A review of immunotargeted therapy for Philadelphia chromosome positive acute lymphoblastic leukaemia: making progress in chemotherapy-free regimens.

Philadelphia chromosome-positive acute lymphoblastic leukemia (PH + ALL) is the most common cytogenetic abnormality of B-ALL in adults and is associated with poor prognosis. Previously, the only curative treatment option in PH + ALL was allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL. Currently, the remission rate and survival rate of Imatinib are superior to those of simple chemotherapy, and it can also improve the efficacy of transplantation. More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin. For patients with ABL1 mutations and those who have relapsed or are refractory to other treatments, targeted oral small molecule drugs, monoclonal antibodies, Bispecific T cell Engagers (BiTE), and chimeric antigen receptor (CAR) T cells immunotherapy are emerging as potential treatment options. These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.

Medication Usage Record-Based Predictive Modeling of Neurodevelopmental Abnormality in Infants under One Year: A Prospective Birth Cohort Study.

Early identification of children with neurodevelopmental abnormality is a major challenge, which is crucial for improving symptoms and preventing further decline in children with neurodevelopmental abnormality. This study focuses on developing a predictive model with maternal sociodemographic, behavioral, and medication-usage information during pregnancy to identify infants with abnormal neurodevelopment before the age of one. In addition, an interpretable machine-learning approach was utilized to assess the importance of the variables in the model. In this study, artificial neural network models were developed for the neurodevelopment of five areas of infants during the first year of life and achieved good predictive efficacy in the areas of fine motor and problem solving, with median AUC = 0.670 (IQR: 0.594, 0.764) and median AUC = 0.643 (IQR: 0.550, 0.731), respectively. The final model for neurodevelopmental abnormalities in any energy region of one-year-old children also achieved good prediction performance. The sensitivity is 0.700 (IQR: 0.597, 0.797), the AUC is 0.821 (IQR: 0.716, 0.833), the accuracy is 0.721 (IQR: 0.696, 0.739), and the specificity is 0.742 (IQR: 0.680, 0.748). In addition, interpretable machine-learning methods suggest that maternal exposure to drugs such as acetaminophen, ferrous succinate, and midazolam during pregnancy affects the development of specific areas of the offspring during the first year of life. This study established predictive models of neurodevelopmental abnormality in infants under one year and underscored the prediction value of medication exposure during pregnancy for the neurodevelopmental outcomes of the offspring.

Associations of concurrent early-life famine exposure and adulthood obesity with type 2 diabetes mellitus in middle-aged Chinese.

BACKGROUND: Evidence has shown that early-life famine exposure and obesity in adulthood are independently associated with the risk of type 2 diabetes mellitus (T2DM). However, few studies had revealed the combined effect of these risk factors. METHODS: Two sets of groups from the China Health and Retirement Longitudinal Study (CHARLS) were selected. The fetal-exposure group born in 1959-1961 from 2011 wave (N = 958) and nonexposure group born in 1963-1965 from 2015 wave (N = 1540) were selected as Comparison 1. The early childhood-exposure group born in 1955-1957 from 2011 wave (N = 1510) and fetal-exposure group born in 1959-1961 from 2015 wave (N = 943) were Comparison 2. Logistic regressions were applied to examine the associations of different famine exposure periods and obesity patterns with T2DM risk. RESULTS: Compared with nonexposed participants without central overweight/obesity in adulthood, central overweight/obesity in adulthood together with nonexposure (odds ratio [OR]: 1.89, 95% confidence interval [CI]: 1.19-3.00) or fetal-exposure (OR: 1.99, 95% CI: 1.23-3.23) was associated with higher risks of T2DM. Compared with the early childhood-exposure group, the fetal-exposed participants showed higher risks of T2DM (OR: 1.30, 95% CI: 1.02-1.66). The coexistence of fetal famine exposure and central overweight/obesity in adulthood was associated with higher risks of T2DM (OR: 1.82, 95% CI: 1.19-2.79). Consistent associations were observed among males and participants from less severely affected areas. CONCLUSIONS: In conclusion, central overweight/obesity in adulthood is associated with the increased risk of T2DM, but the effect of early-life famine exposure is not very clear.

CAG (cytarabine, aclarubicin and granulocyte colony-stimulating factor) regimen for core binding factor acute myeloid leukaemia with measurable residual disease.

Acute myeloid leukaemia (AML) with t (8;21) or inv (16), called core binding factor (CBF) AML, has a favourable prognosis. However, some CBF-AML patients have persistent measurable residual disease (MRD) and are more likely to relapse after standard chemotherapy treatment. The CAG regimen, composed of cytarabine, aclarubicin and granulocyte colony-stimulating factor, has been proven to be effective and safe in treating refractory AML patients. We performed a retrospective study to evaluate the efficacy of the CAG regimen to eliminate MRD detected by RUNX1::RUNX1T1 and CBFß::MYH11 transcript levels by quantitative polymerase chain reaction (Q-PCR) among 23 patients. Molecular response was defined as the ratio of fusion transcript after treatment to that before treatment less than or equal to 0.5. The molecular response rate and median decrease ratio of fusion transcripts at the molecular level of the CAG regimen were 52% and 0.53, respectively. The median fusion transcripts before CAG treatment was 0.25% whereas after CAG was 0.11%. Among the 15 patients who had a poor molecular response to the high/intermediate-dose cytarabine regimen, the median decrease ratios of transcripts at the molecular level of high/intermediate-dose cytarabine and CAG were 1.55 and 0.53 (P = 0.028), respectively, and 6 of 15 patients achieved a molecular response to CAG (40%). The median disease-free survival was 18 months, and the overall survival rate at 3 years among all patients was 72.7% ± 10.7%. The common grades 3-4 adverse events were nausea (100%), thrombocytopenia (39%) and neutropenia (37.5%). The CAG regimen may have activity in CBF-AML patients and could provide a new option for patients who have a poor molecular response to high/intermediate-dose cytarabine.

The associations of obesity phenotypes with the risk of hypertension and its transitions among middle-aged and older Chinese adults.

OBJECTIVES: This study aimed to investigate the associations of obesity phenotypes with hypertension stages, phenotypes, and transitions among middle-aged and older Chinese. METHODS: Using the 2011-2015 waves of the China Health and Retirement Longitudinal Study, we conducted a cross-sectional analysis included 9,015 subjects and a longitudinal analysis included 4,961 subjects, with 4,872 having full data on the hypertension stage and 4,784 having full data on the hypertension phenotype. Based on body mass index and waist circumstance, subjects were categorized into 4 mutually exclusive obesity phenotypes: normal weight with no central obesity (NWNCO), abnormal weight with no central obesity (AWNCO), normal weight with central obesity (NWCO), and abnormal weight with central obesity (AWCO). Hypertension stages were classified into normotension, pre-hypertension, stage 1 hypertension, and stage 2 hypertension. Hypertension phenotypes were categorized as normotension, pre-hypertension, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic-diastolic hypertension (SDH). The association between obesity phenotypes and hypertension was estimated by logistic regression. A comparison between different sexes was conducted by testing the interaction effect of sex. RESULTS: NWCO was associated with normal→stage 2 (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.11 to 3.42), maintained stage 1 (OR, 1.62; 95% CI, 1.14 to 2.29), and normal→ISH (OR, 1.39; 95% CI, 1.05 to 1.85). AWCO was associated with normal→stage 1 (OR, 1.75; 95% CI, 1.40 to 2.19), maintained stage 1 (OR, 2.77; 95% CI, 2.06 to 3.72), maintained stage 2 (OR, 2.80; 95% CI, 1.50 to 5.25), normal→ISH (OR, 1.56; 95% CI, 1.20 to 2.02), and normal→SDH (OR, 2.54; 95% CI, 1.72 to 3.75). An interaction effect of sex existed in the association between obesity phenotypes and hypertension stages. CONCLUSIONS: This study highlights the importance of various obesity phenotypes and sex differences in hypertension progression. Tailored interventions for different obesity phenotypes may be warranted in hypertension management, taking into account sex-specific differences to improve outcomes.

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial.

BACKGROUND: Adults with acute myeloid leukaemia have unsatisfactory clinical outcomes and rates of complete remission. Venetoclax combined with azacytidine or low-dose cytarabine has shown efficacy in adults aged 75 years or older (or 18-74 years with comorbidities precluding intensive chemotherapy) with acute myeloid leukaemia. We aimed to investigate the activity and safety of venetoclax plus 3+7 daunorubicin and cytarabine chemotherapy in adults with acute myeloid leukaemia. METHODS: We conducted a two-stage, single-arm, phase 2 trial at three public hospitals in China. We enrolled patients aged 18-60 years with previously untreated de novo acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received induction treatment with intravenous daunorubicin (60 mg/m2 on days 1-3), intravenous cytarabine (100 mg/m2 on days 1-7), and oral venetoclax (100 mg on day 4, 200 mg on day 5, and 400 mg on days 6-11; DAV regimen). For induction therapy, the length of the treatment was 28-35 days per cycle and the number of treatment cycles was one or two. The primary endpoint was the composite complete remission rate (complete remission plus complete remission with incomplete blood cell count recovery) after one cycle of induction treatment, assessed in the as-treated population. Secondary endpoints were bone marrow measurable residual disease by flow cytometry, event-free survival, overall survival, and adverse events. This trial is ongoing and is registered with Chinese Clinical Trial Registry, ChiCTR2000041509. FINDINGS: Between Dec 25, 2020, and July 7, 2021, 36 patients were assessed for eligibility and 33 were enrolled. 15 (45%) patients were men and 18 (55%) were women, and all were Asian. The composite complete remission rate after one cycle of DAV regimen was 91% (95% CI 76-98; 30 of 33 patients) in the entire cohort. 29 (97%) of 30 patients who reached complete remission had undetectable measurable residual disease (ie, <0·1%). Grade 3 or worse adverse events included neutropenia in 33 (100%) of 33 patients, thrombocytopenia in 33 (100%), anaemia in 33 (100%), febrile neutropenia in 18 (55%), pneumonia in seven (21%), and sepsis in four (12%). No treatment-related deaths occurred. With a median follow-up of 11 months (IQR 9-12), estimated 1-year overall survival was 97% (95% CI 91-100) and 1-year event-free survival was 72% (56-94). INTERPRETATION: The DAV regimen represents an effective induction therapy for newly diagnosed adults with acute myeloid leukaemia, which resulted in a high rate of complete remission. These findings are an important contribution to the field, showing a safe strategy to incorporate venetoclax into the most common induction regimen used to treat newly diagnosed acute myeloid leukaemia internationally. FUNDING: Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang, National Natural Science Foundation of China, Key Research and Development Program of Zhejiang. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Transition of cardiometabolic status and the risk of type 2 diabetes mellitus among middle-aged and older Chinese: A national cohort study.

AIMS/INTRODUCTION: The cardiometabolic index (CMI) has been proposed as a novel indicator of cardiometabolic status. This study aimed to investigate the effects of CMI and its longitudinal transitions on the development of type 2 diabetes mellitus in middle-aged and older Chinese. MATERIALS AND METHODS: We used data from the China Health and Retirement Longitudinal Study (2011-2018). CMI was calculated as the product of the waist circumference to height ratio and the triglyceride to high-density lipoprotein cholesterol ratio. At baseline in 2011, the subjects were classified into low- and high-CMI groups, and then divided into four transition patterns during follow-up, i.e. maintained-low, low-to-high, high-to-low, and maintained-high CMI. The hazard ratios (HRs) of different transition patterns for type 2 diabetes mellitus were calculated using multivariable Cox frailty models. RESULTS: During 2011-2018, 7,347 participants were included. Participants with a high-CMI at baseline had a significantly higher risk of new-onset type 2 diabetes mellitus than those with a low-CMI (HR = 1.78, 95% CI:1.55-2.05). For subjects with a low-CMI at baseline, the risk of developing type 2 diabetes mellitus increased by 75% if their CMI status changed to high during follow-up (HRlow-to-high = 1.75, 95% CI:1.35-2.28). Meanwhile, for subjects with a maintained-high CMI, no significant risk reduction for type 2 diabetes mellitus was found when their CMI changed to low status (HRhigh-to-low = 0.77, 95% CI: 0.58-1.01). CONCLUSIONS: Baseline CMI levels and longitudinal CMI transition patterns were associated with a higher risk of type 2 diabetes mellitus. Early anti-lipid measures should be taken to prevent type 2 diabetes mellitus in middle-aged and older Chinese.

Transition of Lipid Accumulation Product Status and the Risk of Type 2 Diabetes Mellitus in Middle-Aged and Older Chinese: A National Cohort Study.

Background: Lipid accumulation product (LAP), a product of waist circumference (WC) and fasting triglycerides (TG), is a measure of lipid accumulation and an effective predictor of metabolic syndrome. This study aimed to evaluate the associations of LAP and its longitudinal transitions with type 2 diabetes mellitus (T2DM) among middle-aged and older Chinese. Methods: Data were extracted from the China Health and Retirement Longitudinal Study (2011, 2013, 2015, and 2018). LAP was defined as (WC-65) ×TG for men, and (WC-58) ×TG for women. Participants were classified into high- and low-LAP groups at baseline, and subsequently into four transition patterns during 2011-2015: maintained-high, maintained-low, high-to-low, and low-to-high LAP. The longitudinal transition patterns of LAP on the development of T2DM were assessed by multivariable Cox frailty models. Results: Overall, 7397 participants were included for analysis, among whom 849 (11.5%) developed T2DM between 2011 and 2018. Women with high-LAP levels at baseline presented a higher risk of T2DM (hazard ratios [HR]=1.37, 95% confidence interval [CI]: 1.07-1.77), while no significant association was found in men. Compared with women with maintained-low LAP pattern, those with transition patterns of low-to-high LAP and maintained-high LAP were at higher risk of T2DM (HR =1.99 and 1.98, both P<0.05); however, for men, the significantly positive association was only observed in maintained-high LAP transition pattern (HR=1.53, 95% CI: 1.04-2.23). Conclusions: Elevated LAP levels and the transition patterns of maintained-high LAP and low-to-high LAP are significant risk factors for T2DM in women. Preventions are needed to combat T2DM at an early dyslipidemic stage.

Integrated multi-omics data analyses for exploring the co-occurring and mutually exclusive gene alteration events in colorectal cancer.

Co-occurring and mutually exclusive gene alteration events are helpful for understanding carcinogenesis but systematic screening for such events is quite limited. We conducted pairwise screening tests to identify "hit pairs" in colorectal cancer (CRC) by utilizing the cross-omics data from The Cancer Genome Atlas (TCGA). Numerous hit pairs involving somatic mutations, copy number variations, and DNA methylation were found to occur nonrandomly in CRC, such as KRAS and HOXB6, SMAD4 and PMEPA1. Based on these hit pairs, we identified 32 synthetic lethal pairs and 7,527 co-occurring pairs relating to drug response. Our further biological experiments showed that the co-occurrence of mutant FCGBP and NUDT12 silencing (or mutant TMC3 and RPS6KA6 silencing) with small interfering RNA reduced cell viability. Moreover, novel hit pairs could influence prognosis. The patients who carried concurrent mutations of IRF5 and NEFH, SYNE1 and TTN, or MUC16 and NEFH had worse survival outcomes. Particularly, the presence of mutant SYNE1 and TTN pair not only affects prognosis, but also is related to CRC patients' response to drug treatment. Our "hit pair" genes may provide insights into colorectal carcinogenesis and help open new avenues for CRC therapy.