Gene expression prognostic of early relapse risk in low-risk B-cell acute lymphoblastic leukaemia in children.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low-risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low-risk ETV6::RUNX1-positive B-cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome-wide transcriptome and single-nucleotide variants. We found high TIMD4 expression (> 85th-percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio [HR] = 5.07 [1.76, 14.62]; p = 0.03). In an independent validation cohort of low-risk ETV6::RUNX1-positive B-cell ALL (N = 68) high TIMD4 expression at diagnosis had an HR = 4.78 [1.07, 21.36] (p = 0.04) for early relapse. In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.

Refining eligibility criteria of unit selection for myeloablative cord blood transplantation in acute leukemia: Real-world experience of a referral center.

The algorithm for cord blood (CB) unit selection is still somewhat ambiguous. We retrospectively analyzed 620 cases of acute leukemia between 2015 and 2020, who were treated with myeloablative single-unit umbilical CB transplantation (UCBT). We found that, when human leukocyte antigen (HLA) mismatch was ≤3/10, CD34+ cell dosage <0.83 × 105/kg-considerably lower than prevalent guidelines-was permissible without affecting survival. Moreover, synergy between donor killer-cell immunoglobulin-like receptors (KIR) haplotypes-B and donor-recipient HLA-C mismatch protected against relapse-related mortality. We submit that minimum required CD34+ cell dosage can possibly be relaxed to broaden access to UCBT, and donor KIR genotyping should be considered during unit selection.

The Composite Immune Risk Score predicts overall survival after allogeneic hematopoietic stem cell transplantation: A retrospective analysis of 1838 cases.

There has been little consensus on how to quantitatively assess immune reconstitution after hematopoietic stem cell transplantation (HSCT) as part of the standard of care. We retrospectively analyzed 11 150 post-transplant immune profiles of 1945 patients who underwent HSCT between 2012 and 2020. 1838 (94.5%) of the cases were allogeneic HSCT. Using the training set of patients (n = 729), we identified a composite immune signature (integrating neutrophil, total lymphocyte, natural killer, total T, CD4+ T, and B cell counts in the peripheral blood) during days 91-180 after allogeneic HSCT that was predictive of early mortality and moreover simplified it into a formula for a Composite Immune Risk Score. When we verified the Composite Immune Risk Score in the validation (n = 284) and test (n = 391) sets of patients, a high score value was found to be associated with hazard ratios (HR) of 3.64 (95% C.I. 1.55-8.51; p = .0014) and 2.44 (95% C.I., 1.22-4.87; p = .0087), respectively, for early mortality. In multivariate analysis, a high Composite Immune Risk Score during days 91-180 remained an independent risk factor for early mortality after allogeneic HSCT (HR, 1.80; 95% C.I., 1.28-2.55; p = .00085). In conclusion, the Composite Immune Risk Score is easy to compute and could identify the high-risk patients of allogeneic HSCT who require targeted effort for prevention and control of infection.

'Dynamic zero-COVID' policy and viral clearance during an omicron wave in Tianjin, China: a city-wide retrospective observational study.

OBJECTIVE: To report how the Chinese mainland battled its first omicron wave, which happened in Tianjin, a metropolis with 14 million residents. We also sought to better understand how clinical features affected the timing of viral clearance. DESIGN: A retrospective study of the omicron wave in Tianjin between 8 January 2022 and 3 March 2022. SETTING: Except for the first cases on 8 January, all the omicron cases were identified through PCR mass testing in the residential communities. Residential quarantine and serial PCR mass testing were dynamically adjusted according to the trends of new cases. PARTICIPANTS: All the 417 consecutive PCR-positive cases identified through mass screening of the entire city's 14 million residents. 45.3% of the cases were male, and the median age was 37 (range 0.3-90). 389 (93%) cases had complete data for analysing the correlation between clinical features and the timing of viral clearance. MAIN OUTCOME AND MEASURE: Time to viral clearance. RESULTS: Tianjin initiated the 'dynamic zero-COVID' policy very early, that is, when daily new case number was ≈0.4 cases per 1 000 000 residents. Daily new cases dropped to <5 after 3 February, and the number of affected residential subdivisions dropped to ≤2 after 13 February. 64% (267/417) of the cases had no or mild symptoms. The median interval from hospital admission to viral clearance was 10 days (range 3-28). An exploratory analysis identified a feature cluster associated with earlier viral clearance, with HRs of 3.56 (95% CI 1.66 to 7.63) and 3.15 (95% CI 1.68 to 5.91) in the training and validation sets, respectively. CONCLUSIONS: The 'dynamic zero-COVID' policy can suppress an omicron wave within a month. It might be possible to predict in advance which cases will require shorter periods of isolation based on their clinical features.

A Phenogenetic Axis that Modulates Clinical Manifestation and Predicts Treatment Outcome in Primary Myeloid Neoplasms.

Although the concept of "myeloid neoplasm continuum" has long been proposed, few comparative genomics studies directly tested this hypothesis. Here we report a multi-modal data analysis of 730 consecutive newly diagnosed patients with primary myeloid neoplasm, along with 462 lymphoid neoplasm cases serving as the outgroup. Our study identified a "Pan-Myeloid Axis" along which patients, genes, and phenotypic features were all aligned in sequential order. Utilizing relational information of gene mutations along the Pan-Myeloid Axis improved prognostic accuracy for complete remission and overall survival in adult patients of de novo acute myeloid leukemia and for complete remission in adult patients of myelodysplastic syndromes with excess blasts. We submit that better understanding of the myeloid neoplasm continuum might shed light on how treatment should be tailored to individual diseases. Significance: The current criteria for disease diagnosis treat myeloid neoplasms as a group of distinct, separate diseases. This work provides genomics evidence for a "myeloid neoplasm continuum" and suggests that boundaries between myeloid neoplastic diseases are much more blurred than previously thought.

Dynamic forecasting of severe acute graft-versus-host disease after transplantation.

Forecasting of severe acute graft-versus-host disease (aGVHD) after transplantation is a challenging 'large p, small n' problem that suffers from nonuniform data sampling. We propose a dynamic probabilistic algorithm, daGOAT, that accommodates sampling heterogeneity, integrates multidimensional clinical data and continuously updates the daily risk score for severe aGVHD onset within a two-week moving window. In the studied cohorts, the cross-validated area under the receiver operator characteristic curve (AUROC) of daGOAT rose steadily after transplantation and peaked at ≥0.78 in both the adult and pediatric cohorts, outperforming the two-biomarker MAGIC score, three-biomarker Ann Arbor score, peri-transplantation features-based models and XGBoost. Simulation experiments indicated that the daGOAT algorithm is well suited for short time-series scenarios where the underlying process for event generation is smooth, multidimensional and where there are frequent and irregular data missing. daGOAT's broader utility was demonstrated by performance testing on a remotely different task, that is, prediction of imminent human postural change based on smartphone inertial sensor time-series data.

Optimized clinical application of minimal residual disease in acute myeloid leukemia with RUNX1-RUNX1T1.

Minimal residual disease (MRD) levels monitored by polymerase chain reaction are associated with outcomes in acute myeloid leukemia with RUNX1-RUNX1T1. The objectives of our study were to quantitatively compare the predictive value of MRD reduction and absolute copies and assess the influence of other prognostic factors on MRD. A total of 224 consecutive patients with RUNX1-RUNX1T1 aged ≤55 years were included in the MRD study. Patients received different induction regimens including conventional- or intermediate-dose cytarabine plus low-dose daunorubicin and omacetaxine mepesuccinate or daunorubicin at 60 mg/m2/day on days 1-3. As continuous variables, both MRD reduction and absolute MRD level were significantly associated with cumulative incidence of relapse (CIR; hazard ratio [HR] = 1.610, 95% confidence interval [CI]: 1.370-1.890, p < 0.001, and HR = 1.170, 95% CI: 1.120-1.230, p < 0.001, respectively). For the CIR, the area under the curves (AUCs) of MRD reduction and absolute MRD level after the first consolidation chemotherapy were 0.629 and 0.629, respectively. Intermediate-dose cytarabine induction (HR = 0.494; p = 0.039 for CIR, HR, 0.451; p = 0.014 for RFS, and HR, 0.262; p = 0.006 for OS) remained significantly associated with outcomes after adjusting for MRD reduction after the first consolidation therapy (HR = 1.456, p < 0.001, for CIR; HR = 1.467, p = 0.001, for relapse-free survival; and HR = 1.468, p = 0.014, for overall survival) in multivariate analyses. In conclusion, the prognostic significance of MRD after the first consolidation therapy was influenced by the induction regimen in acute myeloid leukemia with RUNX1-RUNX1T1.

Detection rate is not higher for women with BBD history in breast cancer screening.

BACKGROUND: To investigate whether women with benign breast disease (BBD) history have higher breast cancer detection rate in screening. METHODS: We reviewed data for 33 001 female participants in Multi-modality Independent Screening Trial (MIST). Corresponding data for 6823 breast cancer patients were retrieved from the Tianjin Breast Cancer Cases Cohort (TBCCC) and analyzed for comparison. RESULTS: The breast cancer detection rate was 2.83‰ among women with BBD history and 3.28‰ in women without. Moreover, the proportion of carcinoma in situ (CIS) was also lower in women with BBD history than women without (7.69 versus 20.31%). In contrast, analysis of TBCCC data revealed a higher proportion of CIS in patients with BBD history (5.05%) than patients without (3.26%). Our data showed that a larger proportion of women with BBD history had undergone previous breast examinations. Additionally, among participants diagnosed with both breast cancer and BBD in MIST, we found a lower proportion of CIS in women with BBD history (11.76%) compared to women without (32.14%). CONCLUSIONS: Women with BBD history were not found to have higher detection rate in breast cancer screening. Women with BBD history were more likely to be proactive in seeking breast examinations and to have breast cancer be diagnosed in clinic.

Tacrolimus Levels in the Prophylaxis of Acute Graft-Versus-Host Disease in the Chinese Early After Hematopoietic Stem Cell Transplantation.

BACKGROUND: Tacrolimus has been widely accepted as the backbone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (alloHSCT). The present work evaluated whether tacrolimus concentrations early after transplant correlate with the incidence of aGVHD in Chinese alloHSCT recipients. METHODS: One hundred four Chinese alloHSCT recipients were included in this retrospective study. All patients received standard prophylaxis with tacrolimus and short-term methotrexate. Blood samples were taken at steady-state for those on i.v. tacrolimus (Cv) or predose (C0) and 2 hours after the last oral dose (C2). RESULTS: In the first 8 weeks after alloHSCT, significant variability in Cv, C0, and C2 of Chinese patients was observed. It was found that higher tacrolimus C0 and C2 values tended to be associated with a reduced risk of aGVHD, although this was a nonsignificant trend due to the small sample size involved. Receiver operating characteristic curve analysis indicated that Cv levels of ≥16.52 ng/mL, C0 levels of ≥5.56 ng/mL, and C2 levels of ≥7.83 ng/mL minimized the incidence of treatment failure during weeks 3-4 with intravenous administration and weeks 5-6 with oral administration. There was no statistically significant association of the patient liver and kidney function with the blood concentration of tacrolimus in the desired range of 5-20 ng/mL. CONCLUSIONS: Tacrolimus therapeutic drug monitoring improved treatment outcomes of Chinese alloHSCT recipients. Cv measurements during weeks 3-4 and C0 or C2 measurements during weeks 5-6 better predicted aGVHD (I-IV) than the concentrations measured at other time points during the first 6 weeks after alloHSCT.

A survey of overall life satisfaction and its association with breast diseases in Chinese women.

To investigate the association between overall life satisfaction and healthy lifestyle, knowledge of breast cancer, physical examination, and detection rate of breast cancer and benign breast disease in Chinese women. In a multicentered breast disease screening program in China, we enrolled 33,057 women aged 45-65 years without prior diagnosis of breast cancer. After completing an epidemiological questionnaire, all participants were examined by clinical breast examination, breast ultrasound, and mammography independently. All breast cancer cases and a selected sample of benign breast diseases were confirmed pathologically. Univariate and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association between life satisfaction and lifestyle, knowledge of breast cancer, physical examination, and detection rate of breast diseases. Overall life satisfaction was positively associated with women's healthy lifestyle. Compared with less satisfied women, satisfied women were less likely to be smokers (OR = 0.54; 95% CI: 0.47-0.62), have more exercise (OR = 1.49; 95% CI: 1.26-1.75), eat less fried (OR = 0.60; 95% CI: 0.50-0.71), smoked (OR = 0.54, 95% CI: 0.47-0.63), pickled (OR = 0.66, 95% CI: 0.55-0.79), and grilled (OR = 0.63, 95% CI: 0.54-0.74) foods. Satisfied women were more likely to have knowledge of breast cancer (OR = 1.48, 95% CI: 1.29-1.70), and have regular physical examinations (OR = 1.11, 95% CI: 1.01-1.12). Compared to less satisfied women, we found significantly lower detection rate of benign breast diseases (OR = 0.90, 95% CI: 0.82-0.99), and lower but nonsignificant detection rate of breast cancer (OR = 0.66, 95% CI: 0.35-1.25) in satisfied women. Women with a higher overall life satisfaction are more likely to have healthy lifestyle, knowledge of breast cancer, and regular physical examination, thus resulting in a lower detection rate of breast diseases in screening.

[Current status of smoking and passive smoking among aged 45 to 65 years old females in five cities of China].

OBJECTIVE: To investigate the current status of smoking and passive smoking among Chinese females to provide evidence for related strategy development. METHODS: Data from 32 720 women aged 45-65 years old who participated in the 2008 to 2010 Chinese Multi-center Women Breast Cancer Screening Project, were used to analyze the prevalence rates of smoking/heavy smoking, daily smoking, smoking cessation, successful smoking cessation, passive smoking, etc. RESULTS: A total of 913 females, accounted for 2.8% of all the women in the study, had reported the history of smoking. There were significant differences seen regarding the prevalence rates of smoking in different regions (Beijing, 2.8%; Tianjin, 5.9%; Nanchang, 1.7%; Feicheng, 0.9%; Shenyang, 1.8%). The prevalence rates of current smoking, daily smoking, and heavy smoking were 1.8%, 1.0% and 0.2%, respectively. The prevalence rates of smoking and current smoking increased with age but not the prevalence rates of daily smoking and heavy smoking. Among the smokers, the median initiation age of smoking, the median daily cigarette per day, and median year of smoking were 30 years old, 10 cigarette, and 16 years, respectively. And the prevalence rates of smoking cessation and successful smoking cessation were 19.1% and 8.2%. The prevalence rate of passive smoking was 45.7% (12 730/27 874). After combing the number of smokers and the number of passive smokers, the total exposure rate to tobacco was 41.8% (13 670/32 720). CONCLUSION: There was a relatively low level of smoking among Chinese females, so as the rate of smoking cessation. However, passive smoking presented a relatively high level among Chinese females.

Active and passive smoking with breast cancer risk for Chinese females: a systematic review and meta-analysis.

Previous studies suggested that smoking and passive smoking could increase the risk of breast cancer, but the results were inconsistent, especially for Chinese females. Thus, we systematically searched cohort and case-control studies investigating the associations of active and passive smoking with breast cancer risk among Chinese females in four English databases (PubMed, Embase, ScienceDirect, and Wiley) and three Chinese databases (CNKI, WanFang, and VIP). Fifty-one articles (3 cohort studies and 48 case-control studies) covering 17 provinces of China were finally included in this systematic review. Among Chinese females, there was significant association between passive smoking and this risk of breast cancer [odds ratio (OR): 1.62; 95% confidence interval (CI): 1.39-1.85; I2 = 75.8%, P < 0.001; n = 26] but no significant association between active smoking and the risk of breast cancer (OR: 1.04; 95% CI: 0.89-1.20; I2 = 13.9%, P = 0.248; n = 31). The OR of exposure to husband's smoking and to smoke in the workplace was 1.27 (95% CI: 1.07-1.50) and 1.66 (95% CI: 1.07-2.59), respectively. The OR of light and heavy passive smoking was 1.11 and 1.41, respectively, for women exposed to their husband's smoke (< 20 and ≥ 20 cigarettes per day), and 1.07 and 1.87, respectively, for those exposed to smoke in the workplace (< 300 and ≥ 300 min of exposure per day). These results imply that passive smoking is associated with an increased risk of breast cancer, and the risk seems to increase as the level of passive exposure to smoke increases among Chinese females. Women with passive exposure to smoke in the workplace have a higher risk of breast cancer than those exposed to their husband's smoking.

Distribution of mammographic density and its influential factors among Chinese women.

BACKGROUND: Mammographic density (MD) has not been systematically investigated among Chinese women. Breast cancer screening programmes provided detailed information on MD in a large number of asymptomatic women. METHODS: In the Multi-modality Independent Screening Trial (MIST), we estimated the association between MD and its influential factors using logistic regression, adjusting for age, body mass index (BMI) and study area. Differences between Chinese and other ethnic groups with respect to MD were also explored with adjustment for age and BMI. RESULTS: A total of 28 388 women aged 45 to 65 years, who had been screened by mammography, were enrolled in the study. Of these, 49.2% were categorized as having dense breasts (BI-RADS density 3 and 4) and 50.8% as fatty breasts (BI-RADS density 1 and 2). Postmenopausal status [odds ratio (OR) = 0.66; 95% confidence interval (CI): 0.62-0.70] and higher number of live births (OR = 0.56; 95% CI: 0.46-0.68) were inversely associated with MD, whereas prior benign breast disease (OR = 1.48; 95% CI: 1.40-1.56) and later age at first birth (OR = 1.17; 95% CI: 1.08-1.27) were positively associated with MD. In comparison with the data from the Breast Cancer Surveillance Consortium, we found that women in MIST were more likely to have fatty breasts than Americans (from the Breast Cancer Surveillance Consortium) in the older age group (≥50 years) but more likely to have dense breasts in the younger age group (<50 years). CONCLUSIONS: This study suggests that several risk factors for breast cancer were associated with breast density in Chinese women. Information on the determinants of mammographic density may provide valuable insights into breast cancer aetiology.

Association between dietary factors and breast cancer risk among Chinese females: systematic review and meta-analysis.

BACKGROUND: Evidence for associations between dietary factors and breast cancer risk is inconclusive among Chinese females. To evaluate this question, we conducted a systematic review of relevant case-control and cohort studies. METHODS: Studies were systematically searched among 5 English databases (PudMed, ScienceDirect, Wiley, Clinicaltrials.gov, and Cochrane) and 3 Chinese databases (CNKI, WanFang, and VIP) until November 2012. Random effects models were used to estimate summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). RESULTS: Thirty one case-control studies and two cohort studies involving 9,299 cases and 11,413 controls were included. Consumption of both soy and fruit was significantly associated with decreased risk of breast cancer, with summary ORs of 0.65 (95% CIs: 0.43-0.99; I2=88.9%, P<0.001; N=13) and 0.66 (95% CIs: 0.47-0.91; I2=76.7%, P<0.001; N=7), respectively. Consumption of fat was significantly associated with increased risk of breast cancer (OR=1.36; 95% CIs: 1.13-1.63; I2=47.9%, P=0.088; N=6). There was non- significant association between consumption of vegetables and breast cancer risk (OR=0.72; 95% CIs: 0.51-1.02; I2= 74.4%, P<0.001; N=9). However, sensitivity analysis based on adjusted ORs showed decreased risk of breast cancer was also associated with consumption of vegetables (OR=0.49; 95% CIs: 0.30-0.67). CONCLUSION: Both soy food and fruit are significantly associated with decreased risk of breast cancer among Chinese females, and vegetables also seems to be protective while dietary fatexerts a promoting influence.

A meta-analysis of the association between induced abortion and breast cancer risk among Chinese females.

OBJECTIVE: To evaluate the association between induced abortion (IA) and breast cancer risk among Chinese females. METHODS: We searched three English databases (PubMed, ScienceDirect, and Wiley) and three Chinese databases (CNKI, WanFang, and VIP) for studies up to December 2012, supplemented by manual searches. Two reviewers independently conducted the literature searching, study selection, and data extraction and quality assessment of included studies. Random effects models were used to estimate the summary odds ratios (ORs) and the 95 % confidence intervals (CIs). RESULTS: A total of 36 articles (two cohort studies and 34 case-control studies) covering 14 provinces in China were included in this review. Compared to people without any history of IA, an increased risk of breast cancer was observed among females who had at least one IA (OR = 1.44, 95 % CI 1.29-1.59, I (2) = 82.6 %, p < 0.001, n = 34). No significant publication bias was found among the included studies (Egger test, p = 0.176). The risk increased to 1.76 (95 % CI 1.39-2.22) and 1.89 (95 % CI 1.40-2.55) for people who had at least two IAs and at least three IAs, respectively. Subgroup analyses showed similar results to the primary results. Meta-regression analysis of the included studies found that the association between IA and breast cancer risk attenuated with increasing percent of IA in the control group (ß = -0.022, p < 0.001). CONCLUSION: IA is significantly associated with an increased risk of breast cancer among Chinese females, and the risk of breast cancer increases as the number of IA increases. If IA were to be confirmed as a risk factor for breast cancer, high rates of IA in China may contribute to increasing breast cancer rates.

Tea consumption, alcohol drinking and physical activity associations with breast cancer risk among Chinese females: a systematic review and meta-analysis.

OBJECTIVE: To evaluate associations between tea consumption, alcohol drinking and physical activity and breast cancer risk among Chinese females. METHODS: Three English databases (PubMed, ScienceDirect and Wiley) and three Chinese databases (CNKI, WanFang and VIP) were independently searched by 2 reviewers up to December 2012, complemented by manual searches. The quality of included studies was assessed with the Newcastle-Ottawa Scale items. Random-effects models were used to estimate the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Potential publication bias was estimated through Egger's and Begg's tests. Heterogeneity between studies was evaluated with I2 statistics. RESULTS: Thirty-nine studies involving 13,204 breast cancer cases and 87,248 controls were identified. Compared with non-drinkers, regular tea drinkers had decreased risk (OR=0.79, 95%CIs: 0.65-0.95; I2=84.9%; N=16). An inverse association was also found between regular physical activity and breast cancer risk (OR=0.73, 95%CIs: 0.63-0.85; I2=77.3%; N=15). However, there was no significant association between alcohol drinking and breast cancer risk (OR=0.85, 95%CIs: 0.72- 1.02; I2=63.8%; N=26). Most of the results from the subgroup analysis were consistent with the main results. CONCLUSION: Tea consumption and physical activity are significantly associated with a decreased risk of breast cancer in Chinese females. However, alcohol drinking may not be associated with any elevation of risk.