Effect of tixagevimab/cilgavimab for pre-exposure prophylaxis during the China Omicron outbreak.

OBJECTIVES: By the end of 2022, China had made a pivotal decision to optimize the COVID-19 policy. The dominant Omicron variant in China at that time was highly transmissible. In this study, we aimed to evaluate the real-world safety and efficacy of tixagevimab and cilgavimab against this background in China. METHODS: Participants were enrolled if they were over 12 years old and were planning to receive tixagevimab or cilgavimab. All participants received intramuscular administration of tixagevimab (150 mg) and cilgavimab (150 mg). Data were collected on demographics, underlying illness, prior infection, vaccination, adverse events, and COVID-19 outcomes (e.g., infection rate, hospitalization rate, and severe disease). RESULTS: During the study period, 168 (37.9%) of 443 who received tixagevimab/cilgavimab were diagnosed with SARS-CoV-2 infection. All infected patients had mild COVID-19. Two patients (0.5%) were hospitalized for COVID-19, but none of them were admitted to the ICU. None of the patients died during this study. 4 (0.9%) reported mild local adverse events, and no severe systemic adverse reactions were reported. CONCLUSION: Tixagevimab/cilgavimab may have protected high-risk populations against infection with the Omicron variant, hospitalization and severe disease during the China COVID-19 pandemic.

Ambient carbon monoxide and relative risk of daily hospital outpatient visits for respiratory diseases in Lanzhou, China.

At present, evidence of the associations between carbon monoxide (CO) and respiratory diseases (RD) in Northwest China is limited and controversial. The aim of this study is to evaluate the impact of ambient CO on outpatient visits for RD in Lanzhou, China. The daily amount of outpatient visits for total and cause-specific RD, air pollutant, and weather variables were collected in Lanzhou, China from 1st January 2013 to 31st December 2019. A generalized additive model and distributed lag nonlinear model were used to assess associations between CO and outpatient visits for RD. During the study period, a total of 1,623,361 RD outpatient visits were recorded. For each interquartile range (IQR) (0.77 mg/m3) increase in CO, the relative risk (RR) was 1.163 (95% CI: 1.138, 1.188) for total RD at lag07, 1.153 (95% CI: 1.128,1.179) for upper respiratory tract infection (URTI) at lag07, 1.379 (95% CI: 1.338,1.422) for pneumonia at lag07, 1.029 (95% CI: 0.997,1.062) for chronic obstructive pulmonary disease (COPD) lag04, 1.068 (95% CI: 1.028,1.110) for asthma lag03, and 1.212 (95% CI: 1.178,1.247) for bronchitis lag07, respectively. In the subgroup analyses, the impacts of CO were more pronounced on total RD, pneumonia, COPD, and bronchitis in males than females, while the opposite was true in URTI and asthma. The impact of CO on RD was the strongest for children under 15 years-of-age. We also found significantly stronger effects during cold seasons compared to warm seasons. In addition, we observed a roughly linear exposure-response curve between CO and RD with no threshold effect. This study in Lanzhou revealed a remarkable association between CO level and an elevated risk of total and cause-specific RD outpatient visits, especially for pneumonia.

Ambient carbon monoxide and the risk of cardiovascular disease emergency room visits: a time-series study in Lanzhou, China.

Until now, the epidemiological evidence on the association between short-term exposure to ambient carbon monoxide (CO) and cardiovascular diseases (CVDs) is relatively lacking and controversial. This study aims to examine the relationship between ambient CO and daily emergency room visits (ERVs) for total and cause-specific CVD in Lanzhou, China. A distributed lag nonlinear model was used to examine the association. For every 1 mg/m3 increase in the CO concentration, the relative risks of daily ERVs were 1.041 (95% CI: 1.017, 1.065) for total CVD, 1.065 (95% CI: 1.018, 1.114) for ischemic heart disease (IHD), 1.083 (95% CI: 1.020, 1.149) for heart rhythm disturbances (HRD), 1.062 (95% CI: 1.011, 1.115) for heart failure (HF), and 1.057 (95% CI: 1.017, 1.098) for cerebrovascular diseases (CD). For the two different gender subgroups, the short-term impact of CO on total CVD, IHD, and CD was relatively stronger for the females than for the males, while the opposite was true for HRD and HF. In the age subgroup analyses, the effect of ambient CO on total CVD and IHD appeared to be greater for the age ≥ 65 years group, while the opposite was true for HRD, HF, and CD. The associations for all disease categories were stronger in cold seasons than in warm seasons. We also observed a nearly linear correlation between CO and CVD ERVs. In conclusion, the study showed that exposure to ambient CO may increase the risks of ERVs for total and cause-specific CVD. Besides, CO-ERVs associations may vary by gender and age.

Spatiotemporal Epidemiology of the Gonorrhea Epidemic in Relation to Neighborhood-level Structural Factors in an Eastern Province of China, 2016-2020.

Context: Gonorrhea, a highly communicable, sexually transmitted infection, remains a major public-health concern globally. In recent years, Zhejiang province, an eastern province, has had the highest incidence of gonorrhea in China. Objective: The study intended to identify the geographic distribution patterns and spaciotemporal clustering characteristics of the disease's incidence in Zhejiang between 2016 and 2020, to understand the spatial epidemiology of gonorrhea and to pinpoint the locations with relatively high risks of gonorrhea, the hotspots, which could be the key areas for disease prevention and control. Design: The research team performed a retrospective, spaciotemporal-clustering analysis of data about newly reported gonorrhea cases from January 2016 to December 2020 in Zhejiang province, using the China Information System for Disease Control and Prevention. Setting: The study took place at the Zhejiang Provincial Institute of Dermatology in Huzhou, China. Outcome Measures: The research team: (1) used the Geographic Information System software-ArcGIS 10.8 software to draw statistical maps; (2) conducted a spatial-pattern clustering analysis at the district or county level; (3) performed an autocorrelation analysis using Getis-Ord (Gi*) statistics to detect spatial patterns and the hotspots of gonorrhea incidence; and (4) used SaTScan9.7 to analyze the space-time clusters. Results: Zhejiang province reported 85 904 gonorrhea cases from 2016 to 2020, with a male to female ratio of 3.81:1. The average annual incidence rate of gonorrhea was 30.50 per 100 000 individuals in the population, ranging from 22.73 cases to 39.65 cases, and the annual incidence showed a significant downward trend over the five years (χ2 = 16.142, P < .001). The northern and central areas had a higher incidence than the southern area did. Autocorrelation analysis showed that the gonorrhea incidence had a significantly clustered distribution (Moran's I from 0.197 to 0.295, Z score from 4.749 to 6.909, P < .001). The high-high cluster areas were mainly in the urban districts of Hangzhou and some counties and districts of Jiaxing. The Gi* statistics further indicated that the hotspots of gonorrhea were mainly in Hangzhou, Jiaxing, and Huzhou. The Kuldorff's scan identified two clusters, mainly composed of 36 counties or districts in northern Zhejiang, such as Hangzhou and Jiaxing, and central Zhejiang, such as Jinhua and Shaoxing. Conclusions: The gonorrhea incidence rates in northern and central Zhejiang from 2016 to 2020 were higher than those in southern Zhejiang. An area of relatively higher risk for gonorrhea existed mainly in the urban districts of Hangzhou and some counties and districts of Jiaxing, Jinhua, and Shaoxing. In the future, the research team plans to focus on strengthening the prevention and control measures against gonorrhea in those areas.

The clinical characteristics of anemia in native adults living at different altitudes of the Tibetan Plateau.

To provide evidence-based medicine references for formulating prevention and control policies in plateau areas, we explore the characteristics of anemia patients in Tibet (the plateau areas of China), especially those located at an altitude above 4500 m. We collected clinical data from 379 Tibetan anemia patients over the age of 18 years. We found those female patients accounted for the majority of Tibetan anemia patients. Almost half of the anemia patients aged from 28 to 47 years. The percentage of severe anemia and extremely severe anemia was 45.4% and 2.4%, respectively. 88.7% of patients are engaged in agriculture and animal husbandry, and 81.5% of patients just graduated from primary school or below. The most common causes of anemia were nutritional anemia, especially iron-deficiency anemia. At high-altitude localities, folic acid-deficiency anemia needs more attention. Overall, this study showed that altitude influences the incidence, severity, and cause of anemia. Peasants and herdsmen, low education levels, young and middle-aged women, and nutrition status should be paid attention to in future anemia control.

Association between short-term ambient air pollution and outpatient visits for acute exacerbation of chronic obstructive pulmonary disease in Lanzhou, 2013-19.

Evidence between air pollution and hospital visits for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is inconsistent and limited in China. In this study, we constructed a time-series study to evaluate the association between air pollution and AECOPD outpatient visits. Daily hospital outpatient visits for AECOPD in three top level hospitals in Lanzhou from January 2013 to December 2019, as well as the air pollutants and meteorological data in the same period, were collected. Then, generalized additive models with quasi-Poisson regression were utilized to estimate the associations with single-day lags from lag0 to lag7 and cumulative-day lag from lag01 to lag07. For example, lag0 referred to the concentration of air pollutants at the current day and lag1 referred to the previous-day air pollutant concentration and so on. Lag01 meant the average concentration of air pollutants at the current and previous day, and lag07 corresponded to the eight-day moving average value of the current and previous 7 days. In addition, stratified analyses were performed by gender, age, and season. The risk estimates were expressed in terms of the percentage changes (PC) in AECOPD outpatient visits per 10 µg/m3 increment of air pollutants (except that CO was per 1 mg/m3) and their respective 95% confidence intervals (CIs). The strongest effect on AECOPD morbidity was found lag07 for PM2.5 (PC = 1.96, 95% CI 1.07, 2.86 per 10 µg/m3), lag03 for PM10 (PC = 0.25, 95% CI 0.01, 0.49 per 10 µg/m3), lag05 for SO2 (PC = 1.67, 95% CI 0.54, 3.93 per 10 µg/m3), and lag03 for NO2 (PC = 1.37, 95% CI 0.25, 2.51 per 10 µg/m3). No significant association of O3 and CO with AECOPD onset was found. In the subgroup analyses, the associations of PM2.5 and SO2 were more pronounced on males than female, the patients aged < 65 years were more vulnerable to PM2.5 and NO2, but 65-74 years old were more vulnerable to PM2.5, SO2, and NO2. Patients aged ≥ 75 years suffered more from PM2.5, PM10, and SO2. The associations between PM2.5, PM10, SO2, NO2, and AECOPD outpatients were stronger in the cold season than those in the hot season. From exposure-response curves, we observe linear relationships of PM2.5, SO2, NO2, O38h, and CO with hospital outpatient visits for AECOPD. The increase in PM2.5, PM10, SO2, and NO2 concentration will lead to an increase in the number of outpatient visits for AECOPD and have different influence patterns in different genders, ages, and seasons.

Optimization of idarubicin and cytarabine induction regimen with homoharringtonine for newly diagnosed acute myeloid leukemia patients based on the peripheral blast clearance rate: A single-arm, phase 2 trial (RJ-AML 2014).

Individualized chemotherapy, which is at the forefront of acute myeloid leukemia (AML) treatment, has moderately improved outcomes over the past decade. Monitoring the peripheral blood blast burden during induction by flow cytometry has shown significant value in the evaluation of treatment responses. Our previous study reported the day 5 peripheral blast clearance rate (D5-PBCR) as an indicator of early treatment response, and D5-PBCR (+) patients showed poor outcomes. We performed the present phase 2 trial of early intervention in D5-PBCR (+) patients with homoharringtonine (HHT) introduced in the traditional induction regimen with anthracycline and cytarabine. The primary endpoint was complete remission (CR). This study enrolled 151 patients, 65 patients were D5-PBCR (+) and 55 patients completed induction with HHT addition. The overall CR rate after one course of induction was 84.4%, with 87.5% and 80.0% for the D5-PBCR (-) and D5-PBCR (+) groups, respectively. The incidence of grade 3/4 adverse events was comparable between the two groups. At the median follow-up of 53.1 months, median overall survival (OS) was not reached in the entire cohort, and median event-free survival (EFS) was 42.2 months. Neither the OS nor EFS showed significant differences between the D5-PBCR (-) and D5-PBCR (+) groups. Compared to historical data, significant improvements in both OS (p = .020) and EFS (p = .020) were observed in the D5-PBCR (+) group. In conclusion, optimization of induction chemotherapy with idarubicin and cytarabine according to D5-PBCR is feasible in patients with newly diagnosed AML. The addition of HHT demonstrated a good efficacy and safety profile.

Dynamic evaluation of the prognostic value of 18F-FDG PET/CT in extranodal NK/T-cell lymphoma, nasal type.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a type of rare and distinct entity of non-Hodgkin lymphoma with poor prognosis. It is important to evaluate the early treatment response accurately to decide further treatment strategy. 18F-FDG PET/CT plays an important role in response evaluation and prognostic prediction in some kinds of lymphomas. However, data available regarding patients with ENKTL are limited. Thus, in this prospective study, we analyzed the prognostic value of 18F-FDG PET/CT in ENKTL. Thirty-four patients with newly diagnosed ENKTL were enrolled in this phase 2 study (NCT02825147, July 7, 2016). The patients received pre-, mid-, and end-treatment 18F-FDG PET/CT scans. Deauville score (DS), maximal standardized uptake values (SUVmax), and the change in SUVmax (ΔSUVmax) were recorded for response assessment. The median follow-up period was 42.2 months. The 2-year overall survival (OS) and progression-free survival (PFS) were 82.4% and 73.5%, respectively. Univariate analysis revealed that Ann Arbor stage (P < 0.002), mid-treatment DS (P = 0.005), mid-SUVmax (P = 0.001), mid-∆SUVmax (P = 0.004), end-treatment DS (P < 0.001), and end-SUVmax (P = 0.014) were prognostic factors for OS. Ann Arbor stage (P = 0.001), mid-treatment DS (P = 0.008), mid-SUVmax (P = 0.029), mid-∆SUVmax (P < 0.001), and end-treatment DS (P =0.021) were of prognostic significance for PFS. Multivariate analysis showed that mid-SUVmax (P = 0.042) and DS at the middle (P = 0.050) and end (P = 0.044) of treatment were significant independent predictors of PFS. 18F-FDG PET/CT is useful for predicting the prognosis of ENKTL.

Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Functionalized starch as a novel eco-friendly vulcanization accelerator enhancing mechanical properties of natural rubber.

A novel eco-friendly vulcanization accelerator, starch supported sodium isobutyl xanthate (SSX) has been synthesized firstly. The modification of starch using sodium isobutyl xanthate (SIBX) has improved the thermal stability significantly, and the vulcanization process of natural rubber (NR) could be accelerated by SSX at 145 ℃ accordingly. More importantly, SSX can be dispersed into NR matrix uniformly along with the strong interfacial interaction between SSX and NR, as evidenced by the constrained rubber chains around SSX surface. In addition, mechanical properties of the obtained NR have been enhanced remarkably, showing a 22.4 % increase in tensile strength when compared with traditional vulcanization accelerator. Laying on the fact that a novel vulcanization accelerator has been fabricated successfully using SIBX functionalized starch, new strategies for the preparation of green vulcanization accelerators and the functional application of biopolymers can be provided.

Optimizing combination of liver-enriched transcription factors and nuclear receptors simultaneously favors ammonia and drug metabolism in liver cells.

The HepG2 cell line is widely used in studying liver diseases because of its immortalization, but its clinical application is limited by its low expression of the urea synthesis key enzymes and cytochromes P450 (CYPs). On the basis of our previous work, we investigated the transcriptional regulation of arginase 1 (Arg1) and ornithine transcarbamylase (OTC) in HepG2 cells. We also screened for the optimal combination of liver enrichment transcription factors (LETFs) and xenobiotic nuclear receptors that can promote the expression of key urea synthases and five major CYPs in HepG2 cells. Thus, recombinant HepG2 cells were established. Results showed that C/EBPß, not C/EBPα, could upregulate expression of Arg1 and PGC1α and HNF4α cooperatively regulate the expression of OTC. The two optimal combinations C/EBPß+HNF4α+HNF6+PXR and C/EBPß+HNF4α+HNF6+CAR were selected. Compared with the control cells, the recombinant HepG2 cells modified by the two optimal combinations exhibited enhanced ammonia metabolism and CYP enzyme activity. Moreover, the HepG2/(C/EBPß+HNF4α+HNF6+PXR) cells more strongly reduced ammonia than any other combination tested in this study. The present work indicated that optimizing the combination of transcription factors will simultaneously promote hepatocyte ammonia metabolism and drug metabolism. The recombinant HepG2 liver cell line constructed by the optimal combination provided an improved alternative means for bioartificial liver applications and drug toxicity testing.

[Prognostic significance of Ph-positive acute lymphoblastic leukemia].

OBJECTIVE: To explore the prognostic significance of Ph-positive and/or BCR-ABL positive acute lymphoblastic leukemia (Ph⁺ ALL). METHODS: A retrospective analysis of 72 patients with Ph⁺ ALL to probe prognostic factors including sex, age, high white cell counts at diagnosis, additional chromosome abnormality, BCR-ABL transcripts type, imatinib based therapy, allo-HSCT and complete remission (CR) after one-course induction on the outcomes of Ph⁺ALL patients. RESULTS: Of 72 patients with median age 40.5 (13-68) years, 38 patients received imatinib plus chemotherapy. With median follow-up of 11 (0.2-96) months, total CR rate in patients receiving imatinib plus chemotherapy was higher than of patients receiving chemotherapy only (97.4% vs 62.3%, P=0.019). High white blood counts at diagnosis or additional chromosome abnormality had no effects on CR rate. 2-year overall survival (OS) and disease free survival (DFS) in imatinib plus chemotherapy group were (28.9±7.4) % and (25±7.4) %, respectively, which were higher than those in chemotherapy group (P<0.001). OS rate in HSCT group was significantly higher than that in non-HSCT group[ (61.1±11.5) % vs (5.6±3.1) %, P<0.001]. Multivariate prognostic analysis for OS showed that imatinib-based therapy [RR=0.413 (95% CI 0.237-0.721), P=0.002], allo-HSCT [RR=0.175 (95% CI 0.075-0.389), P=0.000] and CR after one-course induction [RR=0.429 (95% CI 0.245-0.750), P=0.003] were of importance for survival. CONCLUSION: allo-HSCT was an optimal choice for Ph⁺ALL patients. Imatinib-based therapy could increase CR rate, maintain CR duration and decrease relapse, resulting in more chance of HSCT. Imatinib improved the outcomes of Ph⁺ALL patients who were not eligible for HSCT.

Pregnancies in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitor.

We presented our experience in chronic myeloid leukemia (CML) patients who conceived children and/or became pregnant while receiving tyrosine kinase inhibitor (TKI). Among 7 male patients, 7 pregnancies resulted in the birth of 7 healthy babies. Among 18 female patients, 8 ended in elective abortion; 3 had spontaneous abortion, and 7 carried to term, resulting in the birth of 8 healthy babies. All children have normal growth and development. All patients remain in TKI therapy and in good response. It is suggested that female patients are advised to practice adequate contraception. No special precautions apply for male patients receiving TKI.

[Nilotinib treatment for imatinib resistant or intolerant chronic myelogenous leukemia.].

OBJECTIVE: To evaluate the safety and efficacy of nilotinib in chronic myelogenous leukemia (CML) patients with resistance or intolerance to imatinib. METHODS: Thirty-five CML patients after imatinib failure or intolerance received oral administration of 400 mg nilotinib twice daily. The overall survival, hematologic and cytogenetic responses, as well as adverse events were evaluated. RESULTS: The median duration of nilotinib therapy was 11 (1 - 23) months, with a median follow-up of 19 months. Nonhematologic adverse events were mostly of grade 1-2. The most common ones possibly related to nilotinib were increase of bilirubin (76%) and rash (46%). Grade 3-4 hematologic adverse events includes thrombocytopenia (37%), neutropenia (26%) and anemia (26%). Nilotinib was proved to be well-tolerated in this study. Grade 3-4 hematologic adverse events happened more frequently in advanced phase CML. The rate of major cytogenetic response in chronic phase (CP) CML was much higher than those in advanced CML (38.5% vs 22.2%). The median time to major cytogenetic response was 3 months. The estimated overall survival at 18 months was (93.5 +/- 1.0)%. CONCLUSION: Nilotinib is a more effective and safe treatment option for imatinib-resistant or -intolerant CML-CP patients.

[Prognostic factors analysis for R-CHOP regimen therapy in diffuse large B cell lymphoma].

OBJECTIVE: To reassess the prognostic factors of diffuse large B cell lymphoma (DLBCL) treated with R-CHOP therapy. METHODS: One hundred and twenty five patients were enrolled in this study from Feb. 2000 to Sep. 2006. They received 6 courses of R-CHOP regimen consisting of rituximab 375 mg/ m2, intravenously, d 1; cyclophosphamide 750 mg/m2, bolus intravenously, d 2; doxorubicin 50 mg/m2, bolus intravenously, d 2; vincristine 1.4 mg/m2, bolus intravenously, d 2 and prednisone 60 mg, orally, d 2 - 6. All the patients were evaluated and followed up after the treatment. RESULTS: Eighty six patients (68.8%) achieved complete response (CR), 16 (12.8%) partial response (PR), 11 (12.8%) stable disease (SD) and 12 (9.6%) progressive disease (PD). In univariate analysis, performance status (PS), clinical stage, LDH level, extranodal disease, international prognostic index (IPI) and bulky disease were statistically significantly correlated with the induction of CR; however, only PS, clinical stage and bulky disease remained significant in multi-variate analysis (P = 0.0098, 0.000 and 0.004, respectively). Twenty four month for time to treatment failure (TTF) rate, overall survival (OS) rate, and disease free survival (DFS) rate was (59.7 +/- 5. 3)%, (67.1 +/- 5.6)% and (77.6 +/- 5.8)%, respectively. In univariate analysis, LDH, clinical stage and PS exerted significant effect on TTF and OS rate, but not on DFS rate; age and extranodal disease was not related with TTF, OS and DFS rate. In multi-variate analysis, achieved CR was the only prognostic factor for TTF (P =0.001) and bulky disease had influence on DFS rate. LDH level, PS, and achieved CR was correlated with the OS rate in multi-variate setting (P = 0.002, 0.009 and 0.001 respectively). CONCLUSION: IPI score has its limitation in predicting the prognosis in the R-CHOP era in DLBCL. Other two relevant prognostic factors are bulky disease and achieved CR after 6 courses of treatment.

[Efficacy and safety of imatinib in treatment of 151 chronic myeloid leukemia patients].

OBJECTIVE: To evaluate the safety and efficacy of imatinib in treatment of chronic myeloid leukemia (CML) patients. METHODS: From December 2003 to March 2007, 151 patients entered Glivec International Patient Assistance Program (GIPAP) in our center and received imatinib therapy. The overall and progression free survival, hematologic, cytogenetic and molecular response, and adverse events were evaluated. The factors associated with outcome of imatinib therapy were also analysed. RESULTS: One hundred and forty-two patients were evaluable with a median follow-up duration of 21.5 (6 -78) months. (1) The rate of cumulative complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and complete molecular response (CMoR) in chronic phase (CP) CML patients were 96.9%, 82.6%, 76.1% and 29.4%, respectively. These rates were significantly higher in patients with CP than in those with accelerated phase (AP) and blast crisis (BC) (P < 0.0001). (2) The overall survival (OS) rates at 1, 2 and 3 year were 100%, (97.3 +/- 1.9)% and (95.8 +/- 2.4)% for CP patients, they were (84.7 +/- 8.2)%, (77.0 +/- 10.4)% and (69.3 +/- 11.9)% for AP patients, and (62.9 +/- 8.9)%, (41.9 +/- 9.2)% and (28.5 +/- 9.1)% for BC patients, respectively (P < 0.0001). The progression-free survival (PFS) rates at 1, 2 and 3 year were (98.9 +/- 1.1)%, (93.9 +/- 2.7)%, (93.9 +/- 2.7)% for CP patients, (68.9 +/- 10.6)%, (61.3 +/- 11.9)%, (61.3 +/- 11.9)% for AP patients, (36.4 +/- 8.8)%, (25.4 +/- 8.1)%, (10.1 +/- 8.2)% (P < 0.0001) for BC patients respectively. (3) Among 92 CP patients, the rates of MCyR and CCyR in newly diagnosed patients were significantly higher than those in interferon therapy failure patients (P = 0.015, P = 0.010). Patients obtained CCyR at 12 months after the initiation of imatinib treatment were associated with longer PFS (P = 0.0099). According to the Sokal scoring system, the rates of MCyR and CCyR in low-risk patients were significantly higher than those in intermediate-risk and high-risk patients (P = 0.0013, P = 0.0024). Sokal score was also significantly associated with disease progression (P = 0.0467). (4) The adverse events of imatinib were moderate and tolerable. CONCLUSIONS: Treatment of CML patients in CP with imatinib can induce high hematologic, cytogenetic and molecular response and overall survival, but can not do satisfactorily for patients in AP and BC.

AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec.

To explore the genetic abnormalities that cooperate with AML1-ETO (AE) fusion gene to cause acute myeloid leukemia (AML) with t(8;21), we screened a number of candidate genes and identified 11 types of mutations in C-KIT gene (mC-KIT), including 6 previously undescribed ones among 26 of 54 (48.1%) cases with t(8;21). To address a possible chronological order between AE and mC-KIT, we showed that, among patients with AE and mC-KIT, most leukemic cells at disease presentation harbored both genetic alteration, whereas in three such cases investigated during complete remission, only AE, but not mC-KIT, could be detected by allele-specific PCR. Therefore, mC-KIT should be a subsequent event on the basis of t(8;21). Furthermore, induced expression of AE in U937-A/E cells significantly up-regulated mRNA and protein levels of C-KIT. This may lead to an alternative way of C-KIT activation and may explain the significantly higher C-KIT expression in 81.3% of patients with t(8;21) than in patients with other leukemias. These data strongly suggest that t(8;21) AML follows a stepwise model in leukemogenesis, i.e., AE represents the first, fundamental genetic hit to initiate the disease, whereas activation of the C-KIT pathway may be a second but also crucial hit for the development of a full-blown leukemia. Additionally, Gleevec suppressed the C-KIT activity and induced proliferation inhibition and apoptosis in cells bearing C-KIT N822K mutation or overexpression, but not in cells with D816 mC-KIT. Gleevec also exerted a synergic effect in apoptosis induction with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia.