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.

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.

Carotid jugular arteriovenous fistula: an unusual complication of internal jugular vein catheterization in children.

Central venous catheterization is essential in the management of patients requiring long-term intravenous access. Various risks during central line insertion have been described in the medical literature, including the potentially life-threatening complication of iatrogenic arteriovenous fistula (AVF). We describe a novel case of carotid jugular AVF following implanted port (BardPort® by C.R. Bard, Inc.) insertion in a pediatric oncology patient who had suffered cerebral infarct due to thromboembolism. Pediatr Blood Cancer 2012; 59: 1302-1304. © 2012 Wiley Periodicals, Inc.

Neurobehavioral Impairment in Pediatric Brain Tumor Survivors: A Meta-Analysis.

Purpose: The neurocognitive outcomes of pediatric brain tumor survivors have been extensively studied but the risk and predictors for neurobehavioral impairment are less clearly defined. We systematically analyzed the rates of emotional, psychosocial, and attention problems in pediatric brain tumor survivors. Methods: PubMed, Web of Science, Embase, Scopus, and Cochrane were searched for articles published between January 2012 to April 2022. Eligible studies reported neurobehavioral outcomes for PBTS aged 2 to <23 years with a brain tumor diagnosis before 18 years of age. A random-effect meta-analysis was performed in R. Results: The search yielded 1187 unique publications, of which 50 were included in the quantitative analysis. The estimated risk of having emotional, psychosocial, and attention problems were 15% (95%CI 10−20%), 12% (95%CI 9−16%), and 12% (95%CI 9−16%), respectively. PBTS were more likely to have emotional difficulties (Hedge's g = 0.43 [95%CI 0.34−0.52]), psychosocial problems (Hedge's g = 0.46 [95%CI 0.33−0.58]), and attention problems (Hedge's g = 0.48 [95%CI 0.34−0.63]) compared to normal/healthy control subjects. There was no significant difference in the rates of neurobehavioral impairment between children with and without history of cranial radiotherapy. Conclusions: PBTS are at elevated risk of neurobehavioral impairment. Neurobehavioral monitoring should be considered as the standard of care for PBTS.

Clonal evolution of 8p11 stem cell syndrome in a 14-year-old Chinese boy: a review of literature of t(8;13) associated myeloproliferative diseases.

We describe a case of coexisting BCR-ABL negative myeloproliferative disorder and precursor T-cell lymphoblastic lymphoma associated with t(8;13) involving FGFR1 at 8p11 in a 14-year-old boy who presented with generalized lymphadenopathy and an abdominal mass. JAK2 mutation and FIP1L1-PDGFRalpha were not detected. RT-PCR revealed the ZNF198-FGFR1 fusion transcript in both the bone marrow (BM) and lymph node (LN) of the patient at diagnosis. Of interest, reciprocal FGFR1-ZNF198 fusion transcript was demonstrated in the BM but not LN. Also differential clonal TcRgamma gene rearrangements in the BM and LN samples were observed. These findings provide novel insights into the genetic pathogenesis.

Late outcomes in children with Langerhans cell histiocytosis.

INTRODUCTION: Langerhans cell histiocytosis (LCH) is a rare disease with diverse clinical courses. Despite improvement in survival outcomes in the recent decades, sequelae of the disease remain a concern. This study aimed to provide information on the long-term outcomes in patients with LCH, particularly on the sequelae and any associated factors. METHOD: Medical records of patients with diagnosis of LCH and being managed in our centre were retrospectively reviewed. Data on the courses of illness, mortality, intervention, types and time of late events were collected and analysed. RESULTS: 70 patients were included with a mean observation time of 12 years (median 10.7 years, range 1-31.3 years). Sequelae related to LCH were present in 56% (n=39), being more common in multisystem diseases and patients with reactivations. Prevalence of sequelae is as follows: orthopaedic related 27%, diabetes insipidus 19%, growth retardation 13%, cosmetic 10%, neurological 7%, hearing 7%, anterior pituitary hormone deficiency 7%, hepatobiliary 4% and ophthalmological 3%. Neurological sequelae could manifest even 10 years after initial diagnosis of LCH. Reactivations, presence of central nervous system (CNS) risk lesions and treatment with radiotherapy were associated with a higher rate of sequelae. The cumulative incidence of reactivation was 34%. Most reactivations occurred in the first 2.5 years after diagnosis. CONCLUSION: Sequelae were common after LCH, although some were mild. Neurological sequelae could be particularly severe and debilitating. Vigilant long-term follow-up would be essential for optimising patient outcomes. Further studies on the prevention and treatment of CNS disease of LCH are warranted.

Indiscernible Benefit of Double-Unit Umbilical Cord Blood Transplantation in Children: A Single-Center Experience From Hong Kong.

Double-unit umbilical cord blood (DU-UCB) may extend the use of UCB transplantation and improve clinical outcomes. Data in the literature show that single-unit dominance happened in a vast majority of recipients, and the mechanism is unknown. We examined the clinical relevance and engraftment kinetics of DU-UCB transplant in 65 consecutive children who underwent unrelated single-unit (n = 25) and double-unit (n = 40) UCB transplantation for various hematological malignancies (n = 45) and nonmalignant disorders (n = 20). Our result showed no discernible benefit to children receiving double-unit transplant over those receiving single-unit transplant when the total nucleated cell (TNC) doses are ≥2.5 × 10(7)/kg, in terms of the hastening of the engraftment of neutrophils and platelets, reduction of nonengraftment, disease recurrence, early mortality, and graft-versus-host disease, despite significantly higher numbers of TNCs in double units. Further analyses demonstrated that the phenomena were not associated with underlying disease, duration of UCB storage, postthaw viability, HLA disparity, ABO incompatibility, gender, or doses of TNCs, CD34(+) cells, CD3(+) cells, or colony-forming units. Engrafting units in DU-UCB transplants were notably associated with higher CD34(+) cell dose. Chimerism studies demonstrated that single-unit dominance started before neutrophil engraftment in DU-UCB transplants. Data from the study suggested no advantage of infusing double-unit UCB, if an adequately dosed single-unit UCB is available. Successful prediction of the dominant graft would optimize algorithms of UCB selection and maximize the long-term engraftment of chosen units.

Arsenic trioxide mediates intrinsic and extrinsic pathways of apoptosis and cell cycle arrest in acute megakaryocytic leukemia.

Arsenic trioxide (ATO) induces apoptosis in a range of solid tumors and leukemia cells, and has been clinically applied for the treatment of acute promyelocytic leukemia with confirmed efficacy. Acute megakaryocytic leukemia (AMKL) is an aggressive malignancy with poor prognosis, if bone marrow transplantation is not possible. In this study, we applied flow cytometry, Western blot analysis and microarray techniques to investigate the effects of ATO on apoptosis and the cell division cycle of AMKL cell lines CHRF-288-11 and MEG-01. Our data demonstrated that ATO is a potent agent against AMKL as indicated by apoptotic markers, Annexin V and caspase-3. ATO activated the intrinsic (mitochondrial) pathway of apoptosis, which involved disrupting mitochondrial membrane potential, increased Bax/Bcl-2 ratio and caspase-9 activation, as well as the extrinsic (death receptor) pathway mediated by Fas and caspase-8 activation. We provided the first evidence that ATO stimulated expressions of CD137 mRNA and protein, which might be relevant to the extrinsic mechanism. ATO induced delays of cell cycle progression at S phase and arrest at G2/M phase of AMKL cells, but caspase-3 expression appeared not to be phase-specific. The multiple-signaling mechanism of ATO warrants it a potential agent to incorporate in the treatment regimen of AMKL.

Thrombospondin-1 induces apoptosis in primary leukemia and cell lines mediated by CD36 and Caspase-3.

Thrombospondin-1 (TSP-1) is a naturally occurring anti-angiogenic compound that induces apoptosis of endothelial and cancer cells via its receptor CD36. The objectives of our study were to investigate the in vitro effects of TSP-1 on the apoptosis of primary human leukemia cells as well as leukemia cell lines and the possible mechanism involving CD36. Our results demonstrated that TSP-1 induced apoptosis in CD36 positive cell lines CHRF-288-11, Meg-01 and HL-60, but not CD36 negative K562, at a dose-dependent manner as demonstrated by DNA ladder formation, Annexin V and propidium iodide (PI) stainings. The addition of anti-CD36 antibody FA6-152 or thrombopoietin (TPO) significantly nullified the effects of TSP-1. TSP-1-mediated apoptosis was consistently associated with the up-regulation of active Caspase-3. Responses of 2 CD36 positive primary AML samples to TSP-1 and FA6-152 were similar with those of leukemia cell lines. TSP-1 significantly induced apoptosis in B-ALL but the counter-effects of FA6-152 were less apparent. CD36 negative AML cells appeared less susceptible to TSP-1 and FA6-152. Our data provided strong evidence that TSP-1 exerted direct apoptotic effects on leukemia cells and could be developed as an adjunct to conventional therapy, particularly for leukemia cells that express CD36 or other TSP-1 receptors.

Preclinical ex vivo expansion of G-CSF-mobilized peripheral blood stem cells: effects of serum-free media, cytokine combinations and chemotherapy.

OBJECTIVES: Ex vivo expansion of granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) is a promising approach for overcoming the developmental delay of bone marrow (BM) reconstitution after transplantation. This project investigated the effects of culture duration, serum-free media, cytokine combinations, and chemotherapy on the outcomes of expansion. METHODS: Enriched CD34+ cells were cultured for 8 or 10 d in serum-free media (QBSF-60 or X-Vivo 10) and four combinations of cytokines consisting of recombinant human pegylated-megakaryocyte growth and development factor, stem cell factor, flt-3 ligand, G-CSF, interleukin (IL)-6, platelet-derived growth factor (PDGF), and IL-1beta. RESULTS: Eight days of culture in QBSF-60 significantly supported efficient expansions of CD34+ cells, CD34+ CD38- cells, colony-forming units (CFU) of myeloid, erythroid, megakaryocytic, and mixed lineages to 3.76-, 14.4-, 28.3-, 24.0-, 38.1-, and 15.7-fold, respectively. Whilst PDGF or IL-6 enhanced the expansion of early, myeloid, and erythroid progenitors, IL-1beta specifically promoted the megakaryocytic lineage. Engraftment of human CD45+ cells were detectable in all non-obese diabetic/severe-combined immunodeficient mice transplanted with expanded PBSC from donor samples, being 5.80 +/- 3.34% of mouse BM cells. The expansion and engraftment capacity of CD34+ cells from subjects postchemotherapy were significantly compromised across the panel of progenitor cells. CONCLUSION: Our results provided an optimized protocol for PBSC expansion, applicable to ameliorating neutropenia and thrombocytopenia in post-BM transplant patients by the prompt provision of progenitor cells. For postchemotherapy patients, expansion products might provide committed progenitors for improving short-term engraftment, but not self-renewable stem cells.

Elevated serum interleukin-15 level in acute graft-versus-host disease after hematopoietic cell transplantation.

OBJECTIVE: To correlate serum cytokine levels and the development of acute graft-versus-host disease (GVHD), the authors conducted a prospective study on serial measurements of interferon (IFN)-gamma and interleukin (IL)-10, IL-12 and IL-15. METHODS: The cytokines were measured in 27 subjects by enzyme-linked immunosorbent assay serially for the first 2 months after hematopoietic cell transplantation. RESULTS: Nineteen subjects with acute GVHD had significantly higher mean peak serum levels of IFN-gamma and IL-15 than the baseline levels at the start of conditioning. The peak level occurred soon after stem cell infusion and returned to the pretransplantation state in the second month. In contrast, there was lesser difference between the mean peak serum levels of IFN-gamma, IL-10, and IL-15 and the baseline level in the eight subjects without GVHD. The peak serum level for IL-15 was, in addition, significantly higher among GVHD subjects than those without GVHD in the first month posttransplantation. However, the level of IL-15 showed no correlation with the severity of GVHD. CONCLUSIONS: These changes point to a possible role of systemic cytokine secretion in the development of acute GVHD. Elevated levels of IL-15 early in the posttransplant period could be a helpful laboratory predictor of acute GVHD.

Second transplant for a thalassemia patient after graft rejection: with immunosuppression and allogeneic peripheral blood stem cell.

A 13-year old girl suffering from beta-thalassaemia major received bone marrow transplantation (BMT) from her HLA identical bother. After initial engraftment, she developed mixed chimerism. Secondary graft rejection occurred at 10 months after BMT and resulted in marrow aplasia. A second transplant with the same bone marrow donor was performed. The patient was conditioned with antithymocyte globulin 90 mg/kg followed by peripheral blood stem cell infusion. There was prompt engraftment and patient reverted to complete chimerism. There were no severe treatment-related complications or acute or chronic graft versus host disease after second transplant. The patient remained transfusion independent at 26 months after second transplant.

Growth and endocrine function following bone marrow transplantation for thalassemia major.

Thalassemia major (TM) patients frequently suffer from growth delay and endocrine dysfunction. Thirty-two TM patients who had survived more than 2 years after bone marrow transplantation (BMT) were recruited for growth and endocrine study. Patients were followed up annually for growth, and the height was expressed as height standard deviation score (HtSDS). The HtSDS at baseline was -1.51 and was more reduced in patients older than 7 years (-1.99) as compared with those younger patients (-0.79) (p =.027). The HtSDS gradually improved after BMT and increased by 0.59 (CI 0.16-1.01) at 5 years after BMT. Forty percent of patients were below 2 SD at time of BMT but this decreased to 15% at the latest assessment. The hormonal profiles of gonadotrophins, sex hormones, and thyroid function were assayed regularly after BMT. With a median follow-up of 67 months, ovarian failure was universal among the 10 girls evaluable for puberty and all required hormonal replacement. Eight of 10 boys had spontaneous puberty but 3 of them had gonadal impairment. One patient developed diabetes mellitus and one had growth hormone deficiency after BMT. In conclusion, improvement of growth after BMT in TM was common. Gonadal failure is universal in girls, and boys were less affected.

[The Immunological Study of Megakaryocytes]

The immunological role of megakaryocytes is not well known. This project studies the involvement of megakaryocytes on immuno-inflammatory processes and the possible mechanism via the adhesion molecule CD36 and the synthesis of relevant cytokines. The expression of adhesion protein CD36 on human platelets, megakaryocytes and megakaryocytic cell lines (Meg-01, Dami, CHRF-288-11 and M-07e) was analyzed by using flow cytometry, ELISA and immunocytochemical methods. The expression of interleukin-1 (IL-1) to interleukin-10 (IL-10), TNF-alpha, TNF-gamma and IFN-gamma on the four megakaryocytic cell lines was also determined by RT-PCR. The effect of IL-1beta, IL-3, IL-6 and TPO on murine megakaryocyte colony formation (CFU-MK) was studied by using a plasma clot culture system. The CFU-MK was confirmed by acetylcholine esterase staining. The results showed that: (1) CD36 was expressed on platelets, megakaryocytes and the four megakaryocytic cell lines, the relative expression level is as follows: platelets > megakaryocytes > Meg-01 > Dami > CHRF-288-11 > M-07e, suggesting that the level of CD36 expression correlates with the degree of maturity of megakaryocytic differentiation; (2) inflammatory cytokines TNF-alpha, IL-1beta, IL-3 and IL-6 were detected in all the four megakaryocytic cell lines, suggesting that different stages of megakaryocytes can be as a source of inflammatory cytokines; and (3) IL-1beta, IL-3 and IL-6, as well as TPO, play a stimulating effect on CFU-MK formation, suggesting that there is an "autocrine" effect on megakaryocytopoiesis. The data obtained suggest that megakaryocytes may involve in immuno-inflammatory processes via the synthesis of platelet adhesion molecules and inflammatory cytokines.

Detection of micrometastasis of neuroblastoma to bone marrow and tumor dissemination to hematopoietic autografts using flow cytometry and reverse transcriptase-polymerase chain reaction.

BACKGROUND: The identification of neuroblastoma metastases to bone marrow (BM) is requisite in staging disease for risk-adopted therapy. However, micrometastases were not elucidated fully. METHODS: Flow cytometry (FCM) with CD45/CD56/CD81 and reverse transcriptase-polymerase chain reactions (RT-PCR) for tyrosine hydroxylase (TH) transcripts were used to evaluate neuroblastoma in bilateral BM aspirates at diagnosis, BM autografts, peripheral blood stem cell (PBSC) collections, and CD34(+) cell products of 27 children. RESULTS: TH transcripts were amplified in histology-negative (H(-)) BM specimens from seven patients (four patients with Stage 3 disease, two with Stage 4 disease, and one with Stage 4S disease), revealing a prevalence of submicroscopic metastasis. The median number of CD45(-)CD81(+)CD56(+) cells in four H(-) TH(-) BM samples from two patients with Stage 1 and Stage 2 disease, respectively, was comparable to that encountered in 10 normal BM controls (0.003% [range, 0.002-0.004%] vs. 0.004% [0-0.008%], P = 0.724). In six H(-) TH(+) BM specimens from three patients whom were otherwise diagnosed with neuroblastoma Stage 3, 0.031% (0.009-0.06%) CD45(-)CD81(+)CD56(+) cells were detected. Besides, 1.474% (0.088-3.009%) CD45(-)CD81(+)CD56(+) cells were identified in four H(-) TH(+) BM specimens from two patients at Stage 4. TH transcripts were evident in four of five BM autografts and in 22 of 45 (48.9%) PBSC specimens. FCM demonstrated 0.018% and 0.049% CD45(-)CD81(+)CD56(+) cells in two TH(+) BM autografts, respectively. The number of CD45(-)CD81(+)CD56(+) cells was higher in 19 TH(+) PBSC specimens than in 20 TH(-) PBSC specimens (0.026% [0.006-1.128%] vs. 0% [0-0.009%], P < 0.0001). CD34(+) cell selection achieved 2.9 (2.1-3.5) log depletion of CD45(-)CD81(+)CD56(+) cells in four manipulated products, rendering six of seven PBSC autografts TH-free. CONCLUSIONS: FCM in combination with RT-PCR evaluated neuroblastoma micrometastasis and assessed the purity of hematopoietic autografts for transplant. However, the clinical relevance remains to be elucidated.