Clinical, neuroimaging, and behavioural risk factors for neurocognitive impairment in Chinese patients with haemophilia: A multicentre study.

BACKGROUND: Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia. OBJECTIVES: To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors. METHODS: We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong. A neurocognitive battery was administered to evaluate their attention, memory, processing speed and cognitive flexibility performances. They also underwent magnetic resonance imaging to identify cerebral microbleeds. Validated self-reported questionnaires were administered to assess their mental health status and adherence to prophylactic treatment. General linear modelling was used to investigate the association of neurocognitive outcomes with risks factors, adjusting for age and education attainment. RESULTS: Forty-two patients were recruited (median age 32.0 years; 78.6% haemophilia A; 80.9% moderate-to-severe disease). Six patients (14.3%) had developed cerebral microbleeds. A subgroup of patients demonstrated impairments in cognitive flexibility (30.9%) and motor processing speed (26.2%). Hemarthrosis in the previous year was associated with worse attention (Estimate = 7.62, 95% CI: 1.92-15.33; p = .049) and cognitive flexibility (Estimate = 8.64, 95% CI: 2.52-13.29; p = .043). Depressive (Estimate = 0.22, 95% CI: 0.10-0.55; p = .023) and anxiety (Estimate = 0.26, 95% CI: 0.19-0.41; p = .0069) symptoms were associated with inattentiveness. Among patients receiving prophylactic treatment (71.4%), medication adherence was positively correlated with cognitive flexibility (p = .037). CONCLUSION: A substantial proportion of patients with haemophilia demonstrated cognitive impairment, particularly higher-order thinking skills. Screening for cognitive deficits should be incorporated into routine care. Future studies should evaluate the association of neurocognitive outcomes with occupational/vocational outcomes.

Neurocognitive function, performance status, and quality of life in pediatric intracranial germ cell tumor survivors.

BACKGROUND: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. METHODS: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. Intracranial GCT survivors in Hong Kong aged ≥ 6 years who received cranial irradiation in the past 15 years were recruited. Neurocognitive function and performance status were assessed by the Hong Kong Wechsler Intelligence scale and Karnofsky/Lansky performance scales (KPS), respectively. Quality of life was assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales. A chart review was performed for tumor characteristics and complications related to the tumor and its treatment. RESULTS: Twenty-five intracranial GCT survivors were recruited. Longer length of time since treatment was associated with lower IQ scores. Larger tumor size was associated with lower KPS scores. Hemiparesis, poor manual dexterity, and complications with multi-organ involvement were associated with significantly lower KPS scores. Higher irradiation dosage was associated with lower PedsQL physical scores. CONCLUSIONS: The majority of GCT survivors had average intellectual functioning, satisfactory performance status and relatively good quality of life, except in the physical aspect. Comprehensive evaluation and long-term follow-up of GCT survivors are essential to provide timely support and improve long-term outcomes.

Acute Leukemia in Down Syndrome Children in Hong Kong: Retrospective Review.

BACKGROUND: Children with Down syndrome (DS) are at higher risk of developing acute leukemia. Treatment continues to evolve as we accumulate better understanding of the distinctive clinical and biological features of acute leukemia in DS patients. PROCEDURE: A retrospective review of the clinical features, treatment outcomes, and survival of DS children with acute leukemia in Hong Kong from 1993 to 2013 was conducted. Patients were identified from the registry of the Hong Kong Pediatric Hematology and Oncology study group. RESULTS: This cohort included a total of 29 patients with DS. Ten were diagnosed with acute lymphoblastic leukemia and 19 had acute myeloid leukemia (AML). The mean follow-up duration was 8.3 years (range, 0.6 mo to 18.1 y). The 5-year overall survival and event-free survival for DS-acute lymphoblastic leukemia and DS-AML were 65.6%, 54.9%, 89.5%, and 89.5%, respectively. CONCLUSIONS: The clinical characteristics and treatment outcomes of DS patients with acute leukemia in Hong Kong were comparable with results from other international study groups. Patients with DS-AML had a better prognosis.

Central nervous system tumors in chinese children under the age of 3: a population study.

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.

Timing of adjuvant radiotherapy and treatment outcome in childhood ependymoma.

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 (<150 days of diagnosis), delayed RT (≥150 days of diagnosis), or no RT. RESULTS: 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). CONCLUSIONS: Our results support the early initiation of adjuvant RT in the multi-modal management of pediatric ependymomas.

A 20-year prospective study of Wilms tumor and other kidney tumors: a report from Hong Kong pediatric hematology and oncology study group.

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.

Prognosis and outcome of relapsed acute lymphoblastic leukemia: a Hong Kong Pediatric Hematology and Oncology Study Group report.

BACKGROUND: In 2000, the Hong Kong Pediatric Hematology Oncology Study Group started a new relapsed acute lymphoblastic leukemia (ALL) treatment protocol based on modified ALL-REZ BFM 96 protocol aiming at improving the treatment outcome in Chinese children. PROCEDURE: All patients in Hong Kong with first relapse of childhood ALL were included. Patients were stratified into four risk groups (S1, S2, S3, and S4) and the treatment consisted of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation, if indicated. RESULTS: Fifty-six patients were recruited and median age at diagnosis of ALL was 4.6 (range, 0.3-17) years. The median time from initial diagnosis to relapse was 2.5 (range, 0.3-9.1) years and follow-up time was 2.7 (range, 0-9.9) years. Forty-nine patients (87.5%) achieved second complete remission (CR2). CR2 rates for S1, S2, S3, and S4 groups were 100%, 93%, 90%, and 67%, respectively. Five-year overall survival (OS) was 50.5 ± 6.9% and event-free survival (EFS) was 41.5 ± 7.1%. There was no significant difference in survival among S1, S2, and S3 groups but S4 patients performed significantly worse with 5-year OS and EFS of 8% and 0%, respectively. CONCLUSION: Children with relapsed ALL of S1-S3 risk groups could be successfully treated with intensified treatment protocol. The S4 high risk group needs more innovative approach to improve treatment outcome.

Hb A2 Hong Kong - A novel δ-globin variant in a Chinese family masks the diagnosis of ß-thalassemia trait.

A 42-year-old Chinese woman (FP) was the mother of a patient with ß-thalassemia major (ß-TM) due to a compound heterozygosity for ß(0)-thalassemia (ß(0)-thal) mutations. She was also found to have a low Hb A(2) level of 1.6% by high performance liquid chromatography (HPLC) despite being a heterozygous carrier of the codons 41/42 (-TCTT) (HBB:c.126_129delCTTT) ß(0)-thal mutation. Doubling the amount of hemolysate loaded for chromatography revealed a widened Hb A(2) peak and raised the level to 4.1%, consistent with ß-thal trait. Direct nucleotide sequencing detected a novel δ-globin gene mutation at codon 29 (HBD:c.89G>A), which leads to a glycine to aspartic acid substitution. A homologous mutation at codon 29 in the ß-globin gene [Hb Lufkin or ß29(B11)Gly→Asp] has been reported in Black families. This report highlights the importance of genotype-phenotype correlation and the potential pitfall of relying on Hb A(2) level for phenotypic diagnosis of ß(0)-thal trait.

A pictorial review of imaging of abdominal tumours in adolescence.

Neoplastic abdominal tumours, particularly those originating from embryonal tissue (such as hepatoblastoma and nephroblastoma) and neural crest cells (such as neuroblastoma), are well-documented in young children. Neoplasms of adulthood, most commonly carcinoma of different visceral organs, are also well-documented. Abdominal tumours in adolescence constitute a distinct pathological group. The radiological features of some of these tumours have been described only in isolated reports. The purpose of this pictorial essay was to review the imaging findings of various kinds of abdominal tumours in adolescent patients (with an age range of 10-16 years) who presented to the Children Cancer Center of our institution in the past 15 years. Some tumours, though rare, have characteristic imaging appearances (especially in CT) that enable an accurate diagnosis before definite histological confirmation.

Incidence and Outcomes of CNS Tumors in Chinese Children: Comparative Analysis With the Surveillance, Epidemiology, and End Results Program.

PURPOSE: Despite being the most common pediatric solid tumors, incidence and outcome of CNS tumors in Chinese children have not been systematically reported. We addressed this knowledge gap by comparing the epidemiology of pediatric CNS tumors in Hong Kong and the United States. PATIENTS AND METHODS: Data between 1999 and 2016 from a population-based cancer registry in Hong Kong, China, on patients < 18 years old with CNS tumors (Hong Kong cohort) and from the US SEER Program (Asian/Pacific Islander and all ethnicities) were compared. Incidence and overall survival (OS) by histology were evaluated. RESULTS: During the study period, 526 children were newly diagnosed with CNS tumors in Hong Kong (crude incidence rate, 2.47 per 100,000; 95% CI, 2.26 to 2.69). Adjusted incidences were significantly lower in the Hong Kong (2.51; 95% CI, 2.30 to 2.74) than in the SEER (Asian/Pacific Islander: 3.26; 95% CI, 2.97 to 3.57; P < .001; all ethnicities: 4.10 per 100,000; 95% CI, 3.99 to 4.22; P < .001) cohorts. Incidences of germ cell tumors (0.57 v 0.24; P < .001) were significantly higher, but those of glial and neuronal tumors (0.94 v 2.61; P < .001), ependymomas (0.18 v 0.31; P = .005), and choroid plexus tumors (0.08 v 0.16; P = .045) were significantly lower in Hong Kong compared with SEER (all ethnicities) cohorts. Compared with the SEER (Asian/Pacific Islander) cohort, histology-specific incidences were similar except for a lower incidence of glial and neuronal tumors in Hong Kong (0.94 v 1.74; P < .001). Among cohorts, OS differed only for patients with glial and neuronal tumors (5-year OS: Hong Kong, 52.5%; SEER [Asian/Pacific Islander], 73.6%; SEER [all ethnicities], 79.9%; P < .001). CONCLUSION: We identified important ethnic differences in the epidemiology of CNS tumors in Chinese children. These results will inform the development of pediatric neuro-oncology services in China and aid further etiologic studies.

Minimal residual disease-based risk stratification in Chinese childhood acute lymphoblastic leukemia by flow cytometry and plasma DNA quantitative polymerase chain reaction.

Minimal residual disease, or MRD, is an important prognostic indicator in childhood acute lymphoblastic leukemia. In ALL-IC-BFM 2002 study, we employed a standardized method of flow cytometry MRD monitoring for multiple centers internationally using uniformed gating, and determined the relevant MRD-based risk stratification strategies in our local patient cohort. We also evaluated a novel method of PCR MRD quantitation using peripheral blood plasma. For the bone marrow flow MRD study, patients could be stratified into 3 risk groups according to MRD level using a single time-point at day-15 (Model I) (I-A: <0.1%, I-B: 0.1-10%, I-C: >10%), or using two time-points at day-15 and day-33 (Model II) (II-A: day-15<10% and day-33<0.01%, II-B: day-15 ≥ 10% or day-33 ≥ 0.01% but not both, II-C: day-15 ≥ 10% and day-33 ≥ 0.01%), which showed significantly superior prediction of relapse (p = .00047 and <0.0001 respectively). Importantly, patients with good outcome (frequency: 56.0%, event-free survival: 90.1%) could be more accurately predicted by Model II. In peripheral blood plasma PCR MRD investigation, patients with day-15-MRD ≥ 10(-4) were at a significantly higher risk of relapse (p = 0.0117). By multivariate analysis, MRD results from both methods could independently predict patients' prognosis, with 20-35-fold increase in risk of relapse for flow MRD I-C and II-C respectively, and 5.8-fold for patients having plasma MRD of ≥ 10(-4). We confirmed that MRD detection by flow cytometry is useful for prognostic evaluation in our Chinese cohort of childhood ALL after treatment. Moreover, peripheral blood plasma DNA MRD can be an alternative where bone marrow specimen is unavailable and as a less invasive method, which allows close monitoring.

Molecular basis of von Hippel-Lindau syndrome in Chinese patients.

BACKGROUND: Von Hippel-Lindau (VHL) syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs. The genetic basis of VHL in Southern Chinese is largely unknown. In this study, we characterized the mutation spectrum of VHL in nine unrelated Southern Chinese families. METHODS: Nine probands with clinical features of VHL, two symptomatic and eight asymptomatic family members were included in this study. Prenatal diagnosis was performed twice for one proband. Two probands had only isolated bilateral phaeochromocytoma. The VHL gene was screened for mutations by polymerase chain reaction, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). RESULTS: The nine probands and the two symptomatic family members carried heterozygous germline mutations. Eight different VHL mutations were identified in the nine probands. One splicing mutation, NM_000551.2: c.463+1G > T, was novel. The other seven VHL mutations, c.233A > G [p.Asn78Ser], c.239G > T [p.Ser80Ile], c.319C > G [p.Arg107Gly], c.481C > T [p.Arg161X], c.482G > A [p.Arg161Gln], c.499C > T [p.Arg167Trp] and an exon 2 deletion, had been previously reported. Three asymptomatic family members were positive for the mutation and the other five tested negative. In prenatal diagnosis, the fetuses were positive for the mutation. CONCLUSIONS: Genetic analysis could accurately confirm VHL syndrome in patients with isolated tumours such as sporadic phaeochromocytoma or epididymal papillary cystadenoma. Mutation detection in asymptomatic family members allows regular tumour surveillance and early intervention to improve their prognosis. DNA-based diagnosis can have an important impact on clinical management for VHL families.

Survival of homozygous alpha-thalassemia with aplasia/hypoplasia of phalanges and jejunal atresia.

We report a case of survival of homozygous alpha-thalassemia with aplasia/hypoplasia of phalanges and jejunal atresia. The occurrence of these malformations is consistent with the postulation that intra-uterine hypoxia due to the presence of hemoglobin Bart's (Hb Bart's) is the causative factor for the development of these malformations. There were two pitfalls in diagnosis: normal spun hematocrit level despite a low hemoglobin level and absence of hydropic features. Our case illustrated that nitric oxide and high frequency ventilation were ineffective in ameliorating persistent pulmonary hypertension of newborn until exchange transfusion was done replacing Hb Bart's with normal hemoglobin.

A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong.

A controlled, open-label and randomized study was conducted to evaluate the safety and efficacy of the oral iron chelator deferiprone (L1) in thalassemia major patients from Hong Kong. Forty-nine patients were recruited in total (median age: 20 years; range: 8 to 40 years). The division of the patients was determined based on liver iron content and put into either the poorly-chelated (Group I) or well-chelated (Group II) groups. In Group I, 20 patients received combined therapy of L1 daily plus desferrioxamine (DFO), in a reduced frequency of twice weekly, while the control group consisted of 16 patients who were treated with DFO alone. In Group II, six patients received L1 only, while the control group consisted of seven patients treated with DFO alone. Only patients who participated for longer than 6 months were analyzed for efficacy (n = 44). The median study period was 18 months. Transient and mild gastrointestinal upset (31%), joint pain (15%) and liver enzyme elevation (23%) were the most common side effects noted for L1. No case of neutropenia was observed in this study. Serum ferritin (SF) levels showed significant decline in the poorly-chelated patients using combined therapy (L1 and reduced frequency DFO) as compared to those on DFO alone. However, their pre- and post-study liver iron content was not significantly different. Evaluation of the well-chelated group demonstrated no significant change in SF or liver iron content in both the study and control arms. We conclude that the short-term use of L1, with or without DFO, was safe and efficacious in our Chinese patient cohort. The long-term efficacy of reducing iron overload by treatment regimens including L1 requires further study.

Interferon and ribavirin as frontline treatment for chronic hepatitis C infection in thalassaemia major.

Hepatitis C virus (HCV) infection is common in transfusion-dependent thalassaemia. The clinical usefulness of 12-month treatment, using interferon alpha 3 MIU/m2 thrice weekly and oral ribavirin 16 mg/kg/d, was evaluated in 18 previously untreated thalassaemia patients. The median age at start of treatment was 16 years (range 7-29). Fourteen were infected with genotype 1b and 4 with genotype 6a. The sustained biochemical and virological response rates 6 months after stopping treatment were both 72.2%. Blood consumption was temporarily increased by 30% due to ribavirin-associated haemolysis. This study demonstrated a high, sustained response rate to combination treatment despite infection with genotype 1b.