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Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8–21.5; P = 5.6 × 10−7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: OR: 2.4; 95% CI: 1.3–4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04–14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07–2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.

AIM: In the context of the Italian Multicentric Epidemiological Study on Risk Factors for Childhood Leukaemia and Non-Hodgkin's Lymphoma (SETIL), the risk of childhood cancer was investigated in relation to parental occupational exposures. METHODS: All cases of childhood leukaemia and non-Hodgkin's lymphoma (NHL) in children aged 0-10 years were identified. Controls were chosen at random from the local population in each region. Parents were interviewed using a structured questionnaire. The collected data were blindly reviewed by expert industrial hygienists in order to estimate exposure to a list of agents. Statistical analyses were performed for each agent using unconditional multivariable logistic regression models, taking into account timing of exposure. RESULTS: 683 cases of acute childhood leukaemia, 97 cases of NHL and 1044 controls were identified. Increased risk of childhood leukaemia was found for maternal exposure to aliphatic (OR 4.3) or aromatic hydrocarbons (OR 3.8) in the preconception period, and for paternal exposure to diesel exhaust (OR 1.4), lead exposure (OR 1.7) and mineral oils (OR 1.4)[corrected]. Risk of NHL appeared to be related to paternal exposure to oxygenated solvents (OR 2.5) and petrol exhaust (OR 2.2). CONCLUSIONS: We found increased risk for childhood leukaemia associated with maternal occupational exposure to aromatic and aliphatic hydrocarbons, particularly in the preconception period; increased risks were also observed for paternal exposure to diesel exhaust fumes, mineral oils and lead. The risk of NHL appeared to be related to paternal exposure to oxygenated solvent and petrol exhausts.

To evaluate the self-reported prevalence of poor adherence to recombinant human growth hormone (rhGH) therapy in a large, representative sample of Italian children and adolescents and to assess treatment and patient level correlates of poor adherence.The study was conducted in 46 pediatric centers throughout Italy. A questionnaire was administered to consecutive children/adolescents treated with rhGH or their parents. Eligible patients were represented by subjects aged between 6 and 16 years, of both sexes, on rhGH treatment for at least 6 months. The questionnaire was administered to the person in charge of preparing the injection. Multivariable logistic regression analysis was performed to identify factors independently associated with adherence.Overall, 1,007 children/adolescents were involved, of whom 24.4% missed 1 or more injections during a typical week and were thus considered as nonadherent. The most frequently reported reasons for missing a dose were being away from home (33.3%), forgetfulness (24.7%), not feeling well (12.9%), and pain (10.3%). Multivariable analysis indicated association between poor adherence and adolescence, low level of parent education, longer duration of treatment, need to convince the child to inject, and low level of awareness of the consequences of not properly following treatment. The likelihood of adherence markedly increased with higher levels of perceived device convenience.Poor adherence is still a major problem in the treatment of growth disorders. Increasing awareness and reassessment of treatment adherence on an annual basis should be part of clinical practice of pediatric endocrinologists involved with rhGH treatment.CI = confidence interval GH = growth hormone rhGH = recombinant human growth hormone.

Objectives Leukaemia is the most common cancer in children, but its aetiology is still poorly understood. We tested the hypothesis that traffic-related air pollution is associated with paediatric leukaemia because of chronic exposure to several potential carcinogens. Methods The Italian SETIL study (Study on the aetiology of lymphohematopoietic malignancies in children) was conducted in 14 Italian regions. All incident cases of leukaemia in children aged ≤10 years from these regions (period 1998–2001) were eligible for enrolment. Two controls per case, matched on birth date, gender and region of residence were randomly selected from the local population registries. Exposure assessment at birth residence included traffic indicators (distance to main roads and length of main roads within 100 m) and estimates of pollutants concentrations (particulate matter -PM 2.5 and PM 10 - and gases -NO 2 and O 3 -) from national dispersion model and land use regression models. The association between the exposure variables and leukaemia was assessed by logistic regression analyses. Results Participation rates were 91.4% among cases and 69.2% in controls; 620 cases (544 acute lymphocytic and 76 acute non-lymphocytic leukaemia) and 957 controls were included. Overall, when considering the residence at birth, 35.6% of cases and 42.4% of controls lived along busy roads, and the mean annual PM 10 levels were 33.3 (SD=6.3) and 33.4 µg/m 3 (SD=6.5), respectively. No association was found, and all ORs, independent of the method of assessment and the exposure windows, were close to the null value. Conclusions Using various exposure assessment strategies, air pollution appears not to affect the incidence of childhood leukaemia.

Purpose: Neuroblastoma (NB) is the most common extra-cranial paediatric solid tumour. Incidence peaks in infancy, suggesting a role of in-utero and neonatal exposures but its aetiology is largely unknown. The aim of the present study is to evaluate the association between maternal characteristics and perinatal factors with the risk of NB, using data from the SETIL database. Methods: SETIL is a large Italian population-based case-control study established to evaluate several potential cancer risk factors in 0-10 year olds. Information about maternal characteristics, reproductive history, environmental and occupational exposures during pregnancy, as well as newborns' characteristics were obtained using a structured questionnaire. Extremely low frequency magnetic field (ELF-MF) home exposure was measured. The study included 1044 healthy controls and 153 NB cases, diagnosed between 1998 and 2001. Results: A twofold risk was associated to exposure in pregnancy to chemical products for domestic work and to hair dye. The risk associated with the latter was higher among 0-17 month old children (OR. =. 5.5, 95%CI: 1.0-29.3). Risk was increased for children whose mothers had suffered work related exposure in the preconception period to solvents (OR. =. 2.0 95%CI: 1.0-4.1) and in particular to aromatic hydrocarbons (OR. =. 9.2, 95%CI: 2.4-34.3). No association was observed with ELF-MF exposure. A higher risk was found among children with congenital malformations (OR. =. 4.9, 95%CI: 1.8-13.6) or neurofibromatosis (2 cases and 0 controls, p=. 0.016). Conclusions: Our study suggests maternal exposure to hair dyes and aromatic hydrocarbons plays a role and deserves further investigation. The association with congenital malformations might also be explained by over-diagnosis.External exposure, in particular during and before pregnancy might contribute to NB occurrence.

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 aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology. Design and Methods We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios. Results During the follow-up period, 4,633 (77%) subjects had not married. The marriage O/E ratios were 0.56 (95% CI: 0.51-0.61) and 0.70 (95% CI: 0.65-0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95% CI: 0.53-0.62) overall, and 1.08 (95% CI: 0.99-1.17) when analyses were restricted to married/cohabiting women Conclusions Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood. ©2011 Ferrata Storti Foundation.

Background The association of childhood leukemia with traffic pollution was considered in a number of studies from 1989 onwards, with results not entirely consistent and little information regarding subtypes. Aim of the study We used the data of the Italian SETIL case-control on childhood leukemia to explore the risk by leukemia subtypes associated to exposure to vehicular traffic. Methods We included in the analyses 648 cases of childhood leukemia (565 Acute lymphoblastic–ALL and 80 Acute non lymphoblastic-AnLL) and 980 controls. Information on traffic exposure was collected from questionnaire interviews and from the geocoding of house addresses, for all periods of life of the children. Results We observed an increase in risk for AnLL, and at a lower extent for ALL, with indicators of exposure to traffic pollutants. In particular, the risk was associated to the report of closeness of the house to traffic lights and to the passage of trucks (OR: 1.76; 95% CI 1.03–3.01 for ALL and 6.35; 95% CI 2.59–15.6 for AnLL). The association was shown also in the analyses limited to AML and in the stratified analyses and in respect to the house in different period of life. Conclusions Results from the SETIL study provide some support to the association of traffic related exposure and risk for AnLL, but at a lesser extent for ALL. Our conclusion highlights the need for leukemia type specific analyses in future studies. Results support the need of controlling exposure from traffic pollution, even if knowledge is not complete.

Aplastic anemia (AA) is a rare disease with a major autoimmune pathogenetic component. CTLA4 is a T-lymphocyte surface molecule involved in the maintenance of immune tolerance. Some polymorphisms associated with a reduced expression of CTLA4, and thus presumably with increased tendency to autoimmunity, have been associated with various autoimmune diseases. In this study, we evaluated the distribution of the low expression polymorphisms -318C > T and 49A > G of CTLA4 in a population of 67 patients with acquired AA and in 100 normal controls. There was no difference in the distribution of the tested polymorphism between patients and controls and, within the patient group, between those who responded to immunosuppression vs those who did not respond. This study indicates that the polymorphisms -318C > T and 49A > G of CTLA4 do not affect the risk of developing AA and do not influence the response to immunosuppression.

The genetic aetiology and the molecular mechanisms that characterize high‐risk neuroblastoma are still little understood. The majority of high‐risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients’ datasets and in 20 neuroblastomas analysed by qRT‐PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non‐coding region with response chemotherapy in 121 Italian patients with high‐risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P = .02) and with decrease PARP1 mRNA levels in NB cell line (P = .003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high‐risk NB.

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.

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).

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.

The impact of bone marrow (BM) GD2-positive cells on survival has been evaluated in 145 Italian children with localised neuroblastoma (NB) evaluated at diagnosis by anti-GD2 immunocytochemistry. Nineteen of these (13.1%) were found to be BM GD2-positive, with the number of positive cells ranging between 1 and 155 out of 1 x 10(6) total cells analysed. Seven/19 (38.8%) GD2-positive vs 12/126 (9.5%) GD2-negative patients relapsed. The 5-year event-free survival (EFS) and overall survival of the GD2-positive patients was significantly worse than that of the GD2-negative ones (62.2 vs 89.9%, P0.001; and 74.9 vs 95.9%, P=0.005, respectively). GD2 positivity was not associated to other known risk factors, and in particular to Myc-N amplification and 1p deletion. Among Myc-N-negative patients, the EFS of those negative for both GD2 and 1p deletion was significantly better than in children positive for either one of these two markers (EFS=96.9 vs 66.0%, P0.001). In conclusion, GD2 positivity may represent a prognostic marker for patients with non-metastatic NB without Myc-N amplification, and its combination with genetic alterations might help identifying patients that require a more careful follow-up.

Background Aetiology of childhood leukaemia and childhood neoplasm is poorly understood. Information on the prevalence of risk factors in the childhood population is limited. SETIL is a population based case–control study on childhood leukaemia, conducted with two companion studies on non-Hodgkin Lymphoma (NHL) and neuroblastoma. The study relies on questionnaire interviews and 50 Hz magnetic field (ELF-MF) indoor measurements. This paper discusses the SETIL study design and includes descriptive information. Methods The study was carried out in 14 Italian regions (78.3% of Italian population aged 0–10). It included leukaemia, NHL and neuroblastoma cases incident in 0–10 year olds in 1998–2001, registered by the Italian Association of Paediatric Haematology and Oncology (AIEOP) (accrual over 95% of estimated incidence). Two controls for each leukaemia case were randomly sampled from the Local Health Authorities rolls, matched by gender, birthdate and residence. The same controls were used in NHL and neuroblastoma studies. Parents were interviewed at home on: physical agents (ELF-MF and ionizing radiation), chemicals (smoking, solvents, traffic, insecticides), occupation, medical and personal history of children and parents, infectious diseases, immunizations and associated factors. Occupational exposure was collected using job specific modules. ELF-MF was measured in the main rooms (spot measurement) and close to child’s bed (48 hours measurement). Results The study included: 683 leukaemia cases (87% ALL, 13% AnLL), 97 NHL, 155 neuroblastomas, and 1044 controls. ELF-MF long term measurements were obtained for 61.1% of controls and 81.6% of leukaemia cases; 8.8% of controls were exposed at over 0.1 microTesla (μT), 3.5% and 2.1% at respectively over 0.2 and 0.3 μT. 25% of controls’ fathers had smoked over 10 cigarettes/day during the year of conception, varying according to education and region. Maternal smoking was less common (71.4% did not smoke in pregnancy). Maternal passive smoking during pregnancy was reported by 31.2% of controls; the child’s passive smoking for 28.6%. Occupational exposure to solvents was estimated in 18.3% of controls’ fathers and 7.7% of mothers. Contact with public was more frequent among mothers (36.1%) than fathers (23.4%). Conclusions SETIL represents a data source on exposure of Italian children to a broad array of potential carcinogenic factors. Electronic supplementary material The online version of this article (doi:10.1186/s13052-014-0103-5) contains supplementary material, which is available to authorized users.

Background In children older than 1 year with localised unresectable neuroblastoma (NB), treatment strategies are heterogeneous according to the national groups. The objective of this phase III non-randomised study was to evaluate the efficacy of conventional chemotherapy followed by surgery. Patients and methods In the presence of surgical risk factors (SRF), six courses of chemotherapy alternating Carboplatin–Etoposide and Vincristin–Cyclophosphamide–Doxorubicin were given, and surgical resection was attempted after four. Survival analyses were performed using an intention-to-treat approach. The main objective was to achieve a 5-year survival over 80%. Results Out of 191 registered children, 160 were evaluable. There were 62.5% older than 18 months and 52.5% had unfavourable histology according to International Neuroblastoma Pathology Classification (INPC). Chemotherapy reduced the number of SRFs by one third. Delayed surgery was attempted in 86.3% of patients and was complete or nearly complete in 74%. The 5-year EFS and OS were 76.4% and 87.6% respectively, with significant better results for patients younger than 18 months or with favourable histology. Conclusion This strategy provides encouraging results in children older than 1 year or 12 months with localised unresectable NB without MYCN amplification. However, in children older than 18 months and with unfavourable histology, additional treatment is recommended.

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

Purpose To describe treatment, clinical course, and survival of a cohort of Italian patients with neuroblastoma. Patients and Methods The study includes data from 2,216 children (age 0 to 14 years) diagnosed between 1979 and 2005. Overall survival (OS) was analyzed by clinical and biologic features at presentation and periods of diagnosis: 1979 to 1984, 1985 to 1991, 1992 to 1998, and 1999 to 2005. The relative risk of second malignant neoplasm (SMN) was assessed by the standardized incidence ratio (SIR), with the Italian population selected as referent. Results Yearly patient accrual increased over time from 58 to 102. Patients age 0 to 17 months represented 45.6% of the total population, and their incidence increased over time from 36.5% to 48.5%. The incidence of stage 1 patients increased over time from 5.8% to 23.2%. A total of 898 patients (40.5%) developed disease progression or relapse, 19 patients developed SMN, and two patients developed myelodysplasia. The cumulative risk of SMN at 20 years was 7.1%, for an SIR of 8.4 (95% CI, 5.1 to 13.2). A total of 858 patients (39%) died (779 of disease, 71 of toxicity, six of SMN, and two of tumor-unrelated surgical complications). Ten-year OS was 55.3% (95% CI, 53.0% to 57.6%) and increased over time from 34.9% to 65.0%; it was significantly better for females and patients age 0 to 17 months at diagnosis, with extra-abdominal primary, and stage 1 and 2 disease. OS improved significantly over time in stage 1 and 3 patients. In patients with stage 4 disease, the improvement occurred between the first and second time cohorts (6.7% v 23.5%), but not afterward. Conclusion The outcome of children with neuroblastoma has progressively improved. Long-term survivors bear a significant risk of SMN.

The Italian Neuroblastoma Registry was investigated to describe 781 children with neuroblastoma experiencing tumour recurrence (424 progressions and 357 relapses). Ten-year overall survival (OS) was 6.8% (95% confidence interval (CI) 4.3-10.0) after progression and 14.4% (95% CI 10.5-18.9) after relapse. For both circumstances, OS was better for age at diagnosis

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

Neuroblastoma occurring as a disseminated disease in children has a poor prognosis. Haematogenous metastases usually involve the marrow, bone, liver and skin. A second neoplasm may also develop. We describe a child with retroperitoneal neuroblastoma (stage 3) who developed a nodular mass in the inguinal area which was suspected to be a metastasis. Histopathology disclosed an angiomatoid (malignant) fibrous histiocytoma, and excision was curative. The occurrence of angiomatoid (malignant) fibrous histiocytoma as a second tumour in a patient with neuroblastoma has not previously been reported.

To the Editor. — The Italian Multicentric Study on Long-Term Survivors of Childhood Cancer provides support to the hypothesis discussed in the important article by Zebrack et al1 that using siblings as a control group may underestimate the level of psychological distress among survivors. We recruited all survivors aged 18 to 35 years treated for childhood cancer (brain tumors excluded) in the 3 Italian Pediatric Research Institutes: Burlo Garofolo (Trieste), Giannina Gaslini (Genova), and Bambino Gesu (Rome). Controls were selected among siblings or other relatives or friends of the cases; when no such control was available, a search was carried out in the same area of residence of the case through random digit dialing. Controls were also matched to cases for age (± 3 years) and if possible gender. Data collection was carried out in 2001 through a structured telephone questionnaire. A total of 501 cases and 501 controls agreed to be interviewed (response rate 89% and 94%, respectively). All respondents were asked about their health status, feelings of depression or anxiety (current, chronic/recurrent, in the past only, or …