Brain Microstructural Changes Associated With Neurocognitive Outcome in Intracranial Germ Cell Tumor Survivors.

BACKGROUND: Childhood intracranial germ cell tumor (GCT) survivors are prone to radiotherapy-related neurotoxicity, which can lead to neurocognitive dysfunctions. Diffusion kurtosis imaging (DKI) is a diffusion MRI technique that is sensitive to brain microstructural changes. This study aimed to investigate the association between DKI metrics versus cognitive and functional outcomes of childhood intracranial GCT survivors. METHODS: DKI was performed on childhood intracranial GCT survivors (n = 20) who had received cranial radiotherapy, and age and gender-matched healthy control subjects (n = 14). Neurocognitive assessment was performed using the Hong Kong Wechsler Intelligence Scales, and functional assessment was performed using the Lansky/Karnofsky performance scales (KPS). Survivors and healthy controls were compared using mixed effects model. Multiple regression analyses were performed to determine the effects of microstructural brain changes of the whole brain as well as the association between IQ and Karnofsky scores and the thereof. RESULTS: The mean Intelligence Quotient (IQ) of GCT survivors was 91.7 (95% CI 84.5 - 98.8), which was below the age-specific normative expected mean IQ (P = 0.013). The mean KPS score of GCT survivors was 85.5, which was significantly lower than that of controls (P < 0.001). Cognitive impairments were significantly associated with the presence of microstructural changes in white and grey matter, whereas functional impairments were mostly associated with microstructural changes in white matter. There were significant correlations between IQ versus the mean diffusivity (MD) and mean kurtosis (MK) of specific white matter regions. The IQ scores were negatively correlated with the MD of extensive grey matter regions. CONCLUSION: Our study identified vulnerable brain regions whose microstructural changes in white and grey matter were significantly associated with impaired cognitive and physical functioning in survivors of pediatric intracranial GCT.

Hepatitis B Virus Seropositivity Is a Poor Prognostic Factor of Pediatric Hepatocellular Carcinoma: a Population-Based Study in Hong Kong and Singapore.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare hepatic malignancy in children. Hepatitis B virus (HBV) infection is a key predisposing factor in endemic regions but its impact on outcome has not been studied. We aim to evaluate the prognostic implication of HBV seropositivity and role of cancer surveillance in children with HCC from East Asian populations with national HBV vaccination. METHODS: Review of population-based databases for patients (< 18 years old) diagnosed with HCC from 1993 to 2017 in two Southeast Asian regions with universal HBV vaccination (instituted since 1988 and 1987 in Hong Kong and Singapore, respectively). RESULTS: Thirty-nine patients were identified (Hong Kong, 28; Singapore, 11). Thirty were male; median age at diagnosis was 10.8 years (range, 0.98-16.6). Abdominal pain was the commonest presentation while five patients were diagnosed through surveillance for underlying condition. Alpha-fetoprotein was raised in 36 patients (mean, 500,598 ng/ml). Nineteen had bilobar involvement, among the patients in whom pretreatment extent of disease (PRETEXT) staging could retrospectively be assigned, 3 had stage I, 13 had stage II, 4 had stage III, and 11 had stage IV disease. Seventeen had distant metastasis. HBsAg was positive in 19 of 38 patients. Two patients had fibrolamellar HCC. Upfront management involved tumor resection in 16 (liver transplantation, 2), systemic chemotherapy in 21, interventional procedures in 6 [transarterial chemoembolization (TACE), 5, radiofrequency ablation (RFA), 1], and radiotherapy in 4 (selective internal radiation, 3, external beam radiation, 1). Five-year event-free survival (EFS) and overall survival (OS) were 15.4 ± 6.0 and 26.1 ± 7.2%, respectively. Patient's HBsAg positivity, metastatic disease and inability to undergo definitive resection represent poor prognostic factors in univariate and multivariable analyses. Patients diagnosed by surveillance had significantly better outcome. CONCLUSION: Pediatric HCC has poor outcome. HBV status remains relevant in the era of universal HBV vaccination. HBV carrier has inferior outcome and use of surveillance may mitigate disease course.

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.

Outcome of Chinese children with craniopharyngioma: a 20-year population-based study by the Hong Kong Pediatric Hematology/Oncology Study Group.

PURPOSE: Craniopharyngioma is a rare low-grade neoplasm in children. Tumor progression occurs frequently, and survivors are at risk of long-term disease and treatment-related morbidities. We reviewed the population-based experience of managing pediatric craniopharyngioma in Hong Kong. METHODS: The Hong Kong Pediatric Hematology/Oncology Study Group database was interrogated for patients with craniopharyngioma younger than 18 years between 1999 and 2018. Patient demographics, clinical characteristics, outcomes, and long-term morbidities were summarized. RESULTS: Twenty-eight patients with craniopharyngioma were included (approximate incidence of 1.1 per 1,000,000 individuals). The treatment approaches were heterogeneous and included surgery only, surgery with adjuvant radiation, and surgery with intracystic interferon. With a median follow-up of 6.1 years, 12 (43%) patients experienced disease progression, and 3 patients died of progression, postoperative complication, and gastrointestinal bleeding. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 56.8% (± 10.0%) and 92.0% (± 5.4%), respectively. The 10-year PFS and OS rates were 37.3% (± 11.4) and 92.0% (± 5.4%), respectively. Patients receiving treatment in a high-volume center had significantly better outcomes than did those treated at other centers (PFS, p = 0.007; OS, p = 0.029). Period of diagnosis, sex, age at diagnosis, greatest tumor dimension, extent of resection, and radiotherapy use did not significantly affect patient survival. Long-term visual impairment (60%) and endocrinopathies (92%) were common. CONCLUSION: Prognosis of pediatric craniopharyngioma in Hong Kong compares unfavorably with published reports. Centralization and standardization of treatment may prove valuable in mitigating patient 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.

Excellent outcome of acute lymphoblastic leukaemia with TCF3-PBX1 rearrangement in Hong Kong.

OBJECTIVE: The aim of this study was to review clinical outcomes and prognosis of paediatric patients with acute lymphoblastic leukaemia (ALL) with TCF3-PBX1 rearrangement. PATIENTS: All children in Hong Kong diagnosed with ALL with TCF3-PBX1 rearrangement over the past two decades were included. METHODS: Six hundred and twenty-four newly diagnosed patients with ALL from four consecutive studies were enrolled from 1997 to 2016. Patients carrying TCF3-PBX1 rearrangement and patients at intermediate risk without the gene expression were compared for clinical characteristics, overall survival and event-free survival (EFS). RESULTS: The TCF3-PBX1 rearrangement was detected in 30 of 624 patients (4.8%). Results were consistent across the consecutive clinical trials employed in the past two decades. Compared with 239 intermediate risk patients without TCF3-PBX1 rearrangement, the 5-year overall survival and EFS for patients with TCF3-PBX1 rearrangement was superior, with both at 100% (P = 0.12 and P = 0.029). CONCLUSION: This population-based study over the past 20 years demonstrated that patients with TCF3-PBX1 rearrangement had favourable EFS compared with other intermediate risk patients treated with a similar chemotherapy backbone.

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.

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.

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.

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.