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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.

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.

Background. Evidence-based guidelines are needed to guide effective long-term follow-up (LTFU) of childhood cancer survivors (CCS) at risk of late adverse effects (LAEs). We aimed to ascertain the use of LTFU guidelines throughout Europe, and seek views on the need for pan-European LTFU guidelines. Procedures. One expert clinician from each of 44 European countries was invited to participate in an online survey. Information was sought regarding the use and content of LTFU guidelines in the respondent's centre and country, and their views about developing pan-European LTFU guidelines. Results. Thirty-one countries (70%) responded, including 24 of 26 full EU countries (92%). LTFU guidelines were implemented nationally in 17 countries (55%). All guidelines included recommendations about physical LAEs, specific risk groups and frequency of surveillance, and the majority about psychosocial LAEs (70%), and healthy lifestyle promotion (65%). A minority of guidelines described recommendations about transition to age-appropriate LTFU services (22%), where LTFU should be performed (22%) and by whom (30%). Most respondents (94%) agreed on the need for pan-European LTFU guidelines, specifically including recommendations about surveillance for specific physical LAEs (97%), action to be taken if a specific LAE is detected (90%), minimum requirements for LTFU (93%), transition and health promotion (both 87%). Conclusions. Guidelines are not universally used throughout Europe. However, there is strong support for developing pan-European LTFU guidelines for CCS. PanCareSurFup (www.pancare.eu) will collaborate with partners to develop such guidelines, including recommendations for hitherto relatively neglected topics, such as minimum LTFU requirements, transition and health promotion. Pediatr Blood Cancer 2015;62:322-328. (C) 2014 Wiley Periodicals, Inc.

BackgroundFertility 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. ProceduresOn 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. ResultsOne 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. ConclusionsThere 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. Pediatr Blood Cancer 2014;61:2054-2058. (c) 2014 Wiley Periodicals, Inc. (Less)

Background Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. Patients and Methods Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. Results Median age at initial SEC was 104 days (IQR 47–234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7–34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P = 0.039) and grade 3 motor deficit (P = 0.084). Conclusions Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted. Pediatr Blood Cancer 2014; 61:1369–1375. © 2014 Wiley Periodicals, Inc.

Background Neuroblastoma (NB), a pediatric tumor of the sympathetic nervous system, is characterized by very frequent chromosomal aberrations at the onset of the disease. Identification of further risk factors for relapse, which could lead to increased survival and potentially reduced late effects among survivors, is still urgently needed. Segmental chromosome aberrations (SCA) are associated with poor prognosis, whereas numerical whole-chromosome aberrations (NCA) are found in patients with a good prognosis; however, a small percentage of the latter patients (10%-15%) subsequently relapse and/or die of disease. Procedure DNA copy-number data from 174 NB patients with an NCA genomic profile were analyzed. Association between NCA and event-free survival (EFS) was investigated by the Kaplan-Meier estimator and prognostic decision tree (DT). Results DT identified 65 patients with normal chromosome X and an excellent five-year EFS (100%) independently from the stage at diagnosis. The association between poor EFS and whole chromosome X alterations was confirmed after stratification into two groups of different expected prognosis and by internal validation via bootstrap analysis. Furthermore, the association was also observed in an independent cohort of NB patients extracted from the data set of the National Cancer Institute TARGET Project for Neuroblastoma, but sample size was small (n = 75) and statistical significance was not achieved. Conclusions Loss of whole chromosome X may represent a new prognostic marker for NB patients with an NCA genomic profile. If confirmed by further studies, this finding could indicate that such patients should be reclassified as intermediate risk and treated accordingly.

These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work-up, and treatment and long-term follow-up of LCH patients are presented.

Background Multiple target molecular monitoring of minimal residual disease in neuroblastoma (NB) patients may increase sensitivity and overcome tumor heterogeneity. However, multiple target analysis is costly and time consuming, thus improvement with respect to single target monitoring needs to be achieved. Procedures Italian patients with localized NB were evaluated at diagnosis for TH, GD2-s, DDC, DCX, ELAV-4, STX, and Phox2b mRNA expressions. Patients with metastatic NB were tested as positive controls, together with NB primary tumors and cell lines, while healthy donors were tested as negative controls. Results All NB-related markers but Phox2b were expressed in healthy donors, and in a high percentage of patients with localized NB without association with clinical events. The introduction of cut-off levels increased marker specificity, although the percentage of positive results was only slightly modified. While TH positivity in PB samples significantly associated with a worse prognosis, a paradox association was found for GD2-s mRNA expression. No correlation and agreement between quantitative and qualitative results obtained with the two assays were found. In the set of samples tested for all markers, no pattern of expression was found to be associated with a specific clinical situation. Conclusion These findings suggest that positive molecular results may not reflect the presence of disease, and that correlation among different markers is small in condition of low tumor burden. Thus, to reduce cost and amount of precious samples, in addition to TH, whose prognostic value was confirmed, only Phox2b warrants further evaluation in multi-center, prospective studies for high risk patients. Pediatr Blood Cancer 2012; 58: 43–49. © 2011 Wiley Periodicals, Inc.

Background Data on the epidemiology of bacteremias and invasive fungal diseases (IFD) in children with acute myeloid leukemia (AML) are scarce. Design and Methods In a multi-center, retrospective study, we analyzed proportion, rate per 1,000 person-days at risk, and cumulative risk of bacteremias and IFD in children with AML. Results Between January 1998 and December 2005, 240 children were treated for AML at 8 Italian Centers, for a total of 521 treatment courses and 63,232 person-days at risk. Bacteremia was observed in 32% of treatment courses and IFD was seen in 10% (P

Background MDM2 SNP309, characterised by a T-to-G substitution in the MDM2 promoter, is associated with higher gene expression compared to wild type and was recently found to be a negative prognostic factor for patients with stage 4 neuroblastoma (NB), but not for children with localised disease. This polymorphism was not associated with any clinical or genetic tumour characteristics, including MYCN amplification and 1p chromosome deletion. Procedure To better define the involvement of MDM2 SNP309 in NB, we explored its association with the main biochemical tumour markers, namely urinary concentrations of vanillyl mandelic acid (VMA) and homovanillic acid (HVA) and blood concentrations of ferritin and lactate dehydrogenase (LDH). A cohort of 497 NB children, enrolled in the Italian Neuroblastoma Registry between January 1985 and December 2005 and previously investigated for the prognostic role of MDM2 SNP309, was considered for this study. Results VMA and HVA concentrations as well as HVA/VMA ratio were not affected by the MDM2 SNP309 genotype. Ferritin and LDH concentrations were significantly lower in TT than in TG/GG only in patients with stage 4 disease (P = 0.007 and 0.015, respectively). No association emerged in patients with localised disease. These findings were not affected by confounding from clinical or biological characteristics. Conclusions The association between MDM2 SNP309 and both ferritin and LDH in patients with stage 4 disease confirms the prognostic role of this polymorphism. The results suggest that the MDM2 SNP309 genotype can impact on tumour responses to hypoxia and might play an important role in the alteration of energetic metabolism in NB cells. Pediatr Blood Cancer. 2010;55:267–272. © 2010 Wiley–Liss, Inc.

Background MDM2 is a major negative regulator of p53 function and is directly regulated by MYCN in neuroblastoma (NB) cells. MDM2 SNP309, a T-to-G substitution in the MDM2 promoter associated with higher gene expression compared to wild-type, may attenuate the p53 pathway in NB, in which p53 mutations are rare. We investigated its impact on NB development and survival in relation with major clinical and biological characteristics. Procedure A consecutive cohort of 497 NB children, diagnosed in Italy between 1995 and 2005, and a healthy control population of 471 adults were genotyped for MDM2 SNP309. NB patients were followed up until June 30, 2008. Results Patients and controls showed similar distribution of MDM2 SNP309 genotypes. In patients, the polymorphism was not associated with any characteristic at diagnosis. In localized stages no effect of the polymorphism on survival was evident. In stage 4 patients overall survival (OS), event free survival (EFS) and survival after relapse (SAR) were significantly poorer for TG/GG than for TT patients (P = 0.008; P = 0.013; P = 0.046, respectively). In this group, such an effect was more evident in patients with MYCN amplification (OS: P

Background Information on the incidence of infectious complications during for treatment for high risk neuroblastoma (HR-NB) is limited. Bacteremias and invasive mycoses may be considered surrogate markers of the infection burden. Patients and Methods Data on bacteremias and invasive mycoses occurring during 3 consecutive protocols for front line (NB-89; NB-92; NB-97) or salvage therapy (TVD) for HR-NB were reviewed. The cumulative risk of developing a first episode and the rate of infections during the entire length of each protocol were evaluated. Results Front line protocols were given to 80 patients for a total of 22,070 days at risk; salvage treatment was given to 24 children for 2,909 days at risk. During front line therapy 41 infectious episodes were diagnosed in 29 (36%) patients, for a 45% cumulative risk and an infection rate (IR) of 0.19/100 patient-days-at risk. Salvage therapy determined five infectious episodes in four (17%) patients, with a 39% cumulative risk, and an IR of 0.17. The IR during the phase of high dose chemotherapy with hematopoietic stem cell rescue (megatherapy) included in the three front line protocols decreased over time (1.54 in NB-89; 0.52 in NB-92 and 0.0 in NB 97; P = 0.001), possibly because of the use of less aggressive conditioning regimens, without radiotherapy. Conclusions The IRs of protocols for HR-NB did not change over time. The megatherapy-related phases are those at highest risk. Pediatr Blood Cancer 2007;49:672–677. © 2006 Wiley-Liss, Inc.

Background Permanent consequences (PC) are often described among subjects with Langerhans cell histiocytosis (LCH) but data on the real incidence are scarce. Within the Histiocyte Society (HS), and in order to design a definitive late effects study, a retrospective survey was organized to describe the prevalence of PC among long-term survivors of LCH. Methods Nine institutions contributed with their LCH patients having a minimum follow-up of 3 years. Information was collected on their disease-history, and on type and date of onset of any PC. Because of the retrospective type of this study, it was accepted that each institution might have used different criteria to assess PC. Results One hundred eighty-two subjects were registered and in 95 (52%) at least 1 PC was reported. For some specific PC (e.g., anterior pituitary dysfunction) information was too scarce to provide reliable data. PC were more frequent among subjects with multisystem (MS) disease (71%), compared to those with single system (SS) disease (24%); P

Background Fertility impairments among women treated during childhood for cancer are known to occur after some, but not all, types of anticancer therapy. Although leukemia is the most common cancer of childhood, until now fertility in survivors has not been comprehensively assessed. Procedure We investigated functional impairment of fertility in women who were long-term survivors of acute lymphoblastic leukemia (ALL) with a retrospective cohort study. Proven fertility (defined as ever pregnant) was evaluated by self-report among 182 females treated on protocols of the Children's Cancer Group (age at interview, 22.6 years on average) and 170 controls drawn from among the survivors' female siblings (23.4 years). The interview included psychosocial inventories designed to detect mood problems. Results Significant fertility deficits were noted in female survivors treated with cranial radiotherapy (CRT) at any dose around the time of menarche (relative fertility (RF)) = 0.27, 95% CI = 0.09, 0.82, P = 0.03). Controlling for marital status, mood at interview, and many fertility-related situations did not change the association. Conclusion This study provides evidence for fertility deficits after treatment for ALL with CRT, and, in addition, for the first time, suggests that girls treated around the time of menarche are especially at risk. Clinical confirmation of these results is needed. If gonadal damage occurs in women receiving these treatments, their risk for further sequelae, such as osteoporosis and heart disease, may be significantly raised, requiring active management and intervention. © 2004 Wiley-Liss, Inc.

Background Since there is no validated assay to monitor disease in children with neuroblastoma (NB), we tested whether NB specific cell-free RNA could be detected in their plasma samples. Moreover, with the aim of reducing patients' discomfort, we compared this assay to a recently standardized procedure that uses a larger amount of whole blood. Procedures Using conditions that excluded RNA recovery from contaminating tumor cells, the total amount of cell-free RNA present in healthy children and patients with NB was quantified. Expression of tyrosine hydroxylase (TH) was assayed by quantitative RT-PCR. Results In patients with NB the amount of cell-free RNA was higher than in healthy children. However, it was less and more degraded than in healthy adults. The median amount of cell-free RNA that was reverse transcribed, measured through the use of standard curves for reference genes, was 0.03 (range 0–30) pg of input RNA, that is, always less than 1/10,000 of that reverse transcribed from total RNA extracted from whole cells. Despite the presence of disease and the positive results obtained with RNA extracted from peripheral blood cells, few cell-free RNA samples tested positive by the TH assay. Similar results were obtained also with TH primers specifically designed to amplify 50 bp RNA fragments. Conclusion These findings suggest that for monitoring disease status detection of cell-free tumor-specific RNAs in patients with NB is not a reliable alternative to whole cell RNA. Pediatr Blood Cancer 2010;54:897–903 © 2010 Wiley-Liss, Inc.