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Purpose: This study aimed to compare health behaviors between the childhood cancer survivors (CCS) and their sibling controls and to examine the pattern of health behaviors of the Hong Kong Chinese CCS and its associations with their health-related quality of life and psychological distress. Methods: A cross-sectional telephone survey was conducted. A total of 614 CCS and 208 sibling controls participated in this study. Patterns of health behaviors including lifestyle behaviors, cancer screening practices, and insurance coverage were compared. Multivariate regression analyses were performed for examining factors associated with health behaviors in CCS. Results: CCS had less alcohol consumption when compared with their sibling controls (adjusted odds ratio (AOR) = 0.65, p = 0.035). The sibling controls were more likely to have cancer screening practices (AOR = 0.38, p = 0.005) and health (AOR = 0.27, p &lt, 0.001) and life insurance coverage (AOR = 0.38, p &lt, 0.001). Among the CCS, those who were male, having a job or higher education, shorter time since diagnosis, and type of cancer suffered were significantly associated with alcohol consumption. Those CCS who were drinkers indicated poorer mental health (p = 0.004) and more psychological distress. Female CCS undertaking cancer screening were more likely to be employed, married/cohabiting, and have received intensive cancer treatment. Conclusion: This study reveals that Chinese childhood cancer survivors are less likely to engage in unhealthy lifestyle behaviors, insurance coverage and cancer screening, when compared with their siblings. Implications for Cancer Survivors: It is crucial for healthcare professionals to identify strategies or target interventions for raising CCS&rsquo, s awareness of their cancer risks and healthy lifestyle throughout their life.

Background We sought to assess myocardial iron load and fibrosis, which may potentially affect cardiac function, in adult survivors of childhood leukemias and their relationships with left (LV) and right ventricular (RV) function. Procedure Fifty-eight (33 males) adult survivors, aged 24.5 ± 4.4, underwent cardiac magnetic resonance (CMR) at 16.6 ± 5.8 years after completion of treatment. Myocardial iron load and fibrosis were quantified using respectively T2* scan and late gadolinium enhancement. Right and left ventricular ejection fraction (EF) was measured by CMR, while myocardial function was assessed using tissue Doppler imaging. Results None of the survivors had significant myocardial iron overload (T2* 0.05). Conclusion Ventricular fibrosis may occur in long term survivors of childhood leukemias and is related to diastolic function in the absence of significant myocardial iron overload. Pediatr Blood Cancer 2015;62:698–703. © 2015 Wiley Periodicals, Inc.

Background Several trials incorporating adjuvant focal RT for treatment of young children with ependymoma have demonstrated improved survival with acceptable adverse effects. The optimal timing of RT administration is, however, unknown. Procedure A retrospective review of territory-wide database was performed to identify pediatric patients with ependymoma diagnosed between 1995 and 2011. OS and EFS were compared between patients receiving upfront RT (

Background and purpose Previous literatures on young adult survivors of childhood cancer show inconsistent findings with regards to their psychological distress and health-related quality of life (HRQOL). Much of the available data focus on negative patient outcomes following cancer treatments prescribed from 1970 to 1990. In the present study, HRQOL and psychological distress of young adult survivors in Hong Kong was examined. It focused on subjects who had received cancer treatments prescribed in the last two decades. Methods A structured telephone survey was conducted with 614 eligible survivors and 208 sibling controls in Hong Kong. Results The survivors reported significantly lower mean scores in physical role and functioning, whereas their mental, social, and psychological well-being was similar to that of their sibling controls. Being female, older age, longer survival time, and specific cancer diagnoses were the factors associated with poorer physical and mental adaptation. HRQOL was negatively correlated with psychological distress. Conclusions Findings of the study suggest that most survivors adjusted fairly well in mental, psychological, and social aspects. Survivors with a higher risk of poor HRQOL could benefit from appropriate screening and counseling at an early stage to mitigate their survivorship difficulties. Prospective follow-up studies on childhood cancer survivors are recommended to detect changes over longer survival periods. Copyright © 2013 John Wiley & Sons, Ltd.

This study sought to characterize the range of oral symptoms and affect upon quality of life reported by pediatric and adolescent patients in relation to the severity of oral mucositis and symptom burden during chemotherapy. A multicenter study included 140 patients between 6 and 18 years of age who had been treated with chemotherapy. Participants completed the self-report Mouth and Throat Soreness-related Questions of the Oral Mucositis Daily Questionnaire (OMDQ) for 14 days and the Oral Mucositis-specific Quality of Life Measure (OMQoL) at baseline, day 7, and day 14. The incidences of non-severe and severe mucositis were 23% (n = 32) and 18% (n = 25), respectively. The symptoms reported by the patients with oral mucositis were related to eating (82.4%), swallowing (78.9%), drinking (75.4%), sleeping (71.9%), and talking (43.9%). Approximately 39% (22 out of 57) of patients with mucositis reported at least two simultaneous symptoms resulting from oral mucositis. About a quarter of them (25%, 14 out of 57) reported having all five symptoms concurrently. The mean area under curve (AUC) scores for symptom severity were significantly higher in the severe mucositis group (mean 0.95 to 1.21; 95% CI 0.76 to 1.34) compared with the non-severe (mean 0.50 to 1.06; 95% CI 0.35 to 1.30) and the without mucositis (mean 0 to 0.09; 95% CI 0 to 0.12) groups (p

There is a dearth of studies with respect to oral mucositis (OM) in the paediatric and adolescent populations. The purpose of this prospective cohort study was to examine the incidence and risk factors associated with OM in paediatric and adolescent patients receiving chemotherapy. OM assessments were made daily until 14 days after chemotherapy using the self-report Mouth and Throat Soreness-Related Questions of the Oral Mucositis Daily Questionnaire (OMDQ MTS). Potential risk factors included age, gender, prior OM, anxiety level, cancer diagnosis, nausea/vomiting, use of growth factor, neutrophil count, liver enzymes, and creatinine value. Multiple logistic, Cox proportional hazards, and ordinal regression analyses were used to determine risk factors for the incidence and time to onset of MTS scores of ⩾2, and MTS scores across 14 days by AUC categories, respectively, after adjusting for chemotherapy. A total of 140 patients who were 6–18 years of age were evaluated. Forty-one percent (95% CI, 32.6–48.8%) developed OM; of these, 23% and 18% reported a maximum MTS score of 2 and 3–4 as the worst OM, respectively. The mean time to onset of OM was 4.7 ± 2.7 days with a mean duration of 6.3 ± 4 days. Prior OM (RR 1.90–3.94), a higher level of anxiety (RR 1.27–1.46), WHO grade 1–2 (RR 1.86–4.59) and 3–4 (RR 3.08–9.19) neutropenia were significantly associated with a higher probability of the incidence, earlier onset, and greater severity of OM, after controlling for chemotherapy (p < 0.01). OM was associated with indirect cytotoxicity, prior OM, and anxiety level after controlling for chemotherapy where neutropenia was found to be the most important factor.

A Chinese girl presented with generalized papular rash and monocytic leukemia 19 days after birth. Cytogenetic analysis showed t(8;16)(p11.2;p13.3) as the sole chromosomal abnormality. Spontaneous regression of the leukemia was observed after 2 months, although the t(8;16) translocation persisted cytogenetically. This was followed 7 months later by the development of acute myeloid leukemia with maturation and cytogenetic evolution with extra chromosomes 4 and 8. Molecular study showed that the reciprocal MYST3 and CREBBP gene fusion characteristic of t(8;16) translocation persisted throughout the clinical course, even during spontaneous regression of the neonatal leukemia, and after chemotherapy-induced remission of the subsequent acute myeloid leukemia. The genetic lesion only became undetectable at the molecular level at the age of 20 months. The possible role of MYST3 and CREBBP gene fusion in the pathogenesis of the leukemia is discussed.

Enhanced fetal hemoglobin (Hb F) production can partially compensate for the lack of adult hemoglobin (Hb A) in patients with β-thalassemia major or intermedia, and ameliorate the clinical severity of these diseases. To further elucidate factors governing Hb F levels, we evaluated demographic, clinical, laboratory, and genetic characteristics in 241 unrelated adult β-thalassemia carriers in Hong Kong. They had wide variations in Hb F and F-cell numbers skewing toward higher levels. Individuals who coinherited the Xmn IT-allele in the Gγ-globin gene promoter had higher Hb F and more F-cells compared with those lacking the Xmn I T-allele. However, both groups exhibited a similarly wide spread of Hb F and F-cells. The correlation of Hb F and F-cells corresponded well to both linear and exponential models, suggesting multiple mechanisms for Hb F augmentation. The heritabilities of Hb F and F-cells were calculated in 66 families (111 parents who were β-thalassemia carriers and 82 asymptomatic offspring) to be 0.7 to 0.9. The Xmn I polymorphism accounted for 9% of the Hb F and 13% of the F-cell heritabilities. These results suggest that these family members are well suited for genome wide association studies that will identify genetic loci regulating Hb F production, and likely novel pharmacological targets for reactivating Hb F production in adults. Am. J. Hematol., 2008. © 2008 Wiley-Liss, Inc.

Aims We tested the hypothesis that myocardial stiffness as assessed by diastolic wall strain (DWS) is altered in adult survivors of childhood leukaemias with preserved left ventricular (LV) ejection fraction and explored its association with myocardial fibrosis and diastolic deformation. Methods and results Ninety-four (53 males) adult survivors of childhood leukaemias aged 22.2 ± 5.5 years and 66 (36 males) healthy controls were studied retrospectively. Diastolic wall strain and calibrated integrated backscatter (cIB) were measured as indices of myocardial stiffness and fibrosis, respectively. Left and right ventricular (RV) diastolic and torsional mechanics were interrogated using speckle tracking echocardiography. Patients had significantly lower LV DWS, and hence stiffer LV myocardium, and greater myocardial cIB in patients than controls (all P < 0.001). Left ventricular longitudinal, radial, and circumferential early diastolic strain rates, circumferential late diastolic strain rate, and peak twisting and untwisting velocities, tricuspid annular early diastolic velocity, and RV-free wall longitudinal early diastolic strain rate were significantly lower in patients than controls (all P < 0.05). Diastolic wall strain correlated inversely with myocardial cIB, and positively with LV longitudinal, radial, and circumferential early diastolic strain rates (all P < 0.05), while myocardial cIB correlated inversely with LV radial and circumferential early diastolic strain rates, circumferential late diastolic strain rate, peak twisting and untwisting velocities, and tricuspid annular e velocity (all P < 0.05). Conclusion In adult survivors of childhood leukaemias, despite the preservation of LV ejection fraction, increased stiffness of the LV myocardium is evident and is associated with myocardial fibrosis and impaired ventricular diastolic function.

Four patients (age 3–11 years at diagnosis) with relapsed acute promyelocytic leukemia (APL), 12–38 months from diagnosis, were treated with oral arsenic trioxide (As2O3). One patient was treated with oral As2O3 monotherapy and chemotherapy. Three patients failed initial oral or intravenous As2O3 monotherapy were treated with oral As2O3 plus ATRA followed by long-term oral maintenance (cumulative As2O3 dose 280–2,100 mg). All patients achieved molecular remission, at a median follow up of 122 (10–132) months with no adverse effects. Oral As2O3, particularly in prolonged maintenance with oral ATRA may obviate the need of stem cell transplantation in relapsed pediatric APL. Pediatr Blood Cancer 2012; 58: 630–632. © 2011 Wiley Periodicals, Inc.

We sought to assess myocardial iron load and fibrosis, which may potentially affect cardiac function, in adult survivors of childhood leukemias and their relationships with left (LV) and right ventricular (RV) function.Fifty-eight (33 males) adult survivors, aged 24.5 ± 4.4, underwent cardiac magnetic resonance (CMR) at 16.6 ± 5.8 years after completion of treatment. Myocardial iron load and fibrosis were quantified using respectively T2* scan and late gadolinium enhancement. Right and left ventricular ejection fraction (EF) was measured by CMR, while myocardial function was assessed using tissue Doppler imaging.None of the survivors had significant myocardial iron overload (T2*20 msec). The prevalence of LV and RV fibrosis was 9% (5/58) and 38% (22/58), respectively. Left ventricular EF was subnormal (EF 45-55%) in 9% (5/58), while RV EF was abnormal (EF45%) in 12% (7/58) and subnormal in 34% (20/58) of survivors. Patients with LV fibrosis had significantly lower mitral annular early diastolic velocity (P = 0.01) and smaller LV end-systolic volume (P = 0.02), while those with RV fibrosis had significantly lower tricuspid late diastolic annular velocity (P = 0.02) and early to late diastolic annular velocity ratio (P = 0.02) compared to those without. Cumulative anthracycline dose correlated with early diastolic mitral (r = -0.28, P = 0.038) and tricuspid (r = -0.40, P = 0.002) annular velocities, but not LV and RV EF or fibrosis (all P 0.05).Ventricular fibrosis may occur in long term survivors of childhood leukemias and is related to diastolic function in the absence of significant myocardial iron overload.

BACKGROUND Renal tumors are one of the most common tumors in children. We aim at evaluating the characteristics and the outcome of Wilms tumor and other malignant kidney tumors in Hong Kong. PROCEDURE Between January 1990 to December 2010, 68 patients under the age of 18 with malignant renal tumors were diagnosed and received treatment in Hong Kong. Clinical records were updated regularly. Prognostic factors and survival rate were evaluated. RESULTS Fifty-four patients were diagnosed with Wilms tumor. The annual incidence was estimated to be 2.29 per million. The mean age was 38 months. Median follow-up was 9.2 years. The event-free survival and overall survival rate at 10 years were 85.2% and 92.6%, respectively. A pair of siblings with familial extrarenal Wilms tumor was included. Pulmonary metastasis did exhibit a significant difference in survival rate. Eight cases of clear cell sarcoma of the kidneys were reported and the survival rate was 100%. CONCLUSIONS The clinical characteristics and outcome of the patients diagnosed Wilms tumor were comparable with other developed countries. Relatively high proportion and excellent outcome were found in clear cell sarcoma of the kidneys.

The management of central nervous system tumors in children below the age of 3 years represents a special challenge to pediatric oncologists with distinctive epidemiology, treatment considerations, and prognosis. Population-based epidemiological data on this particular patient group is lacking in Chinese. We reviewed the population-based pediatric tumor registry in Hong Kong between 1999 and 2011. Eighty-one children with primary central nervous system tumors from 0 to 3 years of age were identified (annual incidence: 4.16 cases per 100,000). Forty-one (50.6%) were male and the mean duration of follow-up was 94 months (±8.1). Primary tumors were infratentorial in 43 (53.1%). The tumor types in decreasing frequency were astrocytoma (n=17), medulloblastoma (n=16), ependymoma (n=13), choroid plexus tumor (n=7), primitive neuroectodermal tumor (n=7), atypical teratoid rhabdoid tumor (n=6), germ cell tumor (GCT, n=5), craniopharyngioma (n=4), and ganglioglioma (n=3). Three patients presented antenatally. Treatment included surgery in 82.7%, chemotherapy in 50.6%, and radiotherapy in 25.9%. There were 29 deaths (35.8%) and 19 relapses (23.5%) during the review period with the 1-year overall survival (OS), 5-year OS, 1-year event-free survival (EFS), and 5-year EFS being 79.4% (±4.6), 63.5% (±5.9), 68.9% (±5.3), and 52.5% (±5.9), respectively. Significantly better OS and EFS were observed in patients who received gross total resection, but those with high-grade tumors, antenatal diagnosis, or atypical teratoid rhabdoid tumor/primitive neuroectodermal tumor had worse outcome. Survival did not differ with age. Comparison with statistics from other studies revealed higher rates of embryonal tumor, GCT, and craniopharyngioma in Hong Kong Chinese. Disease outcome appeared to be better in our cohort comparing to previous reports probably due to the higher proportion of GCT locally.

Several trials incorporating adjuvant focal RT for treatment of young children with ependymoma have demonstrated improved survival with acceptable adverse effects. The optimal timing of RT administration is, however, unknown.A retrospective review of territory-wide database was performed to identify pediatric patients with ependymoma diagnosed between 1995 and 2011. OS and EFS were compared between patients receiving upfront RT (150 days of diagnosis), delayed RT (≥150 days of diagnosis), or no RT.Thirty-one patients with intracranial ependymoma were identified. Median age was 3.5 years and 14 (45%) were male. Primary tumor was supratentorial in 10 (32%) and infratentorial in 21 (68%). All patients underwent initial surgery, with gross-total resection (GTR) in 27 (87%). Twelve (39%) received upfront RT, 10 (32%) had delayed RT and 9 (29%) had no RT. During the study period, there were 11 relapses (35%) and 10 deaths (32%). Five-year OS was 69.9% and 5yr-EFS was 49.3%. In univariate analysis, GTR led to improved OS (P 0.001) and EFS (P = 0.004); superior OS and EFS was observed in patients who received RT when compared with those without (P = 0.018 and 0.011, respectively). Upfront RT also resulted in better OS and EFS than delayed RT (P = 0.049 and 0.014, respectively). No significant effect on survival was observed with age, sex, tumor location, RT dosage, and protocol used. In multivariate analysis, GTR significantly improved OS (P = 0.002) and EFS (P = 0.004).Our results support the early initiation of adjuvant RT in the multi-modal management of pediatric ependymomas.

The purpose of this study is to determine the burden of the peak severity of oral mucositis and severity over time on selected clinical outcomes in paediatric and adolescent patients receiving chemotherapy.A multicentre study enrolled 140 patients between the ages of 6 and 18 years, who had been treated with chemotherapy and completed the self-report Mouth and Throat Soreness-related questions of the Oral Mucositis Daily Questionnaire for 14 days. Clinical data were collected from patients' medical records during the first 14 days after starting chemotherapy.Forty-one percent developed oral mucositis. Multiple linear regression analysis revealed that oral mucositis was significantly associated with an increased loss of baseline body weight, after controlling for nausea/vomiting (β = 0.34, p = 0.002). Multiple logistic regression analysis showed that severe mucositis was significantly associated with a higher probability of fluid replacement, after controlling for nausea/vomiting (adjusted OR = 12.8; 95 % CI = 2.7-61.0; p = 0.001). In addition, severe mucositis was significantly associated with a higher probability of fever, after controlling for neutropoenia (adjusted OR = 5.4; 95 % CI = 1.8-15.4; p = 0.002). No difference was observed for oral or systemic infections among the subgroups. About 5 % of the patients with oral mucositis had delays in chemotherapy (≤ 7 days). None of the patients had dose modification or unplanned hospitalization due to oral mucositis. The associations of peak severity and overall oral mucositis with adverse clinical outcomes in paediatric and adolescent patients were equivalent.Oral mucositis is associated with negative effects on clinical outcomes.

Previous literatures on young adult survivors of childhood cancer show inconsistent findings with regards to their psychological distress and health-related quality of life (HRQOL). Much of the available data focus on negative patient outcomes following cancer treatments prescribed from 1970 to 1990. In the present study, HRQOL and psychological distress of young adult survivors in Hong Kong was examined. It focused on subjects who had received cancer treatments prescribed in the last two decades.A structured telephone survey was conducted with 614 eligible survivors and 208 sibling controls in Hong Kong.The survivors reported significantly lower mean scores in physical role and functioning, whereas their mental, social, and psychological well-being was similar to that of their sibling controls. Being female, older age, longer survival time, and specific cancer diagnoses were the factors associated with poorer physical and mental adaptation. HRQOL was negatively correlated with psychological distress.Findings of the study suggest that most survivors adjusted fairly well in mental, psychological, and social aspects. Survivors with a higher risk of poor HRQOL could benefit from appropriate screening and counseling at an early stage to mitigate their survivorship difficulties. Prospective follow-up studies on childhood cancer survivors are recommended to detect changes over longer survival periods.

Four patients (age 3-11 years at diagnosis) with relapsed acute promyelocytic leukemia (APL), 12-38 months from diagnosis, were treated with oral arsenic trioxide (As(2) O(3) ). One patient was treated with oral As(2) O(3) monotherapy and chemotherapy. Three patients failed initial oral or intravenous As(2) O(3) monotherapy were treated with oral As(2) O(3) plus ATRA followed by long-term oral maintenance (cumulative As(2) O(3) dose 280-2,100 mg). All patients achieved molecular remission, at a median follow up of 122 (10-132) months with no adverse effects. Oral As(2) O(3) , particularly in prolonged maintenance with oral ATRA may obviate the need of stem cell transplantation in relapsed pediatric APL.

Fetal hemoglobin (HbF) is regulated as a multigenic trait. By genome-wide association study, we confirmed that HBS1L-MYB intergenic polymorphisms (HMIP) and BCL11A polymorphisms are highly associated with HbF in Chinese β-thalassemia heterozygotes. In this population, the variance in HbF resulting from the HMIP is 13.5%; that resulting from the BCL11A polymorphism is 6.4%. To identify the functional variant in HMIP, we used 1000 Genomes Project data, single nucleotide polymorphism imputation, comparisons of association results across populations, potential transcription factor binding sites, and analysis of phylogenetic conservation. Based on these studies, a hitherto unreported association between HbF expression and a 3-bp deletion, between 135 460 326 and 135 460 328 bp on chromosome 6q23 was found. This 3-bp deletion is in complete linkage disequilibrium with rs9399137, which is the single nucleotide polymorphism in HMIP most significantly associated with HbF among Chinese, Europeans, and Africans. Chromatin immunoprecipitation assays confirmed erythropoiesis-related transcription factors binding to this region in K562 cells. Based on transient expression of a luciferase reporter plasmid, the DNA fragment encompassing the 3-bp deletion polymorphism has enhancer-like activity that is further augmented by the introduction of the 3-bp deletion. This 3-bp deletion polymorphism is probably the most significant functional motif accounting for HMIP modulation of HbF in all 3 populations. © 2011 by The American Society of Hematology., link_to_subscribed_fulltext

Osteosarcoma is the most common primary malignant bone tumor of children and adolescents. It often presents as a solitary lesion; multicentric osteosarcoma with synchronous lesions occurring at multiple skeletal sites is very rare. We report a 9-year-old boy with multicentric osteosarcoma who presented with a left retrobulbar non-sclerotic mass. The multiple lesions in bone were mostly non-sclerotic on radiological examination except for a single lesion in the left tibia. Biopsy of the retrobulbar mass showed an unclassifiable poorly differentiated malignant tumor. Marrow aspiration smears showed many large, often segregated, round cells that expressed NB84a. However, trephine biopsy showed the formation of tumoral osteoid by the malignant cells, finally permitting the definitive diagnosis of osteosarcoma to be made. A hypertetraploid clone with complex structural abnormalities was demonstrated by cytogenetic study.

We describe a 17-day-old newborn with fever and peripheral blood lymphocytosis. The circulating lymphocytes were large with lobulated and nucleolated nuclei. Their immature and uniform appearance raised the possibility of malignant lymphoma in the leukemic phase. Immunophenotypic study, however, showed that the lymphocytes were CD19+ B cells with expression of both κ and λ light chains. Molecular biology study confirmed a polyclonal nature of the immunoglobulin heavy-chain gene. Cytogenetic analysis showed a normal karyotype, and viral cultures and serologic studies yielded negative results. The polyclonal lymphocytosis was self-limiting and disappeared within a month.

Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? The hypothesis that protection of infants from exposure to infectious agents with delayed first exposure to one or more specific agents together contribute to the aetiology of childhood leukaemia, especially common acute lymphoblastic leukaemia (cALL), has substantial indirect support from descriptive epidemiology and case-control studies in developed Western countries. A case-control study of childhood leukaemia diagnosed at ages 2-14 years has now been conducted in Hong Kong. Cases (n = 98) formed a consecutive series of Chinese children diagnosed with acute leukaemia; controls (n = 228) were identified following a survey using random digit dialling and required to attend for medical examination by a paediatrician. Interviews with mothers were conducted in hospital by one trained interviewer using a structured questionnaire. Odds ratios (OR) and 95% confidence intervals (Cl) are reported for exposure variables capable of serving as proxies for exposure to infection in two critical time periods: first year of life, year before reference date (diagnosis for cases, corresponding date for controls). Analyses used logistic regression with adjustment for appropriate confounders. Change of area of residence reduced risk if during the first time period (OR = 0.47 [95% CI 0.23, 0.98]) and increased risk if during the second (OR = 3.92, [95% CI 1.47, 10.46]). Reported roseola and/or fever and rash in the first year of life reduced risk (OR = 0.33 [95% CI 0.16, 0.68]) whereas tonsillitis in the period 3-12 months before reference date increased risk (OR = 2.56 [95% Cl 1.22, 5.38]). Some other proxies for exposure to infection at the critical times were associated with predicted patterns of risk but day-care attendance failed to show predicted associations. These results provide support for the delayed exposure hypothesis in an affluent geographical setting in which population exposure to infectious agents is quite distinct from the settings of previous case-control studies.

A 21-month-old girl with hemoglobin Bart's hydrops received bone marrow transplantation (BMT) from a matched sibling. No major BMT-related complications developed. Hemoglobin levels remained greater than 10 gm/dl for 20 months without blood transfusion support despite the presence of residual host hemopoietic cells from 2 months after BMT. We suggest consideration of this therapeutic option for surviving patients.

Abstract 1013 More than 3% of Chinese in Hong Kong are heterozygous carriers of β-thalassemia. Homozygotes or compound heterozygotes for β-thalassemia are usually severely ill and require monthly transfusions. Increased production of fetal hemoglobin (HbF) can modulate the disease severity by compensating for the shortfall of HbA caused by the β-thalassemia mutations. HbF level in adults varies and is regulated as a multigenic trait. Three major HbF quantitative trait loci (QTL) have been identified: the C/T SNP also known as the Xmn I site at the Gγ-globin gene promoter, the BCL11A polymorphism on chromosome 2p16, and the HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23. The functional motif for each of these 3 QTLs responsible for their effects upon HbF is not known. We undertook a genome-wide association study (GWAS), using Illumina Human 610-Quad BeadChip array, on 619 Chinese β-thalassemia heterozygotes from Hong Kong. In this population, the variance in HbF due to HMIP is 13.5%, significantly higher than that due to BCL11A polymorphism (6.4%). We used 1,000 Genomes Project data, SNP imputation, comparisons of association results across populations, predicted binding of transcription factors, and phylogenetic conservation to identify the functional variant in HMIP. Based on these lines of evidence, a hitherto unreported association between HbF expression and a 3-bp deletion on chromosome 6q23 was found. In 335 Chinese β-thalassemia heterozygotes, the 3-bp deletion polymorphism is in complete linkage disequilibrium with rs9399137, the SNP found in multiple GWAS to be most significantly associated with HbF (P=1.4E-24 in the Chinese cohort GWAS). Flanking this deletion are conserved binding sites for TAL1/SCL1, E47, GATA, and RUNX1/AML1, which are essential erythropoiesis-related transcription factors. The 3-bp deletion changes the normal DNA binding configuration of these transcription factors and spatial configuration for DNA-protein binding and/or protein-protein interactions. Furthermore, this 3-bp deletion polymorphism resides within a likely erythroid distal regulatory region manifested by DNase I hypersensitivity and GATA-1 binding (Wahlberg et al, Blood 114:1254, 2009). We hypothesized that a 61-bp fragment of DNA that encompasses the site of the 3-bp deletion polymorphism might have enhancer-like activity. When ligated to the Gγ-globin gene 1.4 kb proximal promoter linked to a luciferase reporter gene, the 61-bp fragment of DNA enhances the Gγ-globin gene promoter activity by more than 3-fold after transient transfection into K562 cells. A 58-bp fragment of DNA that includes the 3-bp deletion has 60% more enhancer-like activity than the 61-bp fragment without the deletion. These findings suggest that this 3-bp deletion polymorphism is most likely the functional motif accounting for HMIP modulation of HbF. Further studies are needed to identify target genes for this enhancer-like activity mediated by the DNA sequences encompassing the 3-bp deletion polymorphism in HMIP. These studies also suggest that this experimental approach could be used to identify functional motifs in other genotype-phenotype association studies. Disclosures: No relevant conflicts of interest to declare.

Background: The use of magnetic resonance imaging (MRI) for organ specific iron assessment has allowed better tailoring of chelation therapy. Since endocrine failure is common in thalassemia major (TM) patients, we explored the utility of rapid T2* MRI assessment of hemosiderosis in the pancreas and pituitary. The results were correlated with standard T2* heart and liver MRI assessments and clinical data. Material and methods: A total of 180 TM patients (M:F = 91:89, median age, range 12–48) were scanned on a 1.5 T scanner. (Sonata, Siemens Medical, Erlanger, Germany). T2* myocardium was assessed by a cardiac gated single breath hold 8-echo sequence (CMRtools; London, UK). The T2* liver, pancreas and pituitary were performed by a breath hold 20-echo sequence. Subcutaneous deferoxamine was used for chelation, except for addition of deferiprone in 24 cases for 1 year. Results: There was a high incidence of hemosiderosis of heart (severe T2* Conclusions: MRI pituitary and pancreatic evaluation is viable in a cohort of poorly chelated Chinese thalassemia major patients on subcutaneous deferoxamine treatment. However, an abnormal cardiac T2* result is a good surrogate for endocrine iron overload and appeared more relevant in predicting endocrine complications.