN 2018DR108). JDL has also received unrestricted grants from AstraZeneca AG Switzerland, Boehringer Ingelheim GmbH Switzerland, GSK AG Switzerland, Novartis AG Switzerland and Sanofi AG Switzerland. None of them are related to this scientific work. No other conflicting interests were declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Reported prevalence of cancer-related fatigue (CRF) among childhood cancer survivors (CCS) varies widely, and evidence on factors associated with CRF among CCS is limited. We aimed to investigate the prevalence of CRF and its associated factors among adult CCS in Switzerland., Methods: In a prospective cohort study, we invited adult CCS who survived at least 5 years since last cancer diagnosis, and were diagnosed when age 0-20 years and treated at Inselspital Bern between 1976 and 2015 to complete two fatigue-measuring instruments: the Checklist Individual Strength subjective fatigue subscale (CIS8R; increased fatigue 27-34, severe fatigue ≥ 35) and the numerical rating scale (NRS; moderate fatigue 4-6, severe fatigue 7-10). We collected information about previous cancer treatment and medical history, and calculated β coefficients for the association between CIS8R/NRS fatigue scores and potential determinants using multivariable linear regression., Results: We included 158 CCS (participation rate: 30%) with a median age at study of 33 years (interquartile range 26-38). Based on CIS8R, 19% (N = 30) of CCS reported increased fatigue, yet none reported severe fatigue. CRF was associated with female sex, central nervous system (CNS) tumors, sleep disturbance, and endocrine disorders. Lower CRF levels were observed among CCS age 30-39 years compared to those younger., Conclusions: A considerable proportion of adult CCS reported increased levels of CRF., Implications for Cancer Survivors: CCS who are female and < 30 years old, have a history of CNS tumor, report sleep disturbance, or have an endocrine disorder should be screened for CRF., (© 2023. The Author(s).)

Objective: Childhood cancer survivors are at risk for pulmonary morbidity due to exposure to lung-toxic treatments, including specific chemotherapeutics, radiotherapy, and surgery. Longitudinal data on lung function and its change over time are scarce. We investigated lung function trajectories in survivors over time and the association with lung-toxic treatments., Methods: This retrospective, multicenter cohort study included Swiss survivors diagnosed between 1990 and 2013 and exposed to lung-toxic chemotherapeutics or thoracic radiotherapy. Pulmonary function tests (PFTs), including forced expiration volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, total lung capacity,  and diffusion capacity of the lung for carbon monoxide, were obtained from hospital charts. We calculated z-scores and percentage predicted, described lung function over time, and determined risk factors for change in FEV1 and FVC using multivariable linear regression., Results: We included 790 PFTs from 183 survivors, with a median age of 12 years at diagnosis and 5.5 years of follow-up. Most common diagnosis was lymphoma (55%). Half (49%) of survivors had at least one abnormal pulmonary function parameter, mainly restrictive (22%). Trajectories of FEV1 and FVC started at z-scores of -1.5 at diagnosis and remained low throughout follow-up. Survivors treated with thoracic surgery started particularly low, with an FEV1 of -1.08 z-scores (-2.02 to -0.15) and an FVC of -1.42 z-scores (-2.27 to -0.57) compared to those without surgery., Conclusion: Reduced pulmonary function was frequent but mainly of mild to moderate severity. Nevertheless, more research and long-term surveillance of this vulnerable population is needed., (© 2023 Wiley Periodicals LLC.)

Background: The cancer diagnosis and its intensive treatment may affect the long-term psycho-social adjustment of childhood cancer survivors. We aimed to describe social, emotional, and behavioral functioning and their determinants in young childhood cancer survivors., Procedure: The nationwide Swiss Childhood Cancer Survivor Study sends questionnaires to parents of survivors aged 5-15 years, who have survived at least 5 years after diagnosis. We assessed social, emotional, and behavioral functioning using the Strengths and Difficulties Questionnaire (SDQ). The SDQ includes four difficulties scales (emotional, conduct, hyperactivity, peer problems), a total difficulties indicator, and one strength scale (prosocial). We compared the proportion of survivors with borderline and abnormal scores to reference values and used multivariable logistic regression to identify determinants., Results: Our study included 756 families (response rate of 72%). Thirteen percent of survivors had abnormal scores for the total difficulties indicator compared to 10% in the general population. The proportion of survivors with abnormal scores was highest for the emotional scale (15% vs. 8% in the general population), followed by the peer problems scale (14% vs. 7%), hyperactivity (8% vs. 10%), and conduct scale (6% vs. 7%). Few survivors (4% vs. 7%) had abnormal scores on the prosocial scale. Children with chronic health conditions had a higher risk of borderline and abnormal scores on all difficulties scales (all p < 0.05)., Conclusion: Most childhood cancer survivors do well in social, emotional, and behavioral life domains, but children with chronic health conditions experience difficulties. Therefore, healthcare professionals should offer specific psycho-social support to these survivors., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

This study (NCT01288573) investigated plerixafor's safety and efficacy in children with cancer. Stage 1 investigated the dosage, pharmacokinetics (PK), pharmacodynamics (PD), and safety of plerixafor + standard mobilization (G-CSF ± chemotherapy). The stage 2 primary endpoint was successful mobilization (doubling of peripheral blood CD34+ cell count in the 24 h prior to first apheresis) in patients treated with plerixafor + standard mobilization vs. standard mobilization alone. In stage 1, three patients per age group (2-<6, 6-<12, and 12-<18 years) were treated at each dose level (160, 240, and 320 µg/kg). Based on PK and PD data, the dose proposed for stage 2 was 240 µg/kg (patients 1-<18 years), in which 45 patients were enrolled (30 plerixafor arm, 15 standard arm). Patient demographics and characteristics were well balanced across treatment arms. More patients in the plerixafor arm (24/30, 80%) met the primary endpoint of successful mobilization than in the standard arm (4/14, 28.6%, p = 0.0019). Adverse events reported as related to study treatment were mild, and no new safety concerns were identified. Plerixafor + standard G-CSF ± chemotherapy mobilization was generally well tolerated and efficacious when used to mobilize CD34+ cells in pediatric cancer patients.

Angiogenesis is crucial for the growth of cancer. As such, it has become an established target in fighting cancer. Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potential novel approach to controlling advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has the property of killing resistant cancer cells while significantly reducing undesirable toxic side effects. We review the data regarding the use of metronomic chemotherapy in children with cancer and discuss its potential uses and limits.

Purpose: Pediatric solid malignancies display important angiogenic potential, and blocking tumor angiogenesis represents a new therapeutic approach for these patients. Recent studies have evidenced rare circulating cells with endothelial features contributing to tumor neovascularization and have shown the pivotal role of bone marrow-derived (BMD) progenitor cells in metastatic disease progression. We measured these cells in patients with pediatric solid malignancies as a prerequisite to clinical trials with antiangiogenic therapy., Patients and Methods: Peripheral blood was drawn from 45 patients with localized (n = 23) or metastatic (n = 22) disease, and 20 healthy subjects. Subsets of circulating vascular endothelial growth factor receptor (VEGFR)2+-BMD progenitor cells, defined as CD45-CD34+VEGFR2(KDR)+7AAD- and CD45(dim)CD34+VEGFR2+7AAD- events, were measured in progenitor-enriched fractions by flow cytometry. Mature circulating endothelial cells (CEC) were measured in whole blood as CD31+CD146+CD45-7AAD- viable events. Data were correlated with VEGF and sVEGFR2 plasma levels., Results: The CD45-CD34+VEGFR2(KDR)+7AAD- subset represented <0.003% of circulating BMD progenitor cells (< or =0.05 cells/mL). However, the median level (range) of the CD45(dim)CD34+VEGFR2+7AAD- subset was higher in patients compared with healthy subjects, 1.5% (0%-10.3%) versus 0.3% (0%-1.6%) of circulating BMD progenitors (P < 0.0001), and differed significantly between patients with localized and metastatic disease, 0.7% (0%-8.6%) versus 2.9% (0.6%-10.3%) of circulating BMD progenitors (P < 0.001). Median CEC value was 7 cells/mL (0-152 cells/mL) and similar in all groups. Unlike VEGFR2+-BMD progenitors, neither CECs, VEGF, or sVEGFR2 plasma levels correlated with disease status., Conclusion: High levels of circulating VEGFR2+-BMD progenitor cells correlated with metastatic disease. Our study provides novel insights for angiogenesis mechanisms in pediatric solid malignancies for which antiangiogenic targeting of VEGFR2+-BMD progenitors could be of interest.

Tyrosine kinase receptors are expressed on the surface of tumor and/or endothelial cells and represent attractive targets for new anti-cancer treatment strategies. The so-called "small molecule" tyrosine kinase inhibitors have been designed to interact with the intracellular ATP binding site of these receptors, subsequently causing arrest of tumor cell proliferation, as well as induction of apoptosis and tumor migration. Furthermore, these molecules can impact on tumor angiogenesis. Tyrosine kinase inhibitors have been evaluated in several clinical trials for various adult malignant tumor entities and are currently being studied in pediatric solid malignancies. In this review, we will address the data available supporting the potential use of tyrosine kinase inhibitors in solid malignancies of childhood.

Formation of embryonic blood and lymph vessels is mediated by different steps of vasculogenesis and angiogenesis. The vascular endothelial growth factor family (VEGF) as well as the VEGF-receptors on the surface of blood endothelial cells and lymph endothelial cells are responsible for both processes. In addition to the embryonic development of the vessel systems, the interactions of angiogenesis factors and receptors are also present in solid tumors. Embryonic tumors in children offer an interesting target for new substances developed for anti-angiogenesis. Some data on the role of blood vessels and anti-blood-angiogenesis are available on embryonic tumors. However, studies of lymph-angiogenesis are not found and anti-lymph-angiogenesis is not at all examined in embryonic tumors. This review gives an overview of the challenging field of angiogenesis and anti-angiogenesis of both blood and lymph vessels with a focus on embryonic tumors., (2005 John Wiley & Sons, Ltd.)

Humoral angiogenesis stimulators including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been implicated in the pathogenesis of solid malignancies. However, it has remained unclear whether both stimulators contribute to the development and progression of solid malignancies of children. The aim of the present study was to determine whether VEGF and bFGF are elevated in body fluids of children with solid malignancies and, if so, whether these elevated levels correlate with clinical parameters. Using enzyme-linked immunosorbent assays (ELISAs), we quantified VEGF and bFGF in serum (n = 107) and urine (n = 57) of healthy children and of children with solid malignancies (serum: n(VEGF) = 69, n(bFGF) = 60; urine: n(VEGF) or n(bFGF) = 13). Finally, we compared patients' pre-therapeutic and post-therapeutic levels. Serum VEGF was elevated in children with several solid tumors (Ewing's sarcoma, primitive neuroectodermal tumours, malignant lymphoma, Langerhans cell histiocytosis and medulloblastoma). In contrast, serum bFGF, urinary bFGF or urinary VEGF were not significantly elevated. Upon successful therapy, elevated pre-therapeutic serum VEGF levels declined to levels present in healthy children. VEGF could contribute to the progression of pediatric solid malignancies, and serum VEGF could be used to monitor therapeutic response. Furthermore, the determination of angiogenesis stimulators could identify patients eligible for anti-angiogenic therapy., (Copyright 2001 Wiley-Liss, Inc.)