Stratified Treatment in Pediatric Anaplastic Large Cell Lymphoma: Result of a Prospective Open-Label Multiple-Institution Study.

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin's lymphoma Berlin-Frankfurt-Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% [95% Confidence Interval (CI), 69.0%-83.9%] and 92.3% (95% CI,86.1%-95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5%-95.5%, and 67.9% (95% CI, 55.4%-77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6%-19.0%), 65.7% (95% CI, 47.6%-78.9%), 55.7% (95% CI, 26.2%-77.5%), and 70.7% (95% CI, 48.6%-84.6%), respectively. At the end of follow-up, one of the 5 patients who received maintenance therapy with VBL relapsed, and seven patients receiving ALK inhibitor maintenance therapy did not experience relapse. Conclusion: This study has confirmed the poor prognostic of MDD (+) ，high risk site and SC/LH ,but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

Long-term ambient ozone exposure and incident cardiovascular diseases: National cohort evidence in China.

BACKGROUND: Long-term ozone (O3) exposure has been associated with cardiovascular disease (CVD) mortality in mounting cohort evidence, yet its relationship with incident CVD was poorly understood, especially in low- and middle-income countries (LMICs) experiencing high ambient air pollution. METHODS: We carried out a nationwide perspective cohort study from 2010 through 2018 by dynamically enrolling 36948 participants across Chinese mainland. Warm-season (April-September) O3 concentrations were estimated using satellite-based machine-learning models with national coverage. Cox proportional hazards model with time-varying exposures was employed to evaluate the association of long-term O3 exposure with incident CVD (overall CVD, hypertension, stroke, and coronary heart disease [CHD]). Assuming causality, a counterfactual framework was employed to estimate O3-attributable CVD burden based on the exposure-response (E-R) relationship obtained from this study. Decomposition analysis was utilized to quantify the contributions of four key direct driving factors (O3 exposure, population size, age structure, and incidence rate) to the net change of O3-related CVD cases between 2010 and 2018. RESULTS: A total of 4428 CVD, 2600 hypertension, 1174 stroke, and 337 CHD events were reported during 9-year follow-up. Each 10-µg/m³ increase in warm-season O3 was associated with an incident risk of 1.078 (95% confidence interval [CI]: 1.050-1.106) for overall CVD, 1.098 (95% CI: 1.062-1.135) for hypertension, 1.073 (95% CI: 1.019-1.131) for stroke, and 1.150 (95% CI: 1.038-1.274) for CHD, respectively. We observed no departure from linear E-R relationships of O3 exposure with overall CVD (Pnonlinear= 0.22), hypertension (Pnonlinear= 0.19), stroke (Pnonlinear= 0.70), and CHD (Pnonlinear= 0.44) at a broad concentration range of 60-160 µg/m3. Compared with rural dwellers, those residing in urban areas were at significantly greater O3-associated incident risks of overall CVD, hypertension, and stroke. We estimated 1.22 million (10.6% of overall CVD in 2018) incident CVD cases could be attributable to ambient O3 pollution in 2018, representing an overall 40.9% growth (0.36 million) compared to 2010 (0.87 million, 9.7% of overall CVD in 2010). This remarkable rise in O3-attributable CVD cases was primary driven by population aging (+24.0%), followed by increase in O3 concentration (+10.5%) and population size (+6.7%). CONCLUSIONS: Long-term O3 exposure was associated with an elevated risk and burden of incident CVD in Chinese adults, especially among urban dwellers. Our findings underscored policy priorities of implementing joint control measures for fine particulate matter and O3 in the context of accelerated urbanization and population aging in China.

Integrating Augmented In Situ Measurements and a Spatiotemporal Machine Learning Model To Back Extrapolate Historical Particulate Matter Pollution over the United Kingdom: 1980-2019.

Historical PM2.5 data are essential for assessing the health effects of air pollution exposure across the life course or early life. However, a lack of high-quality data sources, such as satellite-based aerosol optical depth before 2000, has resulted in a gap in spatiotemporally resolved PM2.5 data for historical periods. Taking the United Kingdom as an example, we leveraged the light gradient boosting model to capture the spatiotemporal association between PM2.5 concentrations and multi-source geospatial predictors. Augmented PM2.5 from PM10 measurements expanded the spatiotemporal representativeness of the ground measurements. Observations before and after 2009 were used to train and test the models, respectively. Our model showed fair prediction accuracy from 2010 to 2019 [the ranges of coefficients of determination (R2) for the grid-based cross-validation are 0.71-0.85] and commendable back extrapolation performance from 1998 to 2009 (the ranges of R2 for the independent external testing are 0.32-0.65) at the daily level. The pollution episodes in the 1980s and pollution levels in the 1990s were also reproduced by our model. The 4-decade PM2.5 estimates demonstrated that most regions in England witnessed significant downward trends in PM2.5 pollution. The methods developed in this study are generalizable to other data-rich regions for historical air pollution exposure assessment.

Long-term outcome of children with acute promyelocytic leukemia: a randomized study of oral versus intravenous arsenic by SCCLG-APL group.

Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As4S4), is highly effective in treating adult acute promyelocytic leukemia (APL). However, the treatment efficacy and safety of RIF have not been verified in pediatric patients. SCCLG-APL group conducted a multicenter randomized non-inferiority trial to determine whether intravenous arsenic trioxide (ATO) can be substituted by oral RIF in treating pediatric APL. Of 176 eligible patients enrolled, 91 and 85 were randomized to ATO and RIF groups, respectively. Patients were treated with the risk-adapted protocol. Induction, consolidation, and 96-week maintenance treatment contained all-trans-retinoic acid and low-intensity chemotherapy, and either ATO or RIF. The primary endpoint was 5-year event-free survival (EFS). The secondary endpoints were adverse events and hospital days. After a median 6-year follow-up, the 5-year EFS was 97.6% in both groups. However, the RIF group had significantly shorter hospital stays and lower incidence of infection and tended to have less cardiac toxicity. All 4 relapses occurred within 1.5 years after completion of maintenance therapy. No long-term arsenic retentions were observed in either group. Substituting oral RIF for ATO maintains treatment efficacy while reducing hospitalization and adverse events in treating pediatric APL patients, which may be a future treatment strategy for APL.

Long-Term Exposure to Fine Particulate Matter and Academic Performance Among Children in North Carolina.

This cross-sectional study analyzes the association of exposure to fine particulate matter and academic performance among school age children in North Carolina.

Economic Growth Facilitates Household Fuel Use Transition to Reduce PM2.5-Related Deaths in China.

Exposure to ambient and indoor particle matter (PM2.5) leads to millions of premature deaths in China. In recent years, indoor air pollution and premature deaths associated with polluting fuel cooking demonstrate an abrupt decline. However, the driving forces behind the mortality change are still unclear due to the uncertainty in household fuel use prediction. Here, we propose an integrated approach to estimate the fuel use fractions and PM2.5-related deaths from outdoor and indoor sources during 2000-2020 across China. Our model estimated 1.67 and 1.21 million premature deaths attributable to PM2.5 exposure in 2000 and 2020, respectively. We find that the residential energy transition is associated with a substantial reduction in premature deaths from indoor sources, with 100,000 (95% CI: 76,000-122,000) for urban and 265,000 (228,000-300,000) for rural populations during 2000-2020. Economic growth is the dominant driver of fuel use transition and avoids 21% related deaths (357,000, 315,000-402,000) from polluting fuel cooking since 2000, which offsets the adverse impact of ambient emissions contributed by economic growth. Our findings give an insight into the coupled impact of socioeconomic factors in reshaping health burden in exposure pathways.

Ambient ozone exposure and depression among middle-aged and older adults: Nationwide longitudinal evidence in China.

BACKGROUND: Epidemiological studies have linked long-term ozone (O3) exposure with depression in developed countries. However, available literature is sparse and exists great heterogeneities. We aimed to investigate the association of long-term O3 exposure with depression among Chinese middle-aged and older adults. METHODS: We designed a repeated measurement study based on longitudinal data from four waves (2011, 2013, 2015, and 2018) of the China Health and Retirement Longitudinal Study (CHARLS). Annual mean O3 concentrations assessed through machine learning-based spatiotemporal models were assigned to each participant at city level. Depression score was measured using the 10-item Center for Epidemiologic Studies Depression scale (CES-D-10), with scores above the cut-off point of ten defined as depressive symptom. Mixed-effects models were used to evaluate the impact of O3 on depression score and depressive symptom, and quantify the concentration-response (C-R) relationships. Subgroup analyses were performed to examine the potential effect modifications. RESULTS: A total of 19,582 participants with 60,125 visits were included in our analysis, with mean depression score of 8.1 (standard deviation: 6.3). Multivariable-adjusted mixed-effects model estimated a 6.34% (95% confidence interval [CI]: 3.34%, 9.43%) increase in depression score and an odds ratio (OR) of 1.29 (95% CI: 1.16, 1.45) for depressive symptom associated with per 10-µg/m3 rise in annual mean O3 exposure. Significantly elevated risks were identified only at high concentrations (approximately ≥90 µg/m3). Participants who suffered from chronic diseases had a significant increased risk of depression (% Change in depression score: 8.42% [95% CI: 4.79%, 12.17%], and OR: 1.42 [95% CI: 1.24, 1.62]), and an evident effect modification was identified for depressive symptom (P = 0.01). FINDINGS: Our study provided novel evidence that long-term O3 exposure could be a risk factor for depression among Chinese middle-aged and older adults. Our findings may have significant implications for formulating policies in reducing disease burden of depression by controlling air pollution.

Differentiation syndrome and coagulation disorder - comparison between treatment with oral and intravenous arsenics in pediatric acute promyelocytic leukemia.

Realgar-Indigo naturalis formula (RIF), with A4S4 as a major ingredient, is an oral arsenic used in China to treat pediatric acute promyelocytic leukemia (APL). The efficacy of RIF is similar to that of arsenic trioxide (ATO). However, the effects of these two arsenicals on differentiation syndrome (DS) and coagulation disorders, the two main life-threatening events in children with APL, remain unclear. We retrospectively analyzed 68 consecutive children with APL from South China Children Leukemia Group-APL (SCCLG-APL) study. Patients received all-trans retinoic acid (ATRA) on day 1 of induction therapy. ATO 0.16 mg/kg day or RIF 135 mg/kg·day was administrated on day 5, while mitoxantrone was administered on day 3 (non-high-risk) or days 2-4 (high-risk). The incidences of DS were 3.0% and 5.7% in ATO (n = 33) and RIF (n = 35) arms (p = 0.590), and 10.3% and 0% in patients with and without differentiation-related hyperleukocytosis (p = 0.04), respectively. Moreover, in patients with differentiation-related hyperleukocytosis, the incidence of DS was not significantly different between ATO and RIF arms. The dynamic changes of leukocyte count between arms were not statistically different. However, patients with leukocyte count > 2.61 × 109/L or percentage of promyelocytes in peripheral blood > 26.5% tended to develop hyperleukocytosis. The improvement of coagulation indexes in ATO and RIF arms was similar, with fibrinogen and prothrombin time having the quickest recovery rate. This study showed that the incidence of DS and recovery of coagulopathy are similar when treating pediatric APL with RIF or ATO.

Vincristine and dexamethasone pulses in addition to maintenance therapy among pediatric acute lymphoblastic leukemia (GD-ALL-2008): An open-label, multicentre, randomized, phase III clinical trial.

The efficacy and safety on the addition of vincristine (VCR) and dexamethasone (DEX) pulses to maintenance therapy among childhood acute lymphoblastic leukemia (ALL) remain uncertain. Herein, we perform an open-label, multicentre, randomized, phase III clinical trial that was conducted at nine major medical centers in Guangdong Province, China. Patients were randomly assigned either the conventional maintenance therapy (control group, n = 384) or the VCR/DEX pulse (treatment group, n = 375). When limited to the SR cohort, 10-year EFS was 82.6% (95% CI: 75.9-89.9) in the control group and 80.7% (95% CI: 74-88.1) in the treatment group (pnon-inferiority  = .0002). Similarly, patients with IR also demonstrated non-inferiority of the treatment group to the control group in terms of 10-year EFS (73.6% [95% CI: 67.6-80] vs. 77.6% [95% CI: 71.8-83.9]; pnon-inferiority  = .005). Among the HR cohort, compared with the control group, patients in the treatment group experienced a significant benefit in terms of 10-year EFS (61.1% [95% CI: 47.7-78.2] vs. 72.6% [95% CI: 55.6-94.7], p = .026) and a trend toward higher 10-year OS (73.8% [95% CI: 61.6-88.4] vs. 87.9% [95% CI: 579.2-97.5], p = .068). In the HR cohort, the total rate of drug-induced liver injury and Grade 3 chemotherapy-induced anemia were both lower for patients in the treatment group than in the control group (55.6% vs. 100%, p = .033; 37.5% vs. 60%, p = .036). Conversely, the total prevalence of chemotherapy-induced thrombocytopenia was higher for patients in the treatment group than in the control group (88.9% vs. 40%, p = .027). Pediatric acute lymphoblastic leukemia with high risk is suitable to VCR/DEX pulse during maintenance phase for the excellent outcome, while the standard-to-intermediate-risk patients could eliminate the pulses.

Long-term exposure to ambient NO2 and adult mortality: A nationwide cohort study in China.

INTRODUCTION: A number of population-based studies have investigated long-term effects of nitrogen dioxide (NO2) on mortality, while great heterogeneities exist between studies. In highly populated countries in Asia, cohort evidence for NO2-mortality association was extensively sparse. OBJECTIVES: This study aimed to quantify longitudinal association of ambient NO2 exposure with all-cause mortality in Chinese adults. METHODS: A national cohort of 30,843 adults were drawn from 25 provincial regions across mainland China, and followed up from 2010 through 2018. Participants' exposures to ambient air pollutants were assigned according to their residential counties at baseline, through deriving monthly estimates from high-quality gridded datasets developed by machine learning methods. Cox proportional hazards models with time-varying exposures were utilized to assess the association of all-cause mortality with long-term exposure to ambient NO2. NO2-attributable deaths in China were estimated by province and county for years 2010 and 2018, with reference to the counterfactual exposure of 6.9 µg/m3 (the lowest county-level average in this cohort). RESULTS: We observed a total of 1662 deaths during 224020 person-years of follow-up (median 8.1 year). An approximately linear NO2-mortality relation (p = 0.273 for nonlinearity) was identified across a broad exposure range of 6.9-57.4 µg/m3. Per 10-µg/m3 increase in annual NO2 exposure was associated with an hazard ratio of 1.127 (95% confidence interval: 1.042-1.219, p = 0.003) for all-cause mortality. Risk estimates remained robust after additionally adjusting for the confounding effects of co-pollutants (i.e., PM2.5 or/and O3). In 2018, 1.65 million deaths could be attributed to ambient NO2 exposure (national average 17.3 µg/m3) in China, representing a decrease of 4.3% compared with the estimate of 1.72 million in 2010 (20.5 µg/m3). CONCLUSION: This cohort study provided national evidence for elevated risk of all-cause mortality associated with long-term exposure to ambient NO2 in Chinese adults.

Assessing the effects of ultraviolet radiation, residential greenness and air pollution on vitamin D levels: A longitudinal cohort study in China.

Vitamin D metabolism is essential in aging and can be affected by multiple environmental factors. However, most studies conducted single exposure analyses. We aim to assess the individual and combined effects of ultraviolet (UV) radiation, residential greenness, fine particulate matter (PM2.5), and ozone (O3) on vitamin D levels in a national cohort study of older adults in China. We used the 2012 and 2014 Chinese Longitudinal Healthy Longevity Survey data, and measured the environmental exposure in the same year. We interpolated the UV radiation from monitoring stations, measured residential greenness through satellite-derived Normalized Difference Vegetation Index (NDVI), modeled PM2.5 with satellite data, and estimated O3 using machine learning. We dichotomized serum 25-hydroxy vitamin D (25(OH)D), the primary circulating form of vitamin D, into non-deficiency (≥50 nmol/L) and deficiency (<50 nmol/L) categories. We used the generalized estimating equation for analysis, adjusted for sociodemographic information, lifestyle, physical condition, and season of blood draw, and calculated joint odds ratios based on the Cumulative Risk Index. We also explored the interaction between interested exposures, modification of participants' characteristics, and potential mediation. We included 1,336 participants, with a mean age of 83 at baseline. In single exposure models, the odds ratios of vitamin D deficiency (VDD) for per interquartile range increase in UV radiation, NDVI, PM2.5, and O3 and decrease were 0.39 (95 % CI:0.33,0.46), 0.90 (0.81,1.00), 1.65 (1.53,1.78), 1.67 (1.46,1.92), respectively. UV radiation mediated nearly 48 % and 78 % of the relationship between VDD and PM2.5 and O3, respectively. The association between UV radiation and VDD was stronger in females than men (OR: 2.25 vs 1.22). UV radiation, residential greenness can protect against VDD, while, PM2.5 and O3 increase the risk of VDD. UV radiation partly mediated the association between air pollution and VDD.

Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children's Leukemia Group.

Objectives: The prognostic significance of acute lymphoblastic leukemia (ALL) patients with central nervous system leukemia (CNSL) at diagnosis is controversial. We aimed to determine the impact of CNSL at diagnosis on the clinical outcomes of childhood B-cell ALL in the South China Children's Leukemia Group (SCCLG). Methods: A total of 1,872 childhood patients were recruited for the study between October 2016 and July 2021. The diagnosis of CNSL depends on primary cytological examination of cerebrospinal fluid, clinical manifestations, and imaging manifestations. Patients with CNSL at diagnosis received two additional courses of intrathecal triple injections during induction. Results: The frequency of CNLS at the diagnosis of B-cell ALL was 3.6%. Patients with CNSL at diagnosis had a significantly higher mean presenting leukocyte count (P = 0.002) and poorer treatment response (P <0.05) compared with non-CNSL patients. Moreover, CNSL status was associated with worse 3-year event-free survival (P = 0.030) and a higher risk of 3-year cumulative incidence of relapse (P = 0.008), while no impact was observed on 3-year overall survival (P = 0.837). Multivariate analysis revealed that CNSL status at diagnosis was an independent predictor with a higher cumulative incidence of relapse (hazard ratio = 2.809, P = 0.016). Conclusion: CNSL status remains an adverse prognostic factor in childhood B-cell ALL, indicating that additional augmentation of CNS-directed therapy is warranted for patients with CNSL at diagnosis.

A Nomogram for Predicting Event-Free Survival in Childhood Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study.

Objective: Even though childhood acute lymphoblastic leukemia (ALL) has an encouraging survival rate in recent years, some patients are still at risk of relapse or even death. Therefore, we aimed to construct a nomogram to predict event-free survival (EFS) in patients with ALL. Method: Children with newly diagnosed ALL between October 2016 and July 2021 from 18 hospitals participating in the South China children's leukemia Group (SCCLG) were recruited and randomly classified into two subsets in a 7:3 ratio (training set, n=1187; validation set, n=506). Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were adopted to screen independent prognostic factors. Then, a nomogram can be build based on these prognostic factors to predict 1-, 2-, and 3-year EFS. Concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance and clinical utility of nomogram. Result: The parameters that predicted EFS were age at diagnosis, white blood cell at diagnosis, immunophenotype, ETV6-RUNX1/TEL-AML1 gene fusion, bone marrow remission at day 15, and minimal residual disease at day 15. The nomogram incorporated the six factors and provided C-index values of 0.811 [95% confidence interval (CI) = 0.792-0.830] and 0.797 (95% CI = 0.769-0.825) in the training and validation set, respectively. The calibration curve and AUC revealed that the nomogram had good ability to predict 1-, 2-, and 3-year EFS. DCA also indicated that our nomogram had good clinical utility. Kaplan-Meier analysis showed that EFS in the different risk groups stratified by the nomogram scores was significant differentiated. Conclusion: The nomogram for predicting EFS of children with ALL has good performance and clinical utility. The model could help clinical decision-making.

Associations between short-term ambient ozone exposure and cause-specific mortality in rural and urban areas of Jiangsu, China.

Most previous studies on the acute health effects of ozone are limited to urban areas, largely due to the paucity of air pollutant measurements in rural areas. We here estimated the county-specific daily maximum 8-h average ozone concentration in Jiangsu Province, China during 2015-2018, using a recently developed spatiotemporal machine learning model at a spatial resolution of 0.1° × 0.1° (∼11 × 11 km). Counties were equally divided into urban and rural groups based on the median of the percentage of urban residents across Jiangsu counties obtained from the National Population Census in 2010. We first conducted time-series analyses to estimate the county-specific effect of ozone using generalized linear models, then pooled the effect estimates by random-effects modeling. A 10 µg/m3 increase in the 4-day moving average (lag 0-3) of ambient ozone exposure was associated with increases of 0.66% (95% confidence interval [CI] 0.36%-0.95%) in daily nonaccidental mortality in rural areas and 0.42% in urban areas (95% CI, 0.27%-0.56%). Short-term ambient ozone exposure was associated with an increased risk of mortality caused by chronic obstructive pulmonary disease, hypertension, ischemic heart disease, and stroke. Our finding suggests that both urban and rural residents suffer adverse health effects from short-term ozone exposure.

Decrease in the chronic health effects from PM2.5 during the 13th Five-Year Plan in China: Impacts of air pollution control policies.

The Chinese government implemented a series of policies to improve air quality during the Thirteenth Five-Year Plan (13th FYP). However, the long-term health effects of the 13th FYP air pollution control policies have not been evaluated, and the outbreak of coronavirus disease 2019 (COVID-19) has brought great uncertainty regarding the evaluation of the effects. In this study, we selected 329 cities in mainland China to study the chronic health effects due to the decrease in fine particulate matter (PM2.5) during the 13th FYP. The relative risk (RR) of PM2.5 exposure was obtained from a previous study, and the total premature deaths were calculated. We also applied the grey prediction model to predict the PM2.5 concentration in each city in 2020 to evaluate the impacts of COVID-19. The results showed that the annual PM2.5 concentration was reduced from 49.7 µg/m3 in 2015 to 33.2 µg/m3 in 2020, and premature deaths were reduced from 1,186,201 (95% CI: 910,339-1,451,102) and 446,415 (in key regions, 95% CI: 343,426-544,813) in 2015 to 997,955 (95% CI: 762,167-1,226,652) and 368,786 (in key regions, 95% CI: 282,114-452,567) in 2020, respectively. A total of 188,246 (95% CI: 148,172-224,450) people avoided premature deaths due to the reduction in PM2.5 concentrations from 2015 to 2020. Although the impacts of COVID-19 in 2020 brought a significant reduction of 35.3% in February (14.2 µg/m3, p < 0.0001) and in March by 17.6% (5.8 µg/m3, p = 0.001), we found that COVID-19 showed few obvious influences on China's long-term air pollution control plans. The observed data and predicted data are very close in annual mean values and showed no statistical significance both in all cities (p = 0.98) and in key regions (p = 0.56) in 2020.

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.

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.

Prognostic Value and Outcome for ETV6/RUNX1-Positive Pediatric Acute Lymphoblastic Leukemia: A Report From the South China Children's Leukemia Group.

PURPOSE: To analyzed the outcome of ETV6/RUNX1-positive pediatric acute B lymphoblastic leukemia (B-ALL) with the aim of identifying prognostic value. METHOD: A total of 2,530 pediatric patients who were diagnosed with B-ALL were classified into two groups based on the ETV6/RUNX1 status by using a retrospective cohort study method from February 28, 2008, to June 30, 2020, at 22 participating ALL centers. RESULTS: In total, 461 (18.2%) cases were ETV6/RUNX1-positive. The proportion of patients with risk factors (age <1 year or ≥10 years, WB≥50×109/L) in ETV6/RUNX1-positive group was significantly lower than that in negative group (P<0.001), while the proportion of patients with good early response (good response to prednisone, D15 MRD < 0.1%, and D33 MRD < 0.01%) in ETV6/RUNX1-positive group was higher than that in the negative group (P<0.001, 0.788 and 0.004, respectively). Multivariate analysis of 2,530 patients found that age <1 or ≥10 years, SCCLG-ALL-2016 protocol, and MLL were independent predictor of outcome but not ETV6/RUNX1. The EFS and OS of the ETV6/RUNX1-positive group were significantly higher than those of the negative group (3-year EFS: 90.11 ± 4.21% vs 82 ± 2.36%, P<0.0001, 3-year OS: 91.99 ± 3.92% vs 88.79 ± 1.87%, P=0.017). Subgroup analysis showed that chemotherapy protocol, age, prednisone response, and D15 MRD were important factors affecting the prognosis of ETV6/RUNX1-positive children. CONCLUSIONS: ETV6/RUNX1-positive pediatric ALL showed an excellent outcome but lack of independent prognostic significance in South China. However, for older patients who have the ETV6/RUNX1 fusion and slow response to therapy, to opt for more intensive treatment.

Spatiotemporal distributions of surface ozone levels in China from 2005 to 2017: A machine learning approach.

In recent years, ground-level ozone has become a severe ambient pollutant in major urban areas of China, which has adverse impacts on population health. However, in-situ measurements of the ozone concentration before 2013 in China are quite scarce, which cannot facilitate the assessment of the long-term trends and effects of ozone pollution. In this study, we used daily maximum 8-hour average (MDA8) ozone observations from 2013 to 2017 combined with concurrent ozone retrievals, aerosol reanalysis, meteorological parameters, and land-use data to establish a nationwide MDA8 prediction model based on the eXtreme Gradient Boosting (XGBoost) algorithm. The model achieves high prediction accuracy compared with other studies, with R2 values for the by-year, site-based, and sample-based cross-validation (CV) schemes of 0.61, 0.64, and 0.78, respectively, at the daily level. External testing with regional measurements from 2005 to 2012 and nationwide data in 2018 have shown that the model is robust and reliable for historical data prediction, with external model testing R2 values ranging from 0.60 to 0.87 at the month level in different years. Using the final estimator, we obtained nationwide monthly mean ozone concentrations from 2005 to 2012 and daily MDA8 ozone concentrations from 2013 to 2017 at a resolution of 0.1° × 0.1°. According to the average number of days exceeding the standard and the average of the 90th percentile of the MDA8 ozone concentrations, the Beijing-Tianjin-Hebei (BTH), the Yangtze River Delta, the Pearl River Delta, the Jianghan Plain, the Sichuan Basin, and the Northeast Plain regions were identified as pollution hotspots. During the research period, the overall ozone levels fluctuated slightly, and their trends were not spatially continuous. There was a significant increasing trend in the BTH region by 1.37 (95% CI: 0.46,2.29) µg/m3/year between 2013 and 2017. In 2017, 26.24% of the population lived in areas exceeding the Chinese grade II national air quality standard, which shows that ozone pollution has posed an obvious threat to population health in China. Our products will provide reliable support for future long-term nationwide health impact studies and policy-making for pollution control and prevention.

Spatial distribution of the public's risk perception for air pollution: A nationwide study in China.

Severe air pollution problems have led to a rise in the Chinese public's concern. Risk perception is one of the most important indicators of the public's concern about air pollution. However, there existed few studies exploring the spatial distribution of risk perception. To fill the gap, psychometric paradigm methods was adopted to assess the public's risk perception of air pollution. A nationwide empirical study was conducted from December 2016 to February 2017 and 10,653 completed questionnaires were collected. According to a series of screening strategies, 9744 qualified questionnaires were included as a sample, which covered 31 China provinces (Hong Kong, Macao and Taiwan were not included in this study). We found that 45% of the respondents were dissatisfied with the current air quality, many respondents concerned a lot about air pollution (76%) and worried about the harmful consequences of being exposed to air pollution (86%). There was significant difference in the public's risk perception and attitude toward air pollution among different regions: the respondents in the northeast region, northern coastal region, eastern coastal region and Middle Yellow river region perceived higher air pollution risk and lower satisfaction with air quality than other regions; and the public's trust in the government increased from coastal regions to inland regions. In addition, the hierarchical linear model (HLM) was used to explore the effects of demographic, environmental and economic factors on public risk perception and attitude toward air pollution. Based on this, the characteristics of sensitive populations regarding air pollution were identified. What's more, we found that PM2.5 has a positive influence on perceived risk factor (PR) and can strengthen the positive correlation between PR and satisfaction with air quality (SAQ). Finally, policy implications behind these results were discussed, which can provide references and lay the foundation for policymakers and subsequent researchers.

Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: Interim results of the SCCLG-APL clinical study.

Intravenous arsenic trioxide (ATO) has been adopted as the first-line treatment for acute promyelocytic leukemia (APL). Another arsenic compound named the Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine containing As4 S4 , has been shown to be highly effective in treating adult APL. In the treatment of pediatric APL, the safety and efficacy of RIF remains to be confirmed. This randomized, multicenter, and noninferiority trial was conducted to determine whether intravenous ATO can be substituted by oral RIF in the treatment of pediatric APL. From September 2011 to January 2017, among 92 patients who were 16 years old or younger with newly diagnosed PML-RARa positive APL, 82 met eligible criteria and were randomly assigned to ATO (n = 42) or RIF (n = 40) group. The remaining 10 patients did not fulfilled eligible criteria because five did not accept randomization, four died and one had hemiplegia prior to arsenic randomization due to intracranial hemorrhage or cerebral thrombosis. Induction and consolidation treatment contained ATO or RIF, all-trans-retinoic acid and low intensity chemotherapy. End points included event-free survival (EFS), adverse events and hospital days. After a median 3-year follow-up, the estimated 5-year EFS was 100% in both groups, and adverse events were mild. However, patients in the RIF group had significantly less hospital stay than those in the ATO group. This interim analysis shows that oral RIF is as effective and safe as intravenous ATO for the treatment of pediatric APL, with the advantage of reducing hospital stay. Final trial analysis will reveal mature outcome data.