Risk of subsequent gliomas and meningiomas among 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Childhood cancer survivors are at risk of subsequent gliomas and meningiomas, but the risks beyond age 40 years are uncertain. We quantified these risks in the largest ever cohort. METHODS: Using data from 69,460 5-year childhood cancer survivors (diagnosed 1940-2008), across Europe, standardized incidence ratios (SIRs) and cumulative incidence were calculated. RESULTS: In total, 279 glioma and 761 meningioma were identified. CNS tumour (SIR: 16.2, 95% CI: 13.7, 19.2) and leukaemia (SIR: 11.2, 95% CI: 8.8, 14.2) survivors were at greatest risk of glioma. The SIR for CNS tumour survivors was still 4.3-fold after age 50 (95% CI: 1.9, 9.6), and for leukaemia survivors still 10.2-fold after age 40 (95% CI: 4.9, 21.4). Following cranial radiotherapy (CRT), the cumulative incidence of a glioma in CNS tumour survivors was 2.7%, 3.7% and 5.0% by ages 40, 50 and 60, respectively, whilst for leukaemia this was 1.2% and 1.7% by ages 40 and 50. The cumulative incidence of a meningioma after CRT in CNS tumour survivors doubled from 5.9% to 12.5% between ages 40 and 60, and in leukaemia survivors increased from 5.8% to 10.2% between ages 40 and 50. DISCUSSION: Clinicians following up survivors should be aware that the substantial risks of meningioma and glioma following CRT are sustained beyond age 40 and be vigilant for symptoms.

Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study.

BACKGROUND: Survivors of Hodgkin lymphoma (HL) are at risk of developing non-Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide. METHODS: The Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow-Up Studies (PanCareSurFup) cohort includes 69,460 five-year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression. RESULTS: Overall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4-1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9-2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1-10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7-5.7), leukemia (SIR, 2.8; 95% CI, 1.8-4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4-5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2-3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7-2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8-1.5). CONCLUSIONS: In addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors and health care professionals should be aware of the risk of NHL in these survivors and in any survivors treated with chemotherapy.

Risk of subsequent primary oral cancer in a cohort of 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Survivors of childhood cancer are at risk of subsequent primary malignant neoplasms (SPNs), but the risk for rarer types of SPNs, such as oral cancer, is uncertain. Previous studies included few oral SPNs, hence large-scale cohorts are required to identify groups at risks. METHODS: The PanCareSurFup cohort includes 69,460 5-year survivors of childhood cancer across Europe. Risks of oral SPNs were defined by standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence. RESULTS: One hundred and forty-five oral SPNs (64 salivary gland, 38 tongue, 20 pharynx, 2 lip, and 21 other) were ascertained among 143 survivors. Survivors were at 5-fold risk of an oral SPN (95% CI: 4.4-5.6). Survivors of leukaemia were at greatest risk (SIR = 19.2; 95% CI: 14.6-25.2) followed by bone sarcoma (SIR = 6.4, 95% CI: 3.7-11.0), Hodgkin lymphoma (SIR = 6.2, 95% CI: 3.9-9.9) and soft-tissue sarcoma (SIR = 5.0, 95% CI: 3.0-8.5). Survivors treated with radiotherapy were at 33-fold risk of salivary gland SPNs (95% CI: 25.3-44.5), particularly Hodgkin lymphoma (SIR = 66.2, 95% CI: 43.6-100.5) and leukaemia (SIR = 50.5, 95% CI: 36.1-70.7) survivors. Survivors treated with chemotherapy had a substantially increased risk of a tongue SPN (SIR = 15.9, 95% CI: 10.6-23.7). CONCLUSIONS: Previous radiotherapy increases the risk of salivary gland SPNs considerably, while chemotherapy increases the risk of tongue SPNs substantially. Awareness of these risks among both health-care professionals and survivors could play a crucial role in detecting oral SPNs early.

Impact of era of diagnosis on cause-specific late mortality among 77 423 five-year European survivors of childhood and adolescent cancer: The PanCareSurFup consortium.

Late mortality of European 5-year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends in cause-specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five-year survivors of cancer diagnosed before age 21 between 1940 and 2008 followed for an average age of 21 years and a total of 1.27 million person-years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow-up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval [95% CI] 9.69-10.09), AER 6.47 per 1000 person-years, (95% CI 6.32-6.62). At 60 to 68 years of attained age all-cause mortality was still higher than expected (SMR = 2.41, 95% CI 1.90-3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95% CI 16.5-20.4) to 7.3% (95% CI 6.7-8.0) over the observation period. Compared to the diagnosis period 1960 to 1969, the mortality hazard ratio declined for first neoplasms (P for trend <.0001) and for infections (P < .0001); declines in relative mortality from second neoplasms and cardiovascular causes were less pronounced (P = .1105 and P = .0829, respectively). PanCareSurFup is the largest study with the longest follow-up of late mortality among European childhood and adolescent cancer 5-year survivors, and documents significant mortality declines among European survivors into modern eras. However, continuing excess mortality highlights survivors' long-term care needs.

Primary immunodeficiencies, autoimmune hyperthyroidism, coeliac disease and systemic lupus erythematosus in childhood immune thrombocytopenia.

AIM: To evaluate the cumulative prevalence of coeliac disease, systemic lupus erythematosus, autoimmune hyperthyroidism and primary immunodeficiencies in children with either newly diagnosed/persistent or chronic immune thrombocytopenia (ITP). METHODS: Monocentric retrospective analysis of the clinical and biochemical features of 330 consecutive patients with ITP referred to our Pediatric Hematology Unit between January 2009 and December 2018. RESULTS: The prevalence of systemic lupus erythematosus (0.3%), coeliac disease (0.3%) and autoimmune hyperthyroidism (0.6%) was not increased compared to general paediatric population. Of note, the prevalence of underlying primary immunodeficiencies was 2.4%, remarkably higher than the general paediatric population (P = .005). All the patients diagnosed with immunodeficiency developed either bi-/trilinear cytopenia or splenomegaly. CONCLUSION: Whilst autoimmune and immunological screening is already recommended at the onset of immune thrombocytopenia, we recommend that primary immunodeficiencies be regularly screened during follow-up, especially in case of additional cytopenia or lymphoproliferation.

Thrombocytopenia and Cornelia de Lange syndrome: Still an enigma?

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder caused by mutations in the cohesion complex and its regulators. The syndrome is characterized by multiple organ system abnormalities, pre- and post-natal growth retardation and typical facial features. Thrombocytopenia is a reduction in platelet count to <150 × 10(9) L. It can be caused by congenital or acquired decreased production, increased destruction, or sequestration of platelets. In recent years, several papers reported thrombocytopenia and immune thrombocytopenia in patients affected by CdLS. In 2011, Lambert et al. estimated the risk of idiopathic thrombocytopenia purpura in CdLS patients to be 31-633 times greater than in the general population. We describe the incidence of thrombocytopenia in 127 Italian CdLS patients, identifying patients with transient or persistent thrombocytopenia, but a lower incidence of true idiopathic thrombocytopenic purpura (ITP).

Adolescents with Cancer in Italy: Improving Access to National Cooperative Pediatric Oncology Group (AIEOP) Centers.

This analysis compared the numbers of patients treated at Italian pediatric oncology group (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]) centers with the numbers of cases predicted according to the population-based registry. It considered 32,431 patients registered in the AIEOP database (1989-2012). The ratio of observed (O) to expected (E) cases was 0.79 for children (0-14 years old) and 0.15 for adolescents (15-19 years old). The proportion of adolescents increased significantly over the years, however, from 0.05 in the earliest period to 0.10, 0.18, and then 0.28 in the latest period of observation, suggesting a greater efficacy of local/national programs dedicated to adolescents.

[The contribution of the Italian Association of paediatric haematology and oncology (AIEOP)]. / Il contributo dell'Associazione italiana di ematologia e oncologia pediatrica (AIEOP).

Since 1972, children affected by cancer took advantage from multi-centric diagnostic and therapeutic protocols produced by the Italian Association of paediatric haematology and oncology (AIEOP). At the beginning, these protocols were used in few well-trained centres, later in almost all Italian haemato-oncological centres. The need of a careful monitoring of his own activity induced AIEOP to achieve, in 1989, an Italian hospital- based registry (database Mod.1.01) of malignant tumours diagnosed and treated in the participating centres, with the aim to quantify the number of cases diagnosed and treated in the different centres, the agreement (or not) to official diagnostic- therapeutic protocols, and the extraregional migration. The database Mod.1.01, which is available via web to the current 55 AIEOP centres since 2000, recruits annually about 1,400 children (0-14 years) and 200 adolescents (15-19 years). While the first accounts for over 90% of expected subjects, the latter are only 25%. Leukaemias (30% of cases) are the most frequent childhood cancers, followed by central nervous system (CNS) tumours and lymphomas, 18% of cases both. In children, leukaemias (34%) are prevalent, mostly acute lymphoblastic leukaemia (26%), followed by CNS tumours (18%); in adolescents, lymphomas (30%) are prevalent, mostly Hodgkin lymphomas (22%), followed by bone sarcomas (16%). The recruitment of registered cases in AIEOP protocols is overall good both for children (70%) and for adolescents (60%), achieving outstanding results in leukaemia protocols. Extraregional migration of patients for diagnosis and therapy is decreasing over time, being currently about 20%, higher in adolescents, in solid tumours, and in residents in South Italy and in the islands. On the contrary, an increase of subjects born and resident abroad who are hospitalised in AIEOP centres for diagnosis and treatment, accounting at present for 5% of all cases, was observed. The results confirm that the database Mod.1.01 can be a valid tool able to contribute to epidemiologic research on childhood cancer in Italy.

Practices of pediatric oncology and hematology providers regarding fertility issues: a European survey.

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.

ITP-QoL questionnaire for children with immune thrombocytopenia: Italian version validation's.

BACKGROUND: The ITP-QoL is a disease-specific questionnaire for the assessment of health-related quality of life (HRQoL) in children with immune thrombocytopenia (ITP) and their parents. The aim of this study was to test the psychometric characteristics of the ITP-QoL in the Italian pediatric population in terms of validity and reliability. PROCEDURE: Children aged 8-16 years with acute or chronic ITP and their parents were recruited in Italy. Participants completed the ITP-QoL together with other patient-reported outcomes (PROs). Reliability was calculated using Cronbach's alpha. Convergent validity was determined by means of the Pearson correlation coefficients. RESULTS: A total of 91 ITP patients, mean age of 12.11 ± 2.47 years, and their parents participated; 61.5% of the patients were female. Two patients had acute ITP and 30.2% had a moderate to severe status of ITP. Cutaneous symptoms were more frequent than mucosal symptoms. Due to item and scale analyses 20 items were deleted from the original ITP-QoL. Internal consistency of the ITP-QoL was found to be good with Cronbach's alpha exceeding α = 0.70 for all but one subscale. Concerning convergent validity "moderate" to "high" negative correlations were found between ITP-QoL and KINDL subscales. The ITP-QoL was able to discriminate between clinical subgroups such as number of days lost at school due to ITP and hospitalization. CONCLUSIONS: Our study was able to demonstrate that the Italian version of ITP-QoL (for children aged 8-16 years) is a valid and reliable instrument for the assessment of HRQoL in children with ITP.

Surviving childhood leukemia in a Latin culture: an explorative study based on young adults' written narratives.

This study investigated memories of childhood leukemia conveyed by survivors belonging to a Latin culture, exploring whether benefit findings was spontaneously reported, as by non-Latin survivors. Three hundred patients previously treated for leukemia were contacted by post/e-mail and asked to write freely about their illness experience. The 106 letters received were analyzed for narrative structure and content, according to a grounded theory approach. Participants expressed most of the themes conveyed by childhood cancer survivors in non-Latin countries, and benefit finding was spontaneously reported. To the latter, the usefulness of creating and maintaining personal narratives on cancer experience, sustained by health care professionals, is discussed.

The effects of propofol and ketamine on the cytokine levels of children with acute lymphoblastic leukemia.

The immune system of children with acute lymphoblastic leukemia (ALL) is affected by both the underlying disease and the chemotherapy. Children with ALL receive sedation for diagnostic and therapeutic procedures, which may contribute to immune competence alteration. The effects of propofol-ketamine combination on the immune system of children with ALL have not been investigated. This cohort study was designed to assess the immunomodulatory activity of the propofol-ketamine combination on proinflammatory and anti-inflammatory cytokines of children with ALL undergoing painful procedures. We enrolled 20 children with ALL undergoing bone marrow aspiration (BMA) and lumbar puncture with methotrexate. All children received sedation with IV ketamine (0.5 mg/kg) and propofol (3±2 mg/kg). Plasma concentration of cytokines interleukin (IL)-1ß, IL-2, IL-6, IL-10, IL-8, IL-12p70, and interferon-γ before sedation for BMA was represented as T0, during lumbar puncture with methotrexate sedation 6 hours after T0 was represented as T1, and 24 hours after BMA was represented as T2. Sedation with propofol-ketamine combination did not modify the plasma concentration of the most measured cytokines and the T helper 1/2 ratio in children with ALL. There was a significant reduction in IL-8 concentration 24 hours after BMA associated with the concomitant administration of steroids and methotrexate. These data suggest that sedation with propofol-ketamine combination may not affect the immediate outcome of children with ALL.

Risk Factors for Heart Failure Among Pan-European Childhood Cancer Survivors: A PanCareSurFup and ProCardio Cohort and Nested Case-Control Study.

PURPOSE: Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines. METHODS: This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors. RESULTS: The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m2 had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses. CONCLUSION: Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m2 total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation).

BACKGROUND: Bernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbß, or GPIX and is typically inherited as a recessive disease. However, some years ago it was shown that the monoallelic c.515C>T transition in the GPIBA gene (Bolzano mutation) was responsible for macrothrombocytopenia in a few Italian patients. DESIGN AND METHODS: Over the past 10 years, we have searched for the Bolzano mutation in all subjects referred to our institutions because of an autosomal, dominant form of thrombocytopenia of unknown origin. RESULTS: We identified 42 new Italian families (103 cases) with a thrombocytopenia induced by monoallelic Bolzano mutation. Analyses of the geographic origin of affected pedigrees and haplotypes indicated that this mutation originated in southern Italy. Although the clinical expression was variable, patients with this mutation typically had a mild form of Bernard-Soulier syndrome with mild thrombocytopenia and bleeding tendency. The most indicative laboratory findings were enlarged platelets and reduced GPIb/IX/V platelet expression; in vitro platelet aggregation was normal in nearly all of the cases. CONCLUSIONS: Our study indicates that monoallelic Bolzano mutation is the most frequent cause of inherited thrombocytopenia in Italy, affecting 20% of patients recruited at our institutions during the last 10 years. Because many people from southern Italy have emigrated during the last century, this mutation may have spread to other countries.

Parent-child communication and psychological adjustment in children with a brain tumor.

BACKGROUND: Internalizing problems, anxiety, depression, withdrawal, and consequent social problems are frequently observed in children with brain tumors. The objective of this work is to describe the relationship between these psychological problems and the type of parent-child communication established about the disease. PROCEDURES: A group of 64 children surviving a brain tumor (aged 4-18 years) underwent psychological assessment by means of parent reports on the Child Behavior Checklist (CBCL) and the Vineland Adaptive Behavior Scales (VABS). A semi-structured interview with each child and their parents enabled us to classify the method of communication regarding the disease as "avoidance," "ineffective," and "effective." Demographic, clinical, and functional data relating to the disease were also collected. RESULTS: A significant relationship between the onset of Internalizing problems, withdrawal, anxiety-depression, and social problems and the presence of avoidance or ineffective communication about the disease was observed (P = 0.001, P = 0.001, P = 0.001, and P = 0.01, respectively). These psychological problems did not prove to be associated to demographic or clinical variables; however, they were found to be related to the children's residual functional problems. By contrast, the method of communication proved to be unrelated to clinical or functional variables, but it was associated to demographic variables such as sex and age at assessment. CONCLUSIONS: Effective (complete, truthful, consistent, comprehensible, gradual and continuous, and tailored) communication to the child about his/her condition proved to be associated with a better psychological outcome.