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Objective To study the association among fertility treatments, treatment protocol, and offspring neoplasm risk up to the age of 18 years. Design A population-based retrospective cohort. Setting Soroka University Medical Center (SUMC), the single tertiary medical center and in vitro fertilization (IVF) unit in southern Israel. Patient(s) All offspring born at the SUMC between the years 1995 and 2018 after IVF treatment (the exposed group) and offspring conceived spontaneously (the unexposed group). Intervention(s) The study was performed at the SUMC, the single tertiary medical center and IVF unit in southern Israel. The exposed and unexposed were matched with a ratio of 1:4, based on maternal age and calendar month of delivery. Data collection included a summary of the couple’s medical records, delivery data, and offspring neoplasm diagnoses. Main Outcome Measure(s) Offspring neoplasm of any kind and time to diagnosis in each of the groups. Result(s) A total of 1,583 exposed and 5,874 offspring were included in the study. The incidences of offspring benign neoplasm were 14 (0.9%) versus 21 (0.4%), and the incidences of malignancies were 17 (1.1%) versus 29 (0.5%) among offspring of the IVF and spontaneous groups, respectively. The association between mode of conception and offspring neoplasm risk remained significant after adjusting for confounders, including mode of delivery and pregnancy complications such as hypertensive disorder, gestational diabetes mellitus, and preterm delivery compared with spontaneously conceived offspring. Among the IVF group, the increased risk for neoplasm was found among offspring who were transferred as fresh embryos, at an earlier stage of development (cleavage stage), or after three or more aspirated oocytes. Conclusion(s) IVF treatment is associated with offspring neoplasm risk; specifically, the risk was greater among offspring who were returned as fresh embryos, at an earlier embryotic stage (cleavage stage), or after three or more aspirated oocytes.

Highlights • The present study analyzed the diagnosis pattern of childhood malignant diseases using public health data and viral surveillance data in Korea. • The number of newly diagnosis showed the highest monthly average in January, and the lowest in September. • Seasonal trends were apparent in acute myeloid leukemia, Non-Hodgkin’s lymphoma, acute lymphoblastic leukemia and germ cell tumors. • In winter, significantly more patients were diagnosed with acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and Hodgkin’s lymphoma than in other seasons. • There was a temporal correlation with the diagnostic trends of several diseases and the prevalence of recent human parainfluenza virus., Background Several studies have reported a seasonal trend in the diagnosis of childhood cancer suggesting seasonal factors such as infection. The present study aimed to analyze the diagnosis pattern of childhood malignant diseases using public health data, and to compare this pattern with seasonal viral infection trends. Method Using the open data source of the Health Insurance Review and Assessment Service, we extracted data regarding all patients under 21 years of age and who had any cancer, aplastic anemia or myelodysplastic syndrome between September 2009 and December 2013. The positive detection rates of 11 viruses was collected from the surveillance data of Korea Centers for Disease Control and Prevention, and seasonality analysis were conducted with both data. Results In total, 9085 patients were diagnosed with malignant disease during the study period; there were about 175 new cases per month on average. Monthly stacked time series by year showed an apparent seasonal variation with the highest monthly average in January as 236, and the lowest in September as 120. In winter, significantly more patients were diagnosed with acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, and Hodgkin’s lymphoma than in other seasons. There was a temporal correlation with the diagnostic trends of several diseases and the prevalence of recent human parainfluenza virus. Conclusion This study tentatively suggests that the diagnosis of childhood malignancy follows a seasonal trend in Korea, and has a possible correlation with viral prevalence in several diseases. Further long-term analysis of epidemiological data is needed to explore possible causality.

Objective The aim of this study was to evaluate the association between maternal smoking during pregnancy and future risk of childhood neoplasm risk. Study design A population based cohort analysis comparing the risk for long-term childhood neoplasms in children born (1991–2014) to mothers that smoked during pregnancy vs. those that did not. Childhood neoplasms were pre-defined based on ICD-9 codes, as recorded in the hospital medical files. Children with congenital malformations and multiple gestations were excluded from the analysis. Kaplan-Meier survival curves were constructed to compare cumulative oncological morbidity over time. Cox proportional hazards model was used to control for confounders. Results 241,273 infants met the inclusion criteria; out of those 2841 were born to mothers that smoked during pregnancy. Offspring to smoking mothers had higher incidence of benign (OR 1.6, 95%CI 1.02–2.58; p value = .038) but not malignant tumors. Total cumulative neoplasm incidence was significantly higher in smoking women (Log Rank = 0.001) but no significant difference in the incidence of malignant tumors was noted (Log Rank = 0.834). In a Cox regression model controlling for maternal confounders; a history of maternal smoking during pregnancy remained independently associated only with increased risk for benign tumors (adjusted HR 2.5, 95%CI 1.57–3.83, p = .001). Conclusion Maternal smoking during pregnancy is associated with increased long-term risk for benign but not malignant tumors. This is important when counseling mothers regarding potential future risks and recommended lifestyle modifications. Despite this large population study with long follow-up, childhood malignancies are rare, and clarifying the possible association may require further studies.

Malignant rhabdoid tumor (MRT) is a highly aggressive childhood neoplasm and mainly presents in kidney and brain. We report the case of a patient with extrarenal extracranial MRT in the craniovertebral junction (CVJ). A 3-year-old boy presented with tetraparesis that had rapidly developed for 2 weeks. The tumor was located in the ventral side of the C1 and C2 extradural space and had invaded the lower clivus. The symptom recovered after subtotal resection of the tumor through a lateral approach with removal of bilateral lateral masses at C1 and instrumental occipital-C2 posterior fusion. Definite histological diagnosis of the extradural tumor was difficult; however, a metastatic lesion in the rib showed a proliferation of INI1/SMARCB1-negative spindle and rhabdoid cells, indicating the tumor was MRT. Stereotactic CyberKnife radiotherapy with a marginal dose of 26 Gy contributed to control of local regrowth of the tumor before histopathological confirmation and induction of chemotherapy with ifosfamide, cisplatin, and etoposide. The patient survived for 29 months without local recurrence of the tumor and with independent activity, however then died of multiple metastases. Treatment strategies for MRT in the CVJ should include an optimal surgical approach for reduction of tumor volume and stabilization of the spine, followed by high dose chemotherapy. Stereotactic radiotherapy may be useful for local control.

Genetic factors are important for developing primary and subsequent malignancies in children. This study investigated the role of genetic factors involved in DNA-repair. Designed as a feasibility study, it addressed the possibility of obtaining samples for genetic analyses from former patients through the German Childhood Cancer Registry. Testing feasibility was as important as the biological question itself. We analyzed the expression of DNA-repair genes in untreated primary fibroblasts of 20 individuals with a second neoplasm compared to 20 matched single neoplasm cases using customized cDNA microarrays (1344 gene sequences, about 800 genes). Matching was by first neoplasm, age, and year of first diagnosis. Forty-six percent of the 52 contacted second neoplasm cases and 18% of the 132 single neoplasm patients participated in the study. The DNA-repair gene results show small differences in the basal gene expression of FTH1 and CDKN1A. To our knowledge, this is the first study using gene expression arrays in untreated primary fibroblasts regarding second neoplasms after a childhood neoplasm. We were able to recruit childhood cancer patients for genetic analyses long after diagnosis. The biological importance of the differences in the DNA-repair gene expression has to be elucidated yet.

This population-based case–control study in Taiwan considered incident cases aged 15 years or less and admitted in 2003 to 2007 for all neoplasm (ICD-9-CM: 140–239) ( n = 2606), including 939 leukemia and 394 brain neoplasm cases. Controls were randomly selected, with a case/control ratio of 1:30 and matched on year of birth, from all non-neoplasm children insured in the same year when the index case was admitted. Annual summarized power (ASP, watt-year) was calculated for each of the 71,185 mobile phone base stations (MPBS) in service between 1998 and 2007. Then, the annual power density (APD, watt-year/km 2 ) of each township ( n = 367) was computed as a ratio of the total ASP of all MPBS in a township to the area of that particular township. Exposure of each study subject to radio frequency (RF) was indicated by the averaged APD within 5 years prior to the neoplasm diagnosis (cases) or July 1st of the year when the index case was admitted (controls) in the township where the subject lived. Unconditional logistic regression model with generalized estimation equation was employed to calculate the covariate-adjusted odds ratio [AOR] of childhood neoplasm in relation to RF exposure. A higher than median averaged APD (approximately 168 WYs/km 2 ) was significantly associated with an increased AOR for all neoplasms (1.13; 1.01 to 1.28), but not for leukemia (1.23; 0.99 to 1.52) or brain neoplasm (1.14, 0.83 to 1.55). This study noted a significantly increased risk of all neoplasms in children with higher-than-median RF exposure to MPBS. The slightly elevated risk was seen for leukemia and brain neoplasm, but was not statistically significant. These results may occur due to several methodological limitations.

Neuroblastoma is the most common extracranial solid tumor to occur during infancy and early childhood. However, primary renal neuroblastoma is rare, and only scattered case reports exist in the English medical literature. We report 8 cases that accumulated at our institution over the past 15 years and summarize their clinicopathologic features. The composite picture of a patient with renal neuroblastoma is that of a boy of 17 months of age, who presented with a large renal mass, about 9 cm in size, accompanied by hypertension. The mass was typically hemorrhagic, either encapsulated or unencapsuated, and infiltrating. A renal neuroblastoma can be undifferentiated, poorly differentiated, or differentiating; it falls into either the favorable or the unfavorable histology category, and presentation at higher stages is the rule. The N-myc is usually unamplified, and the bone marrow is usually not involved at presentation. Unless the tumor is undifferentiated or very poorly differentiated, patients with renal neuroblastoma fare well, although not without new and improved modalities of treatment. Primary renal neuroblastoma is perhaps more common than people realize; a higher level of awareness and early recognition are important for its prognosis and management, as they are very different from Wilms tumor.

Learning Objectives After completing this course, the reader will be able to: Appreciate the heterogeneity of neuroblastoma and identify clinical and biological prognostic factors. Explain the determinants and the clinical significance of the neuroblastoma risk stratification system. Select appropriate treatment regimens for neuroblastoma patients that are tailored according to risk stratification. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Neuroblastoma, a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behavior ranging from spontaneous remission to rapid tumor progression and death. To a large extent, outcome can be predicted by the stage of disease and the age at diagnosis. However, the molecular events responsible for the variability in response to treatment and the rate of tumor growth remain largely unknown. Over the past decade, transformation-linked genetic changes have been identified in neuroblastoma tumors that have contributed to the understanding of tumor predisposition, metastasis, treatment responsiveness, and prognosis. The Children's Oncology Group recently developed a Neuroblastoma Risk Stratification System that is currently in use for treatment stratification purposes, based on clinical and biologic factors that are strongly predictive of outcome. This review discusses the current risk-based treatment approaches for children with neuroblastoma and recent advances in biologic therapy.

Considerando que os tumores cerebrais correspondem à segunda neoplasia mais freqüente na infância, sendo apenas superados pelas leucemias, realizamos um estudo clínico prospectivo em setenta pacientes com tumor cerebral, com idade variando de um a quinze anos, por um período de quatro anos (1993-1997), através de acompanhamento ambulatorial. Avaliamos quarenta e um pacientes do sexo masculino e vinte e nove do sexo feminino. Observamos uma freqüência discretamente maior de tumores infratentoriais (38 casos) em relação aos de localização supratentorial (32 casos). O tumor mais freqüentimente observado foi o meduloblastoma (21 casos), seguido pelo astrocitoma (15 casos) e pelo germinoma (11 casos). No acompanhamento ambulatorial, observamos que 75,5% dos pacientes evoluíram com sequelas neurológicas. Em 34,3% houve recidiva tumoral e 21,4% dos pacientes evoluíram para óbito. Taken as proved that brain tumors are the second most frequent childhood neoplasm - only outnumbered by leukemias - we have undertaken a clinical perspective study with seventy brain tumor patients ranging from one to fifteen years of age, throughout a four-year period (1993-1997), based on ambulatory-oriented follow-up. Forty-one male and twenty-nine female patients were analyzed, in that a slightly higher number of infratentorial tumors was observed (thirty-eight cases), compared to those supratentorially located (thirty-two cases). The most repeatedly observed during the study was the medulloblastoma (twenty-one patients), followed by the astrocytoma (fifteen patients) and the germinoma (eleven patients). It should be pointed out that during the ambulatory follow-up 75,5% of patients developed neurological sequels. A tumor recurrence was noticed in 34,3% of them, while 21,4% eventually died. Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina University of Taubaté Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Department of Neurology and Neurosurgery Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Pediatric Neuro-oncology Division UNIFESP, EPM, Department of Neurology and Neurosurgery UNIFESP, EPM, Pediatric Neuro-oncology Division SciELO

Survival rates for childhood cancers were analyzed with a total of 2,209 cases who were registered in a population-based cancer registry in Osaka, Japan in 1975-1984. These cases were reclassified according to Birch's classification and the survival rate of each diagnostic group was calculated by Kaplan-Meier methods. Death certificate-only cases, which amounted to 3.9% of all incidence, were excluded from the calculation. The five-year cumulative survival rate for both sexes was 46% for all cancer children. Among 12 major diagnostic groups, the most favorable survival was seen in retinoblastoma (87.5%), followed by renal tumors, epithelial neoplasms, and gonadal and germ-cell tumors. The outcome was unfavorable in leukemias, sympathetic nervous system tumors, hepatic tumors and malignant bone tumors. Comparing the survival in 1975-1979 with that in 1980-1984, the rate for all childhood cancer rose from 41% to 51%. Improvement in survival was also observed in 4 groups; acute lymphocytic leukemia, acute non-lymphocytic leukemia, non-Hodgkin's lymphoma and osteosarcoma. One attributable factor for the rise of survival was proved to be improvement of medical treatment by Cox's hazard model analysis. Comparison of survival rates in Osaka with those in England and the U.S. revealed that the prognosis for acute lymphocytic leukemia and acute non-lymphocytic leukemia was less favorable in Osaka than in England and the U.S.

In 1971–1988, 4,021 malignant tumors occurring among children under 15 years of age were registered in the Osaka Cancer Registry, a population‐based registry which covers Osaka Prefecture, Japan. These patients were reclassified into 12 diagnostic groups by Birch's scheme using information on clinical diagnosis, histology and primary site. The annual age‐standardized incidence rate for childhood cancer per million children was 130.3 for males and 104.9 for females in 1971–88. Comparing the incidence rates for both sexes in 1981–88 with those in 1971–80 in Osaka, we observed a significant decrease of acute non‐lymphocytic leukemia (ANLL) and a significant increase of all cancers, acute lymphocytic leukemia, non‐Hodgkin lymphoma, sympathetic nervous system tumors, soft‐tissue sarcomas, and gonadal and germ‐cell tumors. Age‐standardized incidence rates in around 1971–80 of the above‐mentioned diagnostic groups were compared among 4 population‐based registries; Osaka, Miyagi (Japan), SEER (U.S.), and the National Registry of Childhood Tumors (England and Wales). Rates for ANLL and gonadal and germ‐cell tumors were higher and those for other diagnostic groups were lower in Osaka, especially for Hodgkin's disease. Thus, in 1980–88 in Osaka, rates for Hodgkin's disease remained low and rates for gonadal and germ‐cell tumors increased, though rates for other cancers appeared to resemble the levels in caucasian populations. The incidence of childhood cancer in Japan was estimated according to the diagnostic groups in Birch's scheme.

The majority of childhood cancer cases survive to adulthood. We describe the experience of marriage and reproduction as indicators of quality of life, in a population-based cohort of adult long-term survivors after early cancer reported to the Childhood Cancer Registry of Piedmont. The study included 1237 survivors with a malignant neoplasm diagnosed during 1967-2000 when aged 0-14 years, who attained age 18 years. Vital and marital status and number of offspring were assessed through the Vital Statistics Offices. Marriage and fertility deficits were estimated by comparison with the Piedmont population. Among the individuals included in this study, 919 (74.3%) never married and never lived as married. The marriage deficit was 32% [observed/expected 0.68; 95% confidence interval (CI): 0.55-0.83] in men and 18% (observed/expected 0.82; 95% CI: 0.68-0.98) in women. A total of 179 children were born to 120 women, with a fertility deficit of 41% (observed/expected 0.59; 95% CI: 0.51-0.69). In conclusion, the observed decrements in marriage in men and women and fertility in women suggest that efforts should be made to improve the recovery from physical and psychological traumas related to diagnosis and treatment of cancer.

We report a boy with acute lymphoblastic leukaemia (ALL) treated with chemotherapy and prophylactic cranial irradiation to a dose of 24 Gy. Six years after diagnosis he developed a glioma and died. Prior to 1979, four cases of second malignant neoplasm (SMN) of the brain had been reported in children treated for ALL. These SMNs occurred within 2 years of the original diagnosis (median 1.3 years) and at least two of four patients had not received prior radiotherapy. Since 1979, 28 cases of SMN of the brain have been reported including nine of 468 (1.9%) long-term survivors in one study. All occurred more than 3.7 years from diagnosis (median 6.5 years; range 4-13 years) and all received cranial irradiation (median 24 Gy; range 20-48 Gy). These data indicate a change in the pattern of SMNs which is most likely due to the introduction of cranial irradiation. As well, the frequency of SMNs in children treated for ALL appears to have increased, although it is still no greater than the risk of SMNs developing following the treatment of any other primary childhood neoplasm.

The aim of this study was to compare the characteristics of respondents and nonrespondents in a survey of childhood cancer survivors recorded in the Childhood Cancer Registry of Piedmont and their current primary care general practitioners. Eligible subjects were identified from the Childhood Cancer Registry of Piedmont and the referring general practitioners were traced through the National Health Service. A postal questionnaire was sent both to childhood cancer survivors and to their general practitioners. Prevalence odds ratios were estimated for demographic and clinical characteristics in survivors and for demographic characteristics in general practitioners. A total of 1005 childhood cancer survivors and 857 general practitioners (132 of them had two or more cancer survivors in care) were included in the study. Completed questionnaires were obtained from 691 survivors (69%) and 615 general practitioners (72%). For survivors, the only associations with nonresponse were for age 35-44 years [prevalence odds ratio: 0.53 (95% confidence interval: 0.33-0.85)], being married [prevalence odds ratio: 1.45 (95% confidence interval: 0.96-2.18)] and diagnosis after 1977 [prevalence odds ratio: 0.66 (95% confidence interval: 0.42-1.03)]. For general practitioners, the only associations were for male sex [prevalence odds ratio: 1.62 (95% confidence interval: 1.13-2.32)] and place of work outside of the city of Turin [prevalence odds ratio: 1.93 (95% confidence interval: 1.07-3.47)]; furthermore associations were relatively weak. An association was also found between nonresponse in survivors and nonresponse in their general practitioners [prevalence odds ratio: 3.40 (95% confidence interval: 2.54-4.56)]. In conclusion, apart from age, marital status and period of diagnosis, there were little differences between respondent and nonrespondents, for the considered clinical and demographical characteristics. Participation of survivors and their general practitioners correlated, suggesting that involvement of the general practitioners in the study may be a method to increase participation of survivors of childhood cancers.

Adrenal cortical carcinoma (ACC) is a rare childhood neoplasm that seldom manifests brain metastases; hence few papers in the literature focus on neurological manifestations associated with ACC. Although ACC is known to be a signature tumor type in several inherited cancer predisposition syndromes, particularly Li Fraumeni, ACC has not been previously associated with neurofibromatosis, type 1 (NF-1), an inherited disorder with frequent CNS lesions that might prompt concern for metastatic disease by neuroimaging studies. We present two pediatric patients with ACC and unusual CNS findings. The first child developed metastasis to the brain 4 years after resection of his adrenal primary and 2 and 1 years, respectively, after metastases to the liver and lungs. Soon after our experience with this patient, a girl with known NF-1 presented with virilization; adrenalectomy disclosed an ACC and systemic metastases were found within months. Disseminated disease prompted concern that her complex intracranial lesions identified by neuroimaging studies might represent brain metastases, but this proved to be NF1-related hamartomatous lesions. We review the literature on ACCs in pediatric patients regarding brain metastases and previous associations with NF-1.

Benign mullerian papilloma of the female reproductive tract is a rare childhood tumor that can easily be mistaken by those unfamiliar with the entity for botryoid rhabdomyosarcoma. Ultrastructural findings have been mentioned only in two individual case reports, and these both were issued many years ago. The aim of this update is to familiarize the reader with the clinical, light, and electron microscopic features associated with this distinctive entity, and thereby hopefully preclude the risk of making a serious diagnostic error. Two cases are illustrated, one very typical in its presentation and the other less so.

A rhabdomyosarcoma of the head and neck region is a rare childhood neoplasm often presenting with vague symptoms that can easily mimic other diseases. We present an unusual case of an alveolar rhabdomyosarcoma of the soft palate in a three-year-old child, that presented as a peritonsillar abscess.

Background The Childhood Cancer Registry of Piedmont (CCRP) started its activity in 1967. It is population based and covers the Piedmont Region (population 4,500,000; NW Italy). This article reports on time trends in survival after a childhood cancer diagnosed during 1970–1994. Procedure During 1970–1994, 2,329 incident cases were registered at CCRP on the basis of histological and/or clinical information, excluding 30 cases reported only by death certificate. Histological or hematological diagnosis was available for 2,067 cases. Vital status was assessed through the offices of the town of residence. At the end of follow-up, 1,202 cases were alive, 1,084 dead and 43 were not traceable. Survival was measured for the major diagnostic groups using both univariate and multivariate statistics. Results The 5-yr survival rate for acute lymphoblastic leukemia (ALL) improved regularly from 24.7% in 1970–1974 to 81.1% in 1990–1994, for acute nonlymphoblastic leukemia (ANLL) from 0% to 38.1%, for non-Hodgkin lymphoma (NHL) from 25.2% to 67.7%, for tumors of the central nervous system (CNS) (all types) from 33.4% to 75.9% and for Ewing tumor from 0% to 90%. Focusing on survival by period of diagnosis, the highest 5-year survival rate was observed for children diagnosed during 1985–1989 for medulloblastoma, neuroblastoma (NB), retinoblastoma, Wilms tumor, osteosarcoma, and rhabdomyosarcoma and for children diagnosed in 1990–1994 for the remaining sites. The trend over time was statistically significant for ALL, ANLL, NHL, CNS tumors, NB, and osteosarcoma as well as for all malignancies together. Conclusions Population-based survival studies are useful complements to clinical studies. Survival results in the present study are similar to those presented for other European countries and the United States. For most types of neoplasm (except CNS) survival probability appears to stabilize 5–10 years after diagnosis. Med. Pediatr. Oncol. 36:481–488, 2001. © 2001 Wiley-Liss, Inc.

Neuroblastoma, a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behavior, ranging from spontaneous remission to rapid tumor progression and death. To some extent, outcome can be predicted by the stage of disease and age at diagnosis. The molecular events responsible for the variability in response to treatment and rate of tumor growth, however, remain largely unknown. Over the past decade, transformation-linked genetic changes have been identified in neuroblastoma tumors that have contributed to our understanding of tumor predisposition, metastasis, treatment responsiveness, and prognosis. This review discusses the recent advances in the understanding of neuroblastoma at the cellular and molecular levels, and the role that tumor biology plays in determining appropriate risk-based treatment for patients with neuroblastoma.

Rhabdomyosarcoma of the head and neck is a rare childhood neoplasm. Most occur in the orbit, which accounts for the scarcity of papers on modern techniques of treatment of soft palate rhabdomyosarcomas. Only 30 cases of soft palate rhabdomyosarcoma have been reported in recent years and none had long-term follow-up periods (greater than 10 yr). This study reports three cases of pediatric soft palate rhabdomyosarcomas treated with surgery, radiotherapy (two of three), and chemotherapy. The complications that occurred in one patient are discussed.

A 2 1/2-year-old male child with rhabdomyosarcoma of the prostate was treated with radiation of the pelvis, consisting of 5,600 rads in 7 1/2 weeks, and combination chemotherapy of Vincristine and Actinomycin D. Surgery had been refused. The child is alive and disease-free more than 5 years after diagnosis, and over 2 years following the cessation of all therapy. Recent advances in radiotherapy and adjuvant chemotherapy have significantly improved the outlook in this aggressive childhood neoplasm and have made a less aggressive and less mutilating surgical approach often desirable. This, in turn, holds out the prospect of improved quality of survival in children so afflicted.