Publications by authors named "Chi Kong Li"

166 Publications

Awareness of diagnosis, treatment and risk of late effects in Chinese survivors of childhood cancer in Hong Kong.

Health Expect 2021 Jun 8. Epub 2021 Jun 8.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong.

Background: For survivors of childhood cancer, awareness of personal health risks is a critical component of long-term health management.

Objective: To evaluate the awareness of the diagnosis, treatment and risk of late effects among survivors of childhood cancer in Hong Kong.

Methods: Between June 2019 and March 2020, this cross-sectional study recruited 155 adult survivors (mean age = 26.9, standard deviation [SD] = 6.4 years) and 45 parents of paediatric survivors (mean age = 11.1, SD = 3.6 years) from a long-term follow-up clinic. At >10 years post-treatment (mean = 13.4, SD = 7.6 years), they completed a structured questionnaire to report their cancer-specific knowledge. Multiple linear regression analysis was conducted to identify clinical, socioeconomic and behavioural factors associated with poor awareness.

Results: The majority of participants accurately recalled their diagnoses (73.5%) and major treatment modalities (chemotherapy 92.4%, radiation 82.9% and surgery 88.2%). However, less than half (45%) of the participants recognized more than 25% of the total late effects for which they were at risk. The highest levels of awareness were reported for endocrine problems (49%), neurocognitive impairment (44%) and secondary cancers (43%), and the lowest for peripheral neuropathy (21%) and vision problems (23%). Compared with survivors of haematological malignancies, those of central nervous system (CNS) tumours (standardized estimate [B] = -9.33, 95% confidence interval [95% CI]: -13.41 to -5.26) and non-CNS solid tumours (B = -8.47, 95% CI: -12.39 to -4.94) had less knowledge about their diagnosis. Retaining medical records (P < .0001) and better medical information-seeking habits (P = .048) were associated with better awareness.

Conclusions: Survivors of childhood cancer in Hong Kong have deficient awareness of their personal health risks. They may benefit from the provision of a survivorship care plan and personalized education regarding treatment-related late effects.

Patient Contribution: Patients contributed in designing the study tools. Results were presented at a non-governmental organization.
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http://dx.doi.org/10.1111/hex.13288DOI Listing
June 2021

Use of complementary or alternative medicine and potential interactions with chronic medications among Chinese survivors of childhood cancer.

J Cancer Surviv 2021 May 14. Epub 2021 May 14.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong.

Purpose: This study explored the pattern of complementary or alternative medicine (CAM) use among Chinese survivors of childhood cancer and identified potential drug-CAM interactions and factors predicting CAM use.

Methods: This cross-sectional study recruited 393 survivors of childhood cancer (male, 57.8%; mean age, 17.7 [SD = 7.3] years; mean years post-treatment, 8.8 [SD = 5.0]) from a public hospital in Hong Kong. Participants reported CAM and over-the-counter medications that they used in the past year. Prescription drug data were extracted from pharmacy dispensing records. Potential interactions between concurrent CAM and chronic medications were identified from well-established CAM-drug/herb-drug interaction databases. A multivariate logistic regression was performed to analyze associations of socio-demographic and clinical factors with CAM use.

Results: Half (n = 205/393, 52.2%) of the participants reported the use of CAM. The most popular CAMs were traditional Chinese medicine (n = 127/205, 62.0%) and natural products (n = 114/205, 55.3%). Among the 69 survivors (33.7%) concurrently using CAM and chronic medications, one-third (n = 21/69, 30.4%) were at risk of drug-CAM interactions that are of moderate significance. Adult survivors were more likely to use CAM than pediatric survivors (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.31-4.41). Brain tumor survivors were more likely than other solid tumor survivors to use non-oral therapies (OR, 2.70; 95% CI, 1.01-7.72).

Conclusions: The prevalence of CAM use among Chinese survivors of childhood cancer was high. A minority of survivors had a risk of clinically significant CAM-drug interactions. Future studies should focus on survivors' behavior and motivations for CAM use.

Implications For Cancer Survivors: As the concurrent use of CAM and chronic medications might result in interactions, healthcare providers should proactively identify such interactions and develop referral pathways to promote evidence-based integrative therapies for survivors.
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http://dx.doi.org/10.1007/s11764-021-01051-5DOI Listing
May 2021

Neurocognitive and Behavioral Outcomes of Chinese Survivors of Childhood Lymphoblastic Leukemia.

Front Oncol 2021 20;11:655669. Epub 2021 Apr 20.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.

Background: Increasing attention has been dedicated to investigate modifiable risk factors of late effects in survivors of childhood cancer. This study aims to evaluate neurocognitive and behavioral functioning in a relatively young cohort of survivors of childhood acute lymphoblastic leukemia (ALL) in Hong Kong, and to identify clinical and socio-environmental factors associated with these outcomes.

Methods: This analysis included 152 survivors of childhood ALL who were ≥5 years post-diagnosis (52% male, mean [SD] age 23.5[7.2] years at evaluation, 17.2[7.6] years post-diagnosis). Survivors completed performance-based neurocognitive tests, and reported their emotional and behavioral symptoms using the Child/Adult Behavior Checklist. Socio-environmental variables (living space, fatigue, physical activity, family functioning, and academic stress) were self-reported using validated questionnaires. Clinical variables and chronic health conditions were extracted from medical charts. Multivariable linear modeling was conducted to test identify factors associated with neurocognitive/behavioral outcomes, adjusting for current age, sex, age at diagnosis and cranial radiation. An exploratory mediation analysis was performed to examine the mediating effects of risk factors on neurocognitive and behavioral outcomes.

Results: As compared to population norms, a minority of survivors developed mild-moderate impairment in motor processing speed (36.2%), memory (9.2%) and attention measures (4.0%-10.5%). Survivors also reported attention problems (12.5%), sluggish cognitive tempo (23.7%) and internalizing (depressive, anxiety and somatic symptoms) problems (17.1%). A minority of survivors developed mild-moderate treatment-related chronic conditions (n=37, 24.3%). As compared to survivors without chronic conditions, survivors with chronic conditions had more executive dysfunction (B=5.09, standard error [SE]=2.05; =0.014) and reported more attention problems (B=5.73, SE=1.43; <0.0001). Fatigue and poor family functioning was associated with multiple measures of behavior problems (all <0.001). A lower level of physical activity was correlated with more self-reported symptoms of inattention (B= -1.12, SE=0.38, =0.004) and sluggish cognitive tempo (B=-1.22, SE=0.41, =0.003). Exploratory analysis showed that chronic health conditions were associated with behavioral measures through fatigue as the mediator.

Conclusion: The majority of young Chinese survivors of ALL had normal cognitive and behavioral function. Regular monitoring of behavioral function should be performed on survivors who develop treatment-related chronic conditions. Health behavior and socio-environment factors may be potentially modifiable risk factors associated with health outcomes in survivors.
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http://dx.doi.org/10.3389/fonc.2021.655669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093634PMC
April 2021

Clinical characteristics of tumor lysis syndrome in childhood acute lymphoblastic leukemia.

Sci Rep 2021 May 6;11(1):9656. Epub 2021 May 6.

Department of Hematology and Oncology, Children's Hospital of Nanjing Medical University, Nanjing, China.

Tumor lysis syndrome (TLS) is a common and fatal complication of childhood hematologic malignancies, especially acute lymphoblastic leukemia (ALL). The clinical features, therapeutic regimens, and outcomes of TLS have not been comprehensively analyzed in Chinese children with ALL. A total of 5537 children with ALL were recruited from the Chinese Children's Cancer Group, including 79 diagnosed with TLS. The clinical characteristics, treatment regimens, and survival of TLS patients were analyzed. Age distribution of children with TLS was remarkably different from those without TLS. White blood cells (WBC) count ≥ 50 × 10/L was associated with a higher risk of TLS [odds ratio (OR) = 2.6, 95% CI = 1.6-4.5]. The incidence of T-ALL in TLS children was significantly higher than that in non-TLS controls (OR = 4.7, 95% CI = 2.6-8.8). Hyperphosphatemia and hypocalcemia were more common in TLS children with hyperleukocytosis (OR = 2.6, 95% CI = 1.0-6.9 and OR = 5.4, 95% CI = 2.0-14.2, respectively). Significant differences in levels of potassium (P = 0.004), calcium (P < 0.001), phosphorus (P < 0.001) and uric acid (P < 0.001) were observed between groups of TLS patients with and without increased creatinine. Laboratory analysis showed that older age was associated with a higher level of creatinine. Calcium level was notably lower in males. WBC count, lactate dehydrogenase, and creatinine levels were significantly higher in T-ALL subgroup, whereas procalcitonin level was higher in B-ALL children. Older age, infant, a higher level of WBC and T-ALL were risk factors TLS occurrence. Hyperleukocytosis has an impact on the severity of TLS, while renal injury may be an important feature in the process of TLS.
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http://dx.doi.org/10.1038/s41598-021-88912-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102476PMC
May 2021

Cognitive Impairment in Survivors of Pediatric Acute Lymphoblastic Leukemia Treated With Chemotherapy Only.

J Clin Oncol 2021 Jun 22;39(16):1705-1717. Epub 2021 Apr 22.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.

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http://dx.doi.org/10.1200/JCO.20.02322DOI Listing
June 2021

Use of Chronic Prescription Medications and Prevalence of Polypharmacy in Survivors of Childhood Cancer.

Front Oncol 2021 1;11:642544. Epub 2021 Apr 1.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.

Background: As survivors of childhood cancer age, development of cancer treatment-related chronic health conditions often occur. This study aimed to describe the pattern of chronic prescription medication use and identify factors associated with polypharmacy among survivors of childhood cancer.

Methods: This was a retrospective study conducted at the pediatric oncology long-term follow-up clinic in Hong Kong. Eligible subjects included survivors who were (1) diagnosed with cancer before 18 years old, (2) were at least 3 years post-cancer diagnosis and had completed treatment for at least 30 days, and (3) receiving long-term follow-up care at the study site between 2015 and 2018. Dispensing records of eligible survivors were reviewed to identify medications taken daily for ≥30 days or used on an "as needed" basis for ≥6 months cumulatively within the past 12-month period. Polypharmacy was defined as the concurrent use of ≥5 chronic medications. Multivariable log-binomial modeling was conducted to identify treatment and clinical factors associated with medication use pattern and polypharmacy.

Results: This study included 625 survivors (mean current age = 17.9 years, standard deviation [SD] = 7.2 years) who were 9.2 [5.2] years post-treatment. Approximately one-third (n = 219, 35.0%) of survivors were prescribed at least one chronic medication. Frequently prescribed medication classes include systemic antihistamines (26.5%), sex hormones (19.2%), and thyroid replacement therapy (16.0%). Overall prevalence of polypharmacy was 5.3% (n = 33). A higher rate of polypharmacy was found in survivors of CNS tumors (13.6%) than in survivors of hematological malignancies (4.3%) and other solid tumors (5.3%) ( = .0051). Higher medication burden was also observed in survivors who had undergone cranial radiation (RR = 6.31; 95% CI = 2.75-14.49) or hematopoietic stem-cell transplantation (HSCT) (RR = 3.53; 95% CI = 1.59-7.83).

Conclusion: Although polypharmacy was observed in a minority of included survivors of childhood cancer, chronic medication use was common. Special attention should be paid to survivors of CNS tumors and survivors who have undergone HSCT or cranial radiation. These individuals should be monitored closely for drug-drug interactions and adverse health outcomes that may result from multiple chronic medications, particularly during hospitalization in an acute care setting.
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http://dx.doi.org/10.3389/fonc.2021.642544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047635PMC
April 2021

Prognostic Factors for CNS Control in Children with Acute Lymphoblastic Leukemia Treated Without Cranial Irradiation.

Blood 2021 Mar 8. Epub 2021 Mar 8.

St. Jude Children's Research Hospital, Memphis, Tennessee, United States.

To identify the prognostic factors that are useful to improve CNS control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on China Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% CI, 78.9%-81.7%), and overall survival 91.1% (95% CI, 90.1%-92.1%). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5%-2.3%), and any CNS relapse 2.7% (95% CI, 2.2%-3.2%). The isolated CNS relapse rate was significantly lower in patients with B-ALL than in those with T-ALL (1.6%; 95% CI,1.2%-2.0% vs 4.6%; 95% CI 2.9%-6.3%; P <0.001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1%-3.0%; P=0.03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0%-7.3%; P <0.001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5%-12.2%; P=0.007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04%-0.7%; P=0.02) and flow cytometry examination of diagnostic cerebrospinal fluid (HR, 0.2; 95% CI, 0.06%-0.6%; P=0.006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic cerebrospinal fluid may improve CNS control in childhood ALL.
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http://dx.doi.org/10.1182/blood.2020010438DOI Listing
March 2021

Identifying Priorities for Harmonizing Guidelines for the Long-Term Surveillance of Childhood Cancer Survivors in the Chinese Children Cancer Group (CCCG).

JCO Glob Oncol 2021 Feb;7:261-276

Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.

Purpose: Survivors of childhood cancer often experience treatment-related chronic health conditions. Given its vast population, China shares a large proportion of the global childhood cancer burden. Yet, screening and treatment of late effects in survivors of childhood cancer remain underaddressed in most regions of China. This study aimed to identify high-priority late effects for harmonizing screening guidelines within the Chinese Children's Cancer Group (CCCG), as well as barriers and enablers of the implementation of surveillance recommendations in local practice.

Methods: To establish clinical consensus, 12 expert panelists who represent major institutions within the CCCG completed a Delphi survey and participated in a focus group discussion. The survey solicited ratings of the prevalence, severity, and priority for screening of 45 late effects. Major themes identified from the focus group were analyzed using thematic analysis.

Results: The Delphi survey identified eight high-priority late effects for harmonization within CCCG: osteonecrosis, osteoporosis, left ventricular dysfunction, secondary brain tumors, treatment-related myeloid leukemia, gonadal dysfunction, growth hormone deficiency, and neurocognitive deficits. The common barriers to implementing survivorship programs include lack of support and resources for clinicians to provide follow-up care. Patients were also concerned about privacy issues and lacked awareness of late effects. Many institutions also lacked rehabilitation expertise and referral pathways.

Conclusion: By identifying obstacles related to the professional setting, patient behavior, and organization of care, our study identified resources and a framework for establishing collaborative strategies to facilitate follow-up care of childhood cancer survivors in China.
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http://dx.doi.org/10.1200/GO.20.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081494PMC
February 2021

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series.

Br J Haematol 2021 Jun 2;193(6):1172-1177. Epub 2021 Feb 2.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22 blasts was 72% (range 40-100%, n = 9). The median dose in the first course was 1.74 mg/m (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.
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http://dx.doi.org/10.1111/bjh.17333DOI Listing
June 2021

An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia.

Haematologica 2021 Jan 28. Epub 2021 Jan 28.

Department of Transplantation and Cell Therapy, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatrics, the University of Tokyo, Tokyo.

Not available.
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http://dx.doi.org/10.3324/haematol.2020.266320DOI Listing
January 2021

Reduced intensity of early intensification does not increase the risk of relapse in children with standard risk acute lymphoblastic leukemia - a multi-centric clinical study of GD-2008-ALL protocol.

BMC Cancer 2021 Jan 13;21(1):59. Epub 2021 Jan 13.

Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.

Background: The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70-85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL.

Methods: The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs.

Results: The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129).

Conclusions: The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.
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http://dx.doi.org/10.1186/s12885-020-07752-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805214PMC
January 2021

Clinical Implications of Minimal Residual Disease Detection in Infants With -Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol.

J Clin Oncol 2021 Feb 6;39(6):652-662. Epub 2021 Jan 6.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Purpose: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with -rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide).

Materials And Methods: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged , immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10), and high (≥ 5 × 10).

Results: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively ( = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively ( < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively ( < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9).

Conclusion: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.
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http://dx.doi.org/10.1200/JCO.20.02333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196086PMC
February 2021

Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease.

Nat Commun 2021 01 4;12(1):65. Epub 2021 Jan 4.

Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China.

Fecal microbiota transplant (FMT) has emerged as a potential treatment for severe colitis associated with graft-versus-host disease (GvHD) following hematopoietic stem cell transplant. Bacterial engraftment from FMT donor to recipient has been reported, however the fate of fungi and viruses after FMT remains unclear. Here we report longitudinal dynamics of the gut bacteriome, mycobiome and virome in a teenager with GvHD after receiving four doses of FMT at weekly interval. After serial FMTs, the gut bacteriome, mycobiome and virome of the patient differ from compositions before FMT with variable temporal dynamics. Diversity of the gut bacterial community increases after each FMT. Gut fungal community initially shows expansion of several species followed by a decrease in diversity after multiple FMTs. In contrast, gut virome community varies substantially over time with a stable rise in diversity. The bacterium, Corynebacterium jeikeium, and Torque teno viruses, decrease after FMTs in parallel with an increase in the relative abundance of Caudovirales bacteriophages. Collectively, FMT may simultaneously impact on the various components of the gut microbiome with distinct effects.
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http://dx.doi.org/10.1038/s41467-020-20240-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782528PMC
January 2021

Astragalus polysaccharide has a protective effect on hematopoiesis in an irradiated mouse model and decreases apoptosis in megakaryocytes.

Mol Med Rep 2021 01 12;23(1). Epub 2020 Nov 12.

Research Center of The Seventh Affiliated Hospital, Sun Yat‑sen University, Shenzhen, Guangdong 518107, P.R. China.

Huangqi, the dried root of Radix Astragali, is an essential herb in Traditional Chinese Medicine and has been used to promote hematopoiesis for centuries. Astragalus polysaccharide (ASPS), the bioactive compound of Huangqi, serves a crucial role in hematopoiesis. The aim of the present study was to investigate the hematopoietic effects, in particular the thrombopoietic effects, and the molecular mechanisms of ASPS using an irradiation‑induced myelosuppressive mouse model. Colony‑forming unit assays, flow cytometric analysis of apoptosis, ELISAs, Giemsa staining and western blotting were performed to determine the hematopoietic and anti‑apoptotic effects of ASPS. The results demonstrated that ASPS enhanced the recovery of red blood cells at day 21 following treatment, as well as platelets and white blood cells at day 14. In addition, ASPS promoted colony formation in all lineages (megakaryocytes, granulocyte monocytes, erythroid cells and fibroblasts). The morphological study of the bone marrow demonstrated that tri‑lineage hematopoiesis was preserved in the ASPS‑ and thrombopoietin (TPO)‑treated groups compared with the control group. The overall cellularity (mean total cell count/area) of the ASPS‑treated group was similar to that of the TPO‑treated group. Additionally, in vitro experiments indicated that treatment with 100 µg/ml ASPS exhibited the maximum effect on colony formation. ASPS attenuated cell apoptosis in megakaryocytic cells via inhibiting the mitochondrial caspase‑3 signaling pathway. In conclusion, ASPS promoted hematopoiesis in irradiated myelosuppressive mice possibly via enhancing hematopoietic stem/progenitor cell proliferation and inhibiting megakaryocytes apoptosis.
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http://dx.doi.org/10.3892/mmr.2020.11653DOI Listing
January 2021

Upfront consolidation treatment with I-mIbG followed by myeloablative chemotherapy and hematopoietic stem cell transplantation in high-risk neuroblastoma.

Pediatr Investig 2020 Sep 27;4(3):168-177. Epub 2020 Sep 27.

Department of Paediatrics The Chinese University of Hong Kong Hong Kong China.

Importance: I-metaiodobenzylguanidine (I-mIBG) has a significant targeted antitumor effect for neuroblastoma. However, currently there is a paucity of data for the use of I-mIBG as a "front-line" therapeutic agent in those patients with newly diagnosed high-risk neuroblastoma as part of the conditioning regimen for myeloablative chemotherapy (MAC).

Objective: To evaluate the feasibility of upfront consolidation treatment with I-mIBG plus MAC and hematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma patients.

Methods: A retrospective, single-center study was conducted from 2003-2019 on newly diagnosed high-risk neuroblastoma patients without progressive disease (PD) after the completion of induction therapy. They received I-mIBG infusion and MAC followed by HSCT.

Results: A total of 24 high-risk neuroblastoma patients were enrolled with a median age of 3.0 years at diagnosis. After receiving this sequential consolidation treatment, 3 of 13 patients who were in partial response (PR) before I-mIBG treatment achieved either complete response (CR) ( 1) or very good partial response (VGPR) ( 2) after HSCT. With a median follow-up duration of 13.0 months after I-mIBG therapy, the 5-year event-free survival and overall survival rates estimated were 29% and 38% for the entire cohort, and 53% and 67% for the patients who were in CR/VGPR at the time of I-mIBG treatment.

Interpretation: Upfront consolidation treatment with I-mIBG plus MAC and HSCT is feasible and tolerable in high-risk neuroblastoma patients, however the survival benefit of this I-mIBG regimen is only observed in the patients who were in CR/VGPR at the time of I-mIBG treatment.
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http://dx.doi.org/10.1002/ped4.12216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520103PMC
September 2020

Treatment of childhood cancer in China: Current status and future direction.

Pediatr Investig 2020 Sep 27;4(3):153-156. Epub 2020 Sep 27.

Department of Pediatric Oncology Sun Yat-Sen University Cancer Center Guangzhou China.

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http://dx.doi.org/10.1002/ped4.12210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520102PMC
September 2020

Double-unit unrelated cord blood transplantation for thalassemia major: Comparison with HLA-identical sibling bone marrow transplantation.

Pediatr Transplant 2021 May 2;25(3):e13901. Epub 2020 Nov 2.

Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR.

UCBT recipients with TM are at high risk of EF related to low number of stem cells and prior alloimmunization after multiple blood transfusions. Here, we evaluated the safety and efficacy of double-unit UCBT using TT-containing conditioning regimens in TM. Retrospective analysis of children who underwent double-unit UCBT for TM in the Prince of Wales Hospital between August 2007 and January 2017, and outcome of double-unit UCBT for TM was compared with outcome of HLA-matched sibling BMT. Ten patients, median age 4.2 years, received double-unit UCBT. All patients except one engrafted at a median of 19 days. None of the patients with successful engraftment had grade III or IV aGVHD. Among nine patients with successful engraftment, six of nine patients evaluable after day 100 developed cGVHD. All patients with cGVHD were well controlled after treatment with steroids and/or supportive care and maintained good quality of life. In comparison with patients receiving BMT, those given UCBT had slower platelet recovery, and more cGVHD. With a median follow-up of 272 months after BMT and 84 months after UCBT, the 8-year OS after BMT and UCBT was 92% and 90% (P = .84), whereas 8-year DFS after BMT and UCBT was 87% and 80% (P = .54). UCB could be an acceptable source of stem cells for transplantation of TM patients when HLA-matched family bone marrow donors are NA.
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http://dx.doi.org/10.1111/petr.13901DOI Listing
May 2021

t(1;22)(p13;q13) Acute Megakaryoblastic Leukemia Complicated by Hepatic Fibrosis: Antifibrosis Therapy?

J Pediatr Hematol Oncol 2020 Oct 28. Epub 2020 Oct 28.

Departments of Paediatrics.

Background: There is no established effective treatment for patients with t(1;22)(p13;q13) acute megakaryoblastic leukemia (AMKL) and hepatic fibrosis.

Observation: Here we report the outcomes of 2 t(1;22)(p13;q13) AMKL patients with hepatic fibrosis. One patient died from liver failure despite the control of leukemia. The other patient was successfully treated with reduced-intensity chemotherapy and antifibrosis therapy with tretinoin and α-tocopheryl acetate, the hepatic fibrosis resolved and leukemia was in remission for 3 years.

Conclusions: Reduced-intensity chemotherapy plus antifibrosis therapy with tretinoin and α-tocopheryl acetate could be a treatment option for these patients with t(1;22)(p13;q13) AMKL and hepatic fibrosis.
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http://dx.doi.org/10.1097/MPH.0000000000001986DOI Listing
October 2020

Health Behaviors of Chinese Childhood Cancer Survivors: A Comparison Study with Their Siblings.

Int J Environ Res Public Health 2020 08 24;17(17). Epub 2020 Aug 24.

Department of Paediatrics & Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China.

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. 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. CCS had less alcohol consumption when compared with their sibling controls (adjusted odds ratio (AOR) = 0.65, = 0.035). The sibling controls were more likely to have cancer screening practices (AOR = 0.38, = 0.005) and health (AOR = 0.27, < 0.001) and life insurance coverage (AOR = 0.38, < 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 ( = 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. 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. : It is crucial for healthcare professionals to identify strategies or target interventions for raising CCS's awareness of their cancer risks and healthy lifestyle throughout their life.
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http://dx.doi.org/10.3390/ijerph17176136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503484PMC
August 2020

Lymphoblastic predominance of blastic phase in children with chronic myeloid leukaemia treated with imatinib: A report from the I-CML-Ped Study.

Eur J Cancer 2020 09 13;137:224-234. Epub 2020 Aug 13.

Inserm CIC 1402, University Hospital, Poitiers, France.

Background: Chronic myeloid leukaemia (CML) is a rare disease in children. The frequency and outcome of children evolving to accelerated phase (AP) or blastic phase (BP) under treatment with imatinib is unknown. The aim of the current study is to assess the incidence of progression from CML in chronic phase with imatinib frontline in a paediatric setting and describe the management and outcome of these patients.

Patients And Methods: In the I-CML-Ped Study database (www.clinicaltrials.gov, #NCT01281735), 19 of 339 paediatric patients in chronic phase treated with imatinib in the frontline evolved to CML-AP or CML-BP.

Results: With a median follow-up of 38 months (range: 2-190 months), the cumulative incidence of progression at 1 and 3 years was 3% (confidence interval [CI] 95%: 1-5%) and 7% (CI 95%: 4-11%), respectively. We observed a large predominance of lymphoid-BP (70%) over myeloid-BP (30%) with imatinib in frontline therapy. Sixteen patients underwent haematopoietic stem cell transplantation, and eight were treated with a tyrosine kinase inhibitor after transplant. Only the transplanted patients are alive. The 5-year overall survival rate of children with CML-AP/BP is 44%, with no statistical difference between the lymphoid-BP and myeloid-BP outcome.

Conclusion: Children evolving to AP or BP under treatment with imatinib have a very poor prognosis with an overall survival under 50%, much worse than children with advanced phase at diagnosis.
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http://dx.doi.org/10.1016/j.ejca.2020.06.024DOI Listing
September 2020

Life Functioning in Chinese Survivors of Childhood Cancer in Hong Kong.

J Adolesc Young Adult Oncol 2021 Jun 27;10(3):326-335. Epub 2020 Jul 27.

Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.

Evidence on self-care ability and occupational outcomes in Chinese survivors of childhood cancer is clearly lacking. This study aims to identify clinical and behavioral factors associated with poor life functioning in this population. This was a cross-sectional study conducted at an ambulatory clinic of a public hospital in Hong Kong. Licensed occupational therapists administered the Life Functioning Assessment Inventory on survivors diagnosed with cancer <19 years old and ≥5 years post-diagnosis. Survivors' career development self-efficacy, subjective happiness, and motivation were evaluated using structured questionnaires. Clinical information was obtained from medical records. Multivariable linear regression was used to evaluate factors associated with life functioning outcomes, adjusting for clinically relevant variables. Eighty survivors were recruited (58.7% male; age at diagnosis: 6.7 [standard deviation (SD) = 4.8] years; age at evaluation: 24.4 [SD = 6.5] years). Compared to survivors of leukemia, survivors of brain tumor performed worse in social functioning ( = -0.79, standard error [SE] = 0.36;  = 0.034). Survivors who had been treated with cranial radiation also had lower worker life functioning than those who had not ( = -0.91, SE = 0.031;  = 0.021). Higher activity motivation was significantly associated with better leisure functioning ( = 0.086, SE = 0.03;  = 0.008), social functioning ( = 0.036, SE = 0.02;  = 0.036), and career development self-efficacy ( = 1.04, SE = 0.26;  < 0.0001). Survivors of brain tumors and survivors who were treated with radiation have poorer life functioning, particularly in social and work domains. Future work includes validating the study findings in a larger cohort of survivors in Hong Kong. Addressing modifiable behavioral factors include motivating survivors to engage in meaningful activities that contribute to self-care and participation in society, as well as providing at-risk survivors with ongoing support from community vocational services.
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http://dx.doi.org/10.1089/jayao.2020.0047DOI Listing
June 2021

Stress and Perception of Procedural Pain Management in Chinese Parents of Children With Cancer.

J Pain Symptom Manage 2021 01 5;61(1):90-102.e5. Epub 2020 Jul 5.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address:

Objectives: Children with cancer are exposed to repeated painful and invasive procedures. This study examines Chinese parents' stress and perception toward their children's procedural pain control.

Methods: We recruited 265 parents of children (aged <18 years) diagnosed with hematological cancer (74.7%) and solid tumors (25.3%) from two major public hospitals. Parents used a scale (0-10) to rate perceived pain experienced by their child when undergoing lumbar puncture (LP), bone marrow aspirate, or/and biopsy. They reported their stress level and attitudes toward analgesics using the adapted Pain Flexibility Scale for Parents and Parental Medication Attitude Questionnaire. General linear modeling was used to identify factors associated with perception outcomes.

Results: Parents (72.8% mothers, age 36.5 [6.8] years) expressed that they were worried (31.7%) and had difficulty with concentration (57.7%) when the child was in pain. Among parents whose children had undergone LP (n = 207), 39.1% perceived that their child still experienced severe pain (pain score >7) even with existing pain control measures. Parents reported concerns over side effects of analgesics (69.4%) and addiction (35.1%). Half of the parents (47.2%) perceived that analgesics should only be reserved for severe pain. Parents who were older (estimate = 2.07, SE = 0.87; P = 0.0054) and had lower education attainment (estimate = -3.38, SE = 1.09; P = 0.0021) had a more negative attitude toward analgesics use. Higher parental distress was associated with avoidance of analgesics use (r = 0.17, P = 0.0052).

Conclusion: Our findings suggested that subgroups of Chinese parents demonstrated distress with their child's pain and harbored misconceptions over analgesics use. Future work includes devising targeted psychoeducation interventions for these parents.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.06.028DOI Listing
January 2021

Virtual Reality Intervention Targeting Pain and Anxiety Among Pediatric Cancer Patients Undergoing Peripheral Intravenous Cannulation: A Randomized Controlled Trial.

Cancer Nurs 2020 Jun 4. Epub 2020 Jun 4.

Author Affiliations: The Nethersole School of Nursing (Dr Wong, Prof Chan, Drs Choi and Chen, and Miss Yeung and Chan) and Department of Paediatrics (Dr Li), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.

Background: Peripheral intravenous cannulation (PIC) is commonly performed in cancer treatment and causes pain and anxiety to children with cancer.

Objective: The aim of this study was to determine whether virtual reality distraction intervention can alleviate pain and anxiety and reduce length of procedure among pediatric cancer patients undergoing PIC.

Methods: One hundred eight pediatric cancer patients aged 6 to 17 years were recruited from a regional public hospital in Hong Kong to participate in this randomized controlled trial. The intervention group received virtual reality distraction intervention, and the control group received standard care. The primary outcome was child-reported pain. Secondary outcomes included child-reported anxiety, pulse rate, and length of procedure. Outcome measurements were conducted at 5 minutes before, during, and immediately after the procedure.

Results: Pediatric cancer patients in the intervention group demonstrated a significantly greater reduction in pain (estimated mean difference = -1.69, P = .007) and anxiety levels (estimated mean difference = -3.50, P < .001) compared with the control group. The mean duration (in minutes) for the PIC procedure was significantly shorter among participants receiving virtual reality intervention compared with the control counterparts (estimated mean difference = -0.75, P = .017). However, no significant difference was observed in pulse rate during and after the procedure between groups.

Conclusions: Findings indicate that virtual reality is safe and effective to alleviate pain and anxiety among pediatric cancer patients undergoing PIC procedure.

Implications For Practice: Virtual reality can be considered as an adjunctive treatment to manage pain and anxiety in pediatric cancer patients before and during PIC procedure.
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http://dx.doi.org/10.1097/NCC.0000000000000844DOI Listing
June 2020

A novel F11 mutation in a Chinese paediatric patient with severe factor XI deficiency.

Thromb Res 2020 06 18;190:89-90. Epub 2020 Apr 18.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.

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http://dx.doi.org/10.1016/j.thromres.2020.04.016DOI Listing
June 2020

Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment.

Eur J Cancer 2020 06 7;132:11-16. Epub 2020 Apr 7.

The Cancer Centre for Children, The Children's Hospital at Westmead, Australia.

Introduction: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia.

Aim And Methods: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey.

Results: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19.

Conclusion: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.
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http://dx.doi.org/10.1016/j.ejca.2020.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141482PMC
June 2020

Massively parallel variant characterization identifies alleles associated with thiopurine toxicity.

Proc Natl Acad Sci U S A 2020 03 24;117(10):5394-5401. Epub 2020 Feb 24.

Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden.

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, deficiency was identified as a genetic cause of thiopurine toxicity, and -informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.
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http://dx.doi.org/10.1073/pnas.1915680117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071893PMC
March 2020

Septicemia after chemotherapy for childhood acute lymphoblastic leukemia in China: A multicenter study CCCG-ALL-2015.

Cancer Med 2020 03 28;9(6):2113-2121. Epub 2020 Jan 28.

Department of Paediatrics, Hong Kong Children's Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.

Background: Septicemia is an important cause of treatment-related mortality and treatment failure in pediatric acute lymphoblastic leukemia (ALL) in developing countries. A multicenter CCCG-ALL-2015 study was conducted in China and factors associated with septicemia and mortality were studied.

Methods: Patients participated in CCCG-ALL-2015 study from January 2015 to December 2017 were included. Patients with documented septicemia were identified from the Data Center and additional data were collected.

Results: A total of 4080 patients were recruited in the study and 527 patients with septicemia were identified (12.9%, 95% CI 11.9%-13.9%). The intermediate risk (IR)/high risk (HR) group had significantly higher incidence of septicemia as compared with low risk (LR) group, 17.1% vs 9.1% (OR 2.07, 95% CI 1.71-2.49, P < .001). Induction phase was the period with majority of septicemia episodes happened, 66.8% in LR and 56.1% in IR/HR groups. Gram-positive bacteria accounted for 54.1%, gram-negative bacteria 44.5%, and fungus 1.4% of positive cultures. Multidrug-resistant organisms were detected in 20.5% of all organisms. The mortality rate after septicemia was 3.4% (95% CI 1.9%-4.9%). Multiple logistic regression identified female gender, comorbid complications, and fungal infection as risk factors associated with mortality. Gram-negative septicemia was associated with higher mortality, 4.9% vs 1.4% (OR 0.28, 95% CI 0.09-0.88, P = .02). There was marked variation in the incidence of septicemia among the 18 centers, from 4.8% to 29.1%.

Conclusion: Overall the incidence and pattern of septicemia in this multicenter study in China was similar to the reports of western countries. The septicemia-related mortality rate was low. There was marked variation in the incidence of septicemia among the centers.
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http://dx.doi.org/10.1002/cam4.2889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064088PMC
March 2020

Neurocognitive impairment in Asian childhood cancer survivors: a systematic review.

Cancer Metastasis Rev 2020 03;39(1):27-41

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, 8th Floor, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Shatin, New Territories, Hong Kong.

Childhood cancer survivors are at higher risk of developing neurocognitive deficits due to the intensive treatment they received at an early age. Most studies on childhood cancer survivorship have so far focused on the Western populations. Due to the ethnic, genetic, environmental, and cultural differences, clinical data of the Western populations may not be representative of Asian countries. This scoping review systematically summarized the existing clinical evidence of the neurocognitive impairment of Asian childhood cancer survivors. We searched the Embase and Medline databases for studies assessing the neurocognitive functions of survivors in Asia, who were diagnosed with cancer before the age of 19 and completed active treatment. The literature search identified 13 studies involving 2212 participants from five Asian countries: South Korea (n = 4, 30.8%), Taiwan (n = 3, 23.1%), Japan (n = 3, 23.1%), Hong Kong (n = 2, 15.4%), and Thailand (n = 1, 7.7%). The included studies focused on CNS tumors (n = 10, 76.9%), hematological malignancies (n = 7, 53.8%), or heterogeneous cancer diagnoses (n = 3, 23.1%). Collectively, mild-to-moderate impairment in intelligence was observed in 10.0 to 42.8% of survivors, which seemed higher than the reported rate in Western survivors. We speculate that the ethnic and genetic variations in drug responses and susceptibility to adverse chronic toxicities may have contributed to the differences in the prevalence and severity of neurocognitive impairment between these two populations. To better understand the effects of culturally relevant and region-specific environmental risk factors on the post-treatment neurocognitive development in cancer survivors, a holistic approach that addresses the complex interactions between biological, physical, and psychosocial factors is needed. This will aid the development of effective intervention strategies to improve the functional and psychosocial outcomes of cancer survivors in Asian societies.
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http://dx.doi.org/10.1007/s10555-020-09857-yDOI Listing
March 2020

Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

JAMA Oncol 2020 03;6(3):358-366

State Key Laboratory of Experimental Hematology and Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin, China.

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation.

Design, Setting, And Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019.

Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy.

Main Outcomes And Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival.

Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups.

Conclusions And Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation.

Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.
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http://dx.doi.org/10.1001/jamaoncol.2019.5868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990720PMC
March 2020

CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity.

Leukemia 2020 03 17;34(3):709-720. Epub 2019 Oct 17.

Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong.

CD9 has been implicated in cancer progression but its prognostic relevance and therapeutic potential in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are largely unknown. In a cohort of pediatric BCP-ALL patients, we found that CD9 cases had a significantly lower 5-year relapse-free survival rate than CD9 cases. Multivariate analysis demonstrated that CD9 positivity independently predicted inferior survival outcomes, and could be applied with established prognostic features, including prednisone response and cytogenetic status, to refine patient stratification. Administration of CD9 antibody substantially suppressed disease progression in NOD/SCID mice xenografted with CD9 cell lines and primary leukemic blasts from patients with high-risk and refractory BCP-ALL, without compromising hematopoietic stem cell engraftment. Combination of anti-CD9 with conventional chemotherapy further reduced leukemic burden and prolonged animal survival. Mechanistically, CD9 blockade inhibited leukemic cell proliferation, induced G/G cell cycle arrest, activated p38, and enhanced chemotherapeutic agent-induced apoptosis. Further, CD9 physically interacted with integrin very late antigen-4, regulated affinity to vascular cell adhesion molecule-1, and was involved in leukemia-stroma interaction. Collectively, our study established CD9 as a new prognostic marker, validated the preclinical efficacy of CD9 antibody, and laid the foundation for clinical development of CD9-targeted therapy for high-risk and refractory pediatric BCP-ALL.
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http://dx.doi.org/10.1038/s41375-019-0593-7DOI Listing
March 2020