Tumor vaccine based on extracellular vesicles derived from γδ-T cells exerts dual antitumor activities.

γδ-T cells are innate-like T cells with dual antitumor activities. They can directly eradicate tumor cells and function as immunostimulatory cells to promote antitumor immunity. Previous studies have demonstrated that small extracellular vesicles (EVs) derived from γδ-T cells (γδ-T-EVs) inherited the dual antitumor activities from their parental cells. However, it remains unknown whether γδ-T-EVs can be designed as tumors vaccine to improve therapeutic efficacy. Here, we found that γδ-T-EVs had immune adjuvant effects on antigen-presenting cells, as revealed by enhanced expression of antigen-presenting and co-stimulatory molecules, secretion of pro-inflammatory cytokines and antigen-presenting ability of DCs after γδ-T-EVs treatment. The γδ-T-EVs-based vaccine was designed by loading tumor-associated antigens (TAAs) into γδ-T-EVs. Compared with γδ-T-EVs, the γδ-T-EVs-based vaccine effectively promoted more tumor-specific T-cell responses. In addition, the vaccine regimen preserved direct antitumor effects and induced tumor cell apoptosis. Interestingly, the allogeneic γδ-T-EVs-based vaccine showed comparable preventive and therapeutic antitumor effects to their autologous counterparts, indicating a better way of centralization and standardization in clinical practice. Furthermore, the allogeneic γδ-T-EVs-based vaccine displayed advantages over the DC-EVs-based vaccine through their dual antitumor activities. This study provides a proof-of-concept for using the allogeneic γδ-T-EVs-based vaccine in cancer control.

IL-33 Orchestrated the Interaction and Immunoregulatory Functions of Alternatively Activated Macrophages and Regulatory T Cells In Vitro.

Our group has previously demonstrated elevated serum-soluble ST2 in patients with active systemic lupus erythematosus, suggesting a role of IL-33 in the underlying pathogenesis. However, inconsistent results have been reported on the effect of exogenous IL-33 on murine lupus activity, which may be mediated by concerted actions of various immune cells in vivo. This study aimed to examine the function of IL-33 on macrophage polarization and regulatory T cells (Treg) and their interactive effects in the lupus setting by in vitro coculture experiments of macrophages and T cells that were performed in the presence or absence of IL-33-containing medium. Compared to IL-4-polarized bone marrow-derived macrophages (BMDM) from MRL/MpJ mice, adding IL-33 enhanced mRNA expression of markers of alternatively activated macrophages, including CD206 and Arg1. IL-33 and IL-4 copolarized BMDM produced higher TGF-ß but not IL-6 upon inflammatory challenge. These BMDM induced an increase in the Foxp3+CD25+ Treg population in cocultured allogeneic T cells from MRL/MpJ and predisease MRL/lpr mice. These copolarized BMDM also showed an enhanced suppressive effect on T cell proliferation with reduced IFN-γ and IL-17 release but increased TGF-ß production. In the presence of TGF-ß and IL-2, IL-33 also directly promoted inducible Treg that expressed a high level of CD25 and more sustained Foxp3. Unpolarized BMDM cocultured with these Treg displayed higher phagocytosis. In conclusion, TGF-ß was identified as a key cytokine produced by IL-4 and IL-33 copolarized alternatively activated macrophages and the induced Treg, which may contribute to a positive feedback loop potentiating the immunoregulatory functions of IL-33.

The impact of the multi-disciplinary molecular tumour board and integrative next generation sequencing on clinical outcomes in advanced solid tumours.

Background: The integration of next-generation sequencing (NGS) comprehensive gene profiling (CGP) into clinical practice is playing an increasingly important role in oncology. Therefore, the HKU-HKSH Multi-disciplinary Molecular Tumour Board (MTB) was established to advance precision oncology in Hong Kong. A multicenter retrospective study investigated the feasibility of the HKU-HKSH MTB in determining genome-guided therapy for treatment-refractory solid cancers in Hong Kong. Methods: Patients who were presented at the HKU-HKSH MTB between August 2018 and June 2022 were included in this study. The primary study endpoints were the proportion of patients who receive MTB-guided therapy based on genomic analysis and overall survival (OS). Secondary endpoints included the proportion of patients with actionable genomic alterations, objective response rate (ORR), and disease control rate (DCR). The Kaplan-Meier method was used in the survival analyses, and hazard ratios were calculated using univariate Cox regression. Findings: 122 patients were reviewed at the HKU-HKSH MTB, and 63% (n = 77) adopted treatment per the MTB recommendations. These patients achieved a significantly longer median OS than those who did not receive MTB-guided therapy (12.7 months vs. 5.2 months, P = 0.0073). Their ORR and DCR were 29% and 65%, respectively. Interpretation: Our study demonstrated that among patients with heavily pre-treated advanced solid cancers, MTB-guided treatment could positively impact survival outcomes, thus illustrating the applicability of NGS CGPs in real-world clinical practice. Funding: The study was supported by the Li Shu Pui Medical Foundation. Dr Aya El Helali was supported by the Li Shu Pui Medical Foundation Fellowship grant from the Li Shu Pui Medical Foundation. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited. METHODS: Human MSCs were derived from bone marrow (BM), adipose tissue (AT) and umbilical cord (UC). In vitro immunomodulatory potential was determined by co-culture experiments between hMSCs and immune cells implicated in aGvHD disease progression. BM-, AT- and UC-hMSCs were tested for their abilities to protect aGvHD in a mouse model of this disease. Survival and clinical symptoms were monitored, and target tissues of aGvHD were examined by histopathology and qPCR. Transplanted cell survival was evaluated by cell tracing and by qPCR. The transcriptome of BM-, AT- and UC-hMSCs was profiled by RNA-sequencing. Focused experiments were performed to compare the expression of complement inhibitors and the abilities of hMSCs to resist complement lysis. RESULTS: Human MSCs derived from three tissues divergently protected against aGvHD in vivo. AT-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to BM- and UC-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGvHD. We found that complement-decay accelerating factor (CD55), an inhibitor of complement, is elevated in AT-hMSCs and contributed to reduced complement activation. We further report that atorvastatin and erlotinib could upregulate CD55 and suppress complement in all three types of hMSCs. CONCLUSION: CD55, by suppressing complement, contributes to the improved protection of AT-hMSCs against aGvHD. The use of AT-hMSCs or the upregulation of CD55 by small molecules thus represents promising new strategies to promote hMSC survival to improve the efficacy of transplantation therapy. As complement injury is a barrier to all types of hMSC therapy, our findings are of broad significance to enhance the use of hMSCs for the treatment of a wide range of disorders.

Systematic Review of the Effectiveness of Complementary and Alternative Medicine on Nausea and Vomiting in Children With Cancer.

BACKGROUND: Nausea and vomiting are distressing symptoms reported by pediatric oncology patients during cancer treatment. More than 40% of them experience these symptoms even after receiving antiemetics. OBJECTIVE: Given the limitations of pharmacological interventions, this systematic review synthesized the evidence for the effectiveness of complementary and alternative medicine in controlling nausea and vomiting among pediatric oncology patients. METHODS: Ten databases were searched to identify relevant randomized controlled trials. The risk of bias of selected studies was graded using the Cochrane risk-of-bias tool for randomized trials. The primary outcomes were nausea and vomiting. The secondary outcomes were intervention adherence and number of adverse events. RESULTS: Nineteen papers met the inclusion criteria and were included in the review. Sixteen studies showed high risk of bias. The tested interventions were acupuncture, acupressure, aromatherapy, hypnosis, massage, active cognitive distraction/relaxation techniques, creative arts therapy, psychoeducation, and combined massage and acupressure. Acupuncture, hypnosis, and massage interventions improved nausea and vomiting. Fifteen trials reported intervention adherence; only 7 monitored adverse events. The most common reason for dropout was refusal from patients and/or their guardians. A total of 34 adverse events were noted. CONCLUSIONS: There is insufficient evidence that complementary and alternative medicine is effective, feasible, or safe in controlling nausea and vomiting among pediatric oncology patients due to high risk of bias. IMPLICATIONS FOR PRACTICE: Acupuncture, hypnosis, and massage appear to have therapeutic benefits. However, more robust studies are needed to address the identified methodological issues and determine the real value of these 3 interventions.

Coriolus versicolor and its bioactive molecule are potential immunomodulators against cancer cell metastasis via inactivation of MAPK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Coriolus versicolor (CV) has been used in traditional Chinese medicine for over 2000 years as a premium medicine for enhancing good health and longevity. The immunomodulatory and anti-cancer effects of polysaccharopeptides (PSP) from cultured CV have been extensively studied; however, the effect and the mechanism of action of other small molecules from CV remain unknown. AIM OF THE STUDY: we aim to examine the immunomodulatory and anti-cancer effects of the small molecules from CV (SMCV) and identify the active compounds that are responsible for the biological effects against glioblastoma multiforme cells. MATERIALS AND METHODS: The effects of SMCV/active compound on cytokine and MMP mRNA expressions and productions were assessed by quantitative reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. An active compound from SMCV was identified with a bioassay-guided fractionation scheme. The potential mode of action of the active compound was further investigated by identifying the cell signaling pathway. The protein expressions of phospho-ERK, phospho-JNK and phospho-p38 MAPKs were measured by Western Blotting. The anti-invasive effect of SMCV/bioactive compound against T98G, lung carcinoma (A549), and breast adenocarcinoma (MDA-MB-231) cells were determined using invasion assay. RESULTS: Our results showed that SMCV had strong immunomodulatory effect by suppressing LPS-induced TNF-α production, whereas increasing poly I:C-induced IFN-ß level in PBMac. SMCV not only possessed indirect anti-cancer effect by suppressing TNF-α-induced MMP-3 production in glioblastoma T98G cells, but also directly reduced the invasion ability of malignant cells including T98G, A549 and MDA-MB-231. Using bioassay-guided fractionation scheme, we isolated 9-KODE methyl ester (compound AM) that was responsible for the bioactivity of SMCV. This compound suppressed TNF-α-induced MMP-3 production in T98G cells and the suppression may be correlated with the inactivation of p38 mitogen-activated protein kinase (MAPK) pathway. Moreover, compound AM also directly reduced T98G cell invasion. CONCLUSION: Results of our present study provides scientific evidence that SMCV possesses immunomodulatory and anti-cancer effects. Its bioactive compound, compound AM, is a potential new drug candidate against the invasion and metastasis of glioblastoma cells.

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.

Epidemiology and outcomes of pediatric transplant-associated thrombotic microangiopathy in Hong Kong.

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) is an under-recognized yet potentially devastating complication of hematopoietic stem cell transplantation (HSCT) which had increased awareness in recent years. This report summarizes the demographics and outcomes of pediatric TA-TMA in Hong Kong. METHODS: All patients aged below 18 years who underwent HSCT in the Hong Kong Children's Hospital and were diagnosed to have TA-TMA during the 2-year period from April 1, 2019 to March 31, 2021 were included. RESULTS: A total of 73 transplants (51 allogeneic and 22 autologous) in 63 patients had been performed. Six patients (four males and two females) developed TA-TMA at a median duration of 2.5 months post-HSCT. The incidence rate was 9.52%. Of the six TA-TMA patients, five underwent allogenic one underwent autologous HSCT, respectively. Three of them were histologically proven. All four patients with cyclosporine had stopped the drug once TA-TMA was suspected. Median six doses of eculizumab were administered to five out of six patients. Three patients died (two due to fungal infection and one due to acute-on-chronic renal failure) within 3 months upon diagnosis of TA-TMA. Among three survivors, two stabilized with mild stage 2 chronic kidney disease (CKD) while the other suffered from stage 5 end-stage CKD requiring lifelong dialysis. CONCLUSION: In conclusion, recognition and diagnosis of TA-TMA are challenging. Early recognition and prompt administration of complement blockage with eculizumab may be beneficial in selected cases. Further prospective research studies are recommended to improve the management and outcomes of TA-TMA.

Efficacy of Mobile Instant Messaging-Delivered Brief Motivational Interviewing for Parents to Promote Physical Activity in Pediatric Cancer Survivors: A Randomized Clinical Trial.

Importance: Physical activity has beneficial effects that mitigate cancer- and treatment-related late effects. However, children who survive cancer are often physically inactive. Brief motivational interviewing may be an effective approach for increasing children's physical activity levels. Objective: To examine the effects of mobile instant messaging-delivered brief motivational interviewing for parents in promoting regular physical activity in children who have survived cancer. Design, Setting, and Participants: An assessor-blinded randomized clinical trial was conducted at 2 Hong Kong pediatric oncology outpatient clinics from March 1, 2019, to January 29, 2021. A total of 161 children who had survived cancer, aged 9 to 16 years, and their parents were randomized (1:1) to an intervention or control group. Interventions: The intervention group received a 6-month mobile instant messaging-delivered brief motivational interviewing using a strategy menu. Parent-child dyads in both groups received a health advice session and were directed to a physical activity website at baseline. Main Outcomes and Measures: The primary outcome was the children's physical activity levels at 12-month follow-up, measured by the Chinese University of Hong Kong: Physical Activity Rating for Children and Youth (total sores: 0-10, higher scores indicate greater physical activity levels). Secondary outcomes were cancer-related fatigue levels, handgrip strength, peak expiratory flow rate, and quality of life. Intention-to-treat analysis was performed. Results: Of the 161 children included in the study, 93 were boys (57.8%), and the mean (SD) age was 12.4 (2.4) years. Generalized estimating equation analyses showed a significant improvement in outcomes in the intervention group compared with the control group: physical activity levels (group-by-time interaction, 6 months: ß = 3.09; 95% CI, 2.65-3.53; P < .001; 12 months: ß = 3.91; 95% CI, 3.45-4.36; P < .001), cancer-related fatigue (6 months: ß = -5.69; 95% CI, -8.03 to -3.35; P < .001; 12 months: ß = -9.16; 95% CI, -11.31 to -7.00; P < .001), left handgrip strength (6 months: ß = 2.69; 95% CI, 0.96-4.43; P = .002; 12 months: ß = 5.52; 95% CI, 3.70-7.33; P < .001), right handgrip strength (6 months: ß = 2.75; 95% CI, 1.01-4.50; P = .002; 12 months: ß = 5.45; 95% CI, 3.62-7.27; P < .001), peak expiratory flow rate (12 months: ß = 28.51; 95% CI, 16.10-40.92; P < .001), and quality of life (6 months: ß = 5.01; 95% CI, 1.19-8.82; P = .01); 12 months: ß = 14.19; 95% CI, 10.84-17.54; P < .001). Conclusions and Relevance: In this randomized clinical trial, mobile instant messaging-delivered brief motivational interviewing was effective in promoting the adoption and maintenance of regular physical activity and ameliorating cancer- or treatment-related adverse effects in children who survived cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03859271.

Associations of Physical Activity and Handgrip Strength with Different Domains of Quality of Life in Pediatric Cancer Survivors.

There is a paucity of evidence about the associations of physical activity (PA) and handgrip strength (HGS) within different domains of quality of life (QoL) in Chinese pediatric cancer survivors. We, therefore, conducted this multicenter cross-sectional study aimed to investigate whether increased PA level and HGS are associated with higher scores in different QoL domains (i.e., physical, emotional, social, and school functioning) in pediatric cancer survivors. PA was assessed with a validated self-reported PA rating scale. In total, 191 Chinese pediatric cancer survivors aged 9 to 16 years were included in the analysis. Results showed that engaging in a higher level of PA was significantly associated with improved QoL in different domains, including physical (ß = 0.543, p < 0.001), emotional (ß = 0.449, p < 0.001), social (ß = 0.434, p < 0.001), and school functioning (ß = 0.407, p < 0.001). Greater HGS was also associated with better physical (ß = 0.230, p ≤ 0.001) and emotional (ß = 0.261, p ≤ 0.001) functioning. Findings from this study provide evidence of the significant beneficial impact of regular PA on pediatric cancer survivors' QoL along their survivorship trajectory.

Outcome prediction of chronic myeloid leukemia (CML) in children.

We evaluated the feasibility of existing risk assessment tools for chronic myeloid leukemia (CML) in children. Fifty-five patients with newly diagnosed CML between 1996 and 2019 were included. Forty-nine patients presented in chronic phase, thirty-six of whom were treated with upfront tyrosine kinase inhibitor (CP-TKI group); one presented in accelerated phase and four in blastic phase. Treatment, survival, responses, and tolerance were evaluated. All patients in the CP-TKI group received imatinib as their first TKI treatment. The 10-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of TKI-treated group was 97%, 91.4%, and 72.3%, respectively. At 60 months, the rates of major molecular response were 81.2% and deep molecular response was 67.5%. The EUTOS long-term survival (ELTS) risk grouping did not predict OS, PFS, or EFS. The IMAFAIL risk groups were correlated with the risk of imatinib failure. Further studies are required to modify the existing risk assessment tools for children.

Comprehensive analysis of recessive carrier status using exome and genome sequencing data in 1543 Southern Chinese.

Traditional carrier screening has been utilized for the detection of carriers of genetic disorders. Since a comprehensive assessment of the carrier frequencies of recessive conditions in the Southern Chinese population is not yet available, we performed a secondary analysis on the spectrum and carrier status for 315 genes causing autosomal recessive disorders in 1543 Southern Chinese individuals with next-generation sequencing data, 1116 with exome sequencing and 427 with genome sequencing data. Our data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.30% of the population) was a carrier for treatable inherited conditions. In alignment with current American College of Obstetricians and Gynecologists (ACOG) pan-ethnic carrier recommendations, 1 in 26 individuals were identified as carriers of cystic fibrosis, thalassemia, and spinal muscular atrophy in the Southern Chinese population. When the >1% expanded carrier screening rate recommendation by ACOG was used, 11 diseases were found to meet the criteria in the Southern Chinese population. Approximately 1 in 3 individuals (35.5% of the population) were carriers of these 11 conditions. If the 1 in 200 carrier frequency threshold is used, and additional seven genes would meet the criteria, and 2 in 5 individuals (38.7% of the population) would be detected as a carrier. This study provides a comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population and can serve as a reference for careful evaluation of the conditions to be included in expanded carrier screening for Southern Chinese people.

Anti-GD2 Directed Immunotherapy for High-Risk and Metastatic Neuroblastoma.

Neuroblastoma is one of the few childhood cancers that carries a tumor-specific antigen in the form of a glycolipid antigen known as GD2. It has restricted expression in normal tissue, such as peripheral afferent nerves. Monoclonal antibodies targeting GD2 have been applied clinically to high-risk neuroblastoma with significant success. However, there are different anti-GD2 products and administration regimens. For example, anti-GD2 has been used in combination with chemotherapy during the induction phase or with retinoic acid during the maintenance stage. Regimens also vary in the choice of whether to add cytokines (i.e., IL-2, GMCSF, or both). Furthermore, the addition of an immune enhancer, such as ß-glucan, or allogeneic natural killer cells also becomes a confounder in the interpretation. The question concerning which product or method of administration is superior remains to be determined. So far, most studies agree that adding anti-GD2 to the conventional treatment protocol can achieve better short- to intermediate-term event-free and overall survival, but the long-term efficacy remains to be verified. How to improve its efficacy is another challenge. Late relapse and central nervous system metastasis have emerged as new problems. The methods to overcome the mechanisms related to immune evasion or resistance to immunotherapy represent new challenges to be resolved. The newer anti-GD2 strategies, such as bispecific antibody linking of anti-GD2 with activated T cells or chimeric antigen receptor T cells, are currently under clinical trials, and they may become promising alternatives. The use of anti-GD2/GD3 tumor vaccine is a novel and potential approach to minimizing late relapse. How to induce GD2 expression from tumor cells using the epigenetic approach is a hot topic nowadays. We expect that anti-GD2 treatment can serve as a model for the use of monoclonal antibody immunotherapy against cancers in the future.

Exosomes derived from γδ-T cells synergize with radiotherapy and preserve antitumor activities against nasopharyngeal carcinoma in immunosuppressive microenvironment.

BACKGROUND: Radiotherapy is the first-line treatment for patients nasopharyngeal carcinoma (NPC), but its therapeutic efficacy is poor in some patients due to radioresistance. Adoptive T cell-based immunotherapy has also shown promise to control NPC; however, its antitumor efficacy may be attenuated by an immunosuppressive tumor microenvironment. Exosomes derived from γδ-T cells (γδ-T-Exos) have potent antitumor potentials. However, it remains unknown whether γδ-T-Exos have synergistic effect with radiotherapy and preserve their antitumor activities against NPC in an immunosuppressive tumor microenvironment. METHODS: γδ-T-Exos were stained with fluorescent membrane dye, and their interactions with NPC were determined both in vitro and in vivo. NPC cell deaths were detected after treatment with γδ-T-Exos and/or irradiation. Moreover, effects of γδ-T-Exos on radioresistant cancer stem-like cells (CSCs) were determined. The therapeutic efficacy of combination therapy using γδ-T-Exos and irradiation on NPC tumor progression was also monitored in vivo. Finally, the tumor-killing and T cell-promoting activities of γδ-T-Exos were determined under the culture in immunosuppressive NPC supernatant. RESULTS: γδ-T-Exos effectively interacted with NPC tumor cells in vitro and in vivo. γδ-T-Exos not only killed NPC cells in vitro, which was mainly mediated by Fas/Fas ligand (FasL) and death receptor 5 (DR5)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways, but also controlled NPC tumor growth and prolonged tumor-bearing mice survival in vivo. Furthermore, γδ-T-Exos selectively targeted the radioresistant CD44+/high CSCs and induced profound cell apoptosis. The combination of γδ-T-Exos with radiotherapy overcame the radioresistance of CD44+/high NPC cells and significantly improved its therapeutic efficacy against NPC in vitro and in vivo. In addition, γδ-T-Exos promoted T-cell migration into NPC tumors by upregulating CCR5 on T cells that were chemoattracted by CCR5 ligands in the NPC tumor microenvironment. Although NPC tumor cells secreted abundant tumor growth factor beta to suppress T-cell responses, γδ-T-Exos preserved their direct antitumor activities and overcame the immunosuppressive NPC microenvironment to amplify T-cell antitumor immunity. CONCLUSIONS: γδ-T-Exos synergized with radiotherapy to control NPC by overcoming the radioresistance of NPC CSCs. Moreover, γδ-T-Exos preserved their tumor-killing and T cell-promoting activities in the immunosuppressive NPC microenvironment. This study provides a proof of concept for a novel and potent strategy by combining γδ-T-Exos with radiotherapy in the control of NPC.

circMine: a comprehensive database to integrate, analyze and visualize human disease-related circRNA transcriptome.

Many circRNA transcriptome data were deposited in public resources, but these data show great heterogeneity. Researchers without bioinformatics skills have difficulty in investigating these invaluable data or their own data. Here, we specifically designed circMine (http://hpcc.siat.ac.cn/circmine and http://www.biomedical-web.com/circmine/) that provides 1 821 448 entries formed by 136 871 circRNAs, 87 diseases and 120 circRNA transcriptome datasets of 1107 samples across 31 human body sites. circMine further provides 13 online analytical functions to comprehensively investigate these datasets to evaluate the clinical and biological significance of circRNA. To improve the data applicability, each dataset was standardized and annotated with relevant clinical information. All of the 13 analytic functions allow users to group samples based on their clinical data and assign different parameters for different analyses, and enable them to perform these analyses using their own circRNA transcriptomes. Moreover, three additional tools were developed in circMine to systematically discover the circRNA-miRNA interaction and circRNA translatability. For example, we systematically discovered five potential translatable circRNAs associated with prostate cancer progression using circMine. In summary, circMine provides user-friendly web interfaces to browse, search, analyze and download data freely, and submit new data for further integration, and it can be an important resource to discover significant circRNA in different diseases.

Treatment barriers and clinical outcome of children with medulloblastoma in China: a report from the Chinese Children's Cancer Group (CCCG).

BACKGROUND: Medulloblastoma (MB) is the most common malignant central nervous system tumor of childhood. Management requires interdisciplinary care and is associated with unique challenges in developing regions. Here, we report the characteristics, clinical outcome and treatment barriers for Chinese children with MB based on a multi-institutional cohort from the Chinese Children's Cancer Group (CCCG). METHODS: Retrospective cohort study among 12 Chinese pediatric oncology units from the CCCG Brain Tumor Workgroup on patients aged <18 years diagnosed with MB from 2016 to 2019. RESULTS: 221 patients (male:female = 138:83) were included, 175 (79%) were ≥3 years of age, and 46 (21%) <3 years. 177 patients (80%) were completely staged, among which 50 (28%) had metastasis and 70 (40%) were considered to have high-risk (HR) disease. Gross/near-total resection was achieved in 203 patients (92%). In patients where molecular grouping could be assigned, 19 (16%), 35 (29%), and 65 (54%), respectively had WNT-activated, SHH-activated, and Group 3/4 MB. The median duration between resection and initiation of adjuvant therapy was 36 days. Respective 2-year PFS and OS rates were 76.0 ± 3.0% and 88.0 ± 2.3%. PFS was significantly associated with age, metastatic status and clinical risk grouping. Chemotherapy use during CSI or alkylator choice were not significant predictors for patient outcome. CONCLUSIONS: We reported the clinical profiles and outcome from the largest cohort of Chinese children with MB after multi-modal therapy. Strengths and limitations on the local provision of neuro-oncology service are identified.

HLA alleles associated with asparaginase hypersensitivity in Chinese children.

Asparaginase is an important drug to treat childhood haematological malignancies. Data on the association between human leukocyte antigens (HLA) and asparaginase hypersensitivity among Chinese are lacking. We conducted a retrospective study to identify HLA alleles associated with asparaginase hypersensitivity among Chinese children with acute lymphoblastic leukaemia (ALL), mixed phenotype leukaemia and non-Hodgkin lymphoma (NHL), who received asparaginases with HLA typing performed between 2009 and 2019. 107 Chinese patients were analysed. 66.3% (71/107) developed hypersensitivity to at least one of the asparaginases. HLA-B*46:01 (OR 3.8, 95% CI 1.4-10.1, p < 0.01) and DRB1*09:01 (OR 4.3, 95% CI 1.6-11.4, p < 0.01) were significantly associated with L-asparaginase hypersensitivities, which remained significant after adjustment for age, gender and B cell ALL [HLA-B*46:01 (adjusted OR 3.5, 95% 1.3-10.5, p = 0.02) and DRB1*09:01 (OR 4.4, 95% CI 1.6-13.3, p < 0.01)].

Translation and psychometric evaluation of the Chinese version of the resilience scale for children with cancer.

BACKGROUND: To test the psychometric properties of a traditional Chinese version of the Resilience Scale for Children (RS-10) and examine its factorial structure via a confirmatory factor analysis (CFA). METHODS: One hundred and eighty-six Hong Kong Chinese children with cancer were recruited in the paediatric oncology units of two public acute-care hospitals in Hong Kong to participate in this cross-sectional study. The psychometric properties of the traditional Chinese version of the RS-10 were assessed, namely its content equivalence, convergent and discriminant validity, construct validity, internal consistency and test-retest reliability. RESULTS: The newly translated traditional Chinese version of the RS-10 demonstrated adequate internal consistency (Cronbach's α = .83, McDonald's Ω = .80), excellent test-retest reliability (.89), good content equivalence (CVI = 96%) and appropriate convergent (r = - .52, P = .01) and discriminant validity (r = .61, P = .01). The CFA results demonstrated that there was a good fit between the factor structure of the Chinese version of the RS-10 and the observed data (χ2/df = 2.34, TLI = .951, RMSEA = .053, CFI = .962, GFI = .948, SRMR = .052), thereby confirming the construct validity of this instrument. CONCLUSIONS: The traditional Chinese version of the RS-10 was found to be a reliable and valid tool for assessing the resilience of Hong Kong Chinese children with cancer. The newly developed traditional Chinese version of the RS-10 is an appropriate clinical research tool for evaluating the effectiveness of nursing interventions in enhancing the resilience of and promoting mental well-being in children with cancer. Trial registration NCT03544190.

Neurological complications in Chinese children undergoing hematopoietic stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation, despite being a curative treatment for various pediatric disorders, is associated with significant acute and chronic complications. METHODS: This retrospective review of 196 hematopoietic stem cell transplantation episodes (144 allogeneic, 52 autologous) performed in a tertiary pediatric unit focused on neurological symptoms and complications occurred from the start of conditioning to within 3 years of transplantation. Indications for transplantation included both benign and malignant diseases. For episodes involving allogeneic transplantation, 42% of donors were matched-unrelated, 19% were matched-sibling, and 12% were haploidentical.  RESULTS: Neurological complications developed in 17% of all hematopoietic stem cell transplantation episodes. Tumors of central nervous system and leukemia or lymphoma were two indications reported to have higher incidence of 42% and 21%, respectively. The occurrence of neurological complications was significantly associated with primary diagnosis (p = 0.01), central nervous system involvement by underlying disease (p = 0.001), and radiation-based conditioning (p = 0.018). Upon multivariate analysis, central nervous system involvement by underlying disease remained to be the only significant factor (p = 0.019), while radiation-based containing conditioning (p = 0.029) is revealed to be associated when considering allogeneic transplantation alone. Pre-transplant central nervous system-directed treatment, allogeneic versus autologous donor, stem cell source, donor type, busulfan use, and cyclosporin use were not significantly associated with neurological complications. Patients with neurological complications were also found to have an inferior 2-year overall survival (53.9% ± 8.8% versus 63.8% ± 4.2%; p = 0.016). CONCLUSION: Neurological complications were common in pediatric hematopoietic stem cell transplantation and were associated with adverse outcome; non-radiation containing conditioning regimens might be beneficial in mitigating the risk of such complications.