[Prognostic significance of DEK-NUP214 fusion gene in patients with acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation].

Objective: To investigate the dynamic change and clinical impact of DEK-NUP214 fusion gene in patients with acute myeloid leukemia (AML) receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Real-time quantitative polymerase chain reaction (RQ-PCR) and multicolor flow cytometry (FCM) were used to detect DEK-NUP214 gene expression and leukemia-associated immunophenotype (LAIP) in 15 newly diagnosed patients with positive DEK-NUP214 and receiving allo-HSCT from September 2012 to September 2017 at Peking University People's Hospital. The clinical outcome was analyzed using Kaplan-Meier survival curves. The impact of DEK-NUP214 expression was analyzed by log-rank test. Results: The subjects were followed-up with a median period of 657 (62-2 212) days. The median DEK-NUP214 expression level at diagnosis was 488% (274%-1 692%). Thirteen patients achieved complete remission before allo-HSCT. Thirteen patients had a residual DEK-NUP214 expression of 0.38% (0.029%-738.9%) before allo-HSCT. After allo-HSCT, DEK-NUP214 expression in 9/13 patients remained positive, which dropped by around 500 folds (5.7-5 663.0 folds) within a month post-transplant. Five patients died and 2 patients relapsed. The 3-year cumulative incidence of relapse in patients with positive DEK-NUP214 before transplant was 17.5%±11.3% and the 3-year overall survival was 60.5%±13.8%. After allo-HSCT, DEK-NUP214-negative patients had a better outcome. Conclusion: Quantitative monitor of DEK-NUP214 fusion gene could be a sensitive indicator of MRD status after allo-HSCT.

[Analysis of the influential factors of late diagnosis among newly identified HIV/AIDS cases in Anhui Province, 2011-2015].

Objective: To analyze the base situation and influential factors of late diagnosis among newly identified HIV/AIDS cases in Anhui Province from 2011 to 2015. Methods: Database information of the newly identified HIV/AIDS cases in Anhui Province from 2011 to 2015 were downloaded from the National HIV/AIDS Comprehensive Information System of China's disease prevention and control information system. To analyze the data including basic information, sample source, route of HIV transmission, population mobility, venereal disease, death and first CD4 count; and the number of 7 073 cases were classified according to late diagnosis and non-late diagnosis criteria. The Chi-square test and logistic regression analysis were used to analyze the influential factors of HIV late diagnosis. Results: A total of 7 073 newly identified HIV/AIDS cases were analyzed, and the mean age was (38.5±15.0) years. The proportion of late diagnosis in all counted cases was 41.7% (2 949/7 073); from 2011 to 2015, the proportions of late diagnosis were 59.7% (485/812), 46.5% (531/1 141), 42.7% (587/1 376), 36.1% (609/1 686), and 35.8% (737/2 058), respectively. Compared with the 0 to 19 years group, the 40 to 59 years group and over 60 years old group have higher risk of late diagnosis (OR=2.68, 95%CI: 1.94-3.71; OR=2.18, 95%CI: 1.53-3.10, respectively). Compared with the high education group, the illiterate and primary school education group have higher risk of late diagnosis (OR=1.74, 95%CI: 1.36-2.22; OR=1.64, 95%CI: 1.34-2.01, respectively). Compared with other sample sources, medical institutions have higher risk of late diagnosis (OR=2.64, 95%CI: 2.28-3.05). Compared with migrant population, the resident population have higher risk of late diagnosis (OR=1.80, 95%CI: 1.53-2.11). Conclusion: The proportion of late diagnosis among newly identified HIV/AIDS cases in Anhui province was relatively high from 2011 to 2015. The main risk factors of late diagnosis included cases reported by medical institutions, resident population, over 40 years old age group and low education level.

[Experts consensus on the management of the right heart function in critically ill patients].

To establish the experts consensus on the right heart function management in critically ill patients. The panel of consensus was composed of 30 experts in critical care medicine who are all members of Critical Hemodynamic Therapy Collaboration Group (CHTC Group). Each statement was assessed based on the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) principle. Then the Delphi method was adopted by 52 experts to reassess all the statements. (1) Right heart function is prone to be affected in critically illness, which will result in a auto-exaggerated vicious cycle. (2) Right heart function management is a key step of the hemodynamic therapy in critically ill patients. (3) Fluid resuscitation means the process of fluid therapy through rapid adjustment of intravascular volume aiming to improve tissue perfusion. Reversed fluid resuscitation means reducing volume. (4) The right ventricle afterload should be taken into consideration when using stroke volume variation (SVV) or pulse pressure variation (PPV) to assess fluid responsiveness.(5)Volume overload alone could lead to septal displacement and damage the diastolic function of the left ventricle. (6) The Starling curve of the right ventricle is not the same as the one applied to the left ventricle,the judgement of the different states for the right ventricle is the key of volume management. (7) The alteration of right heart function has its own characteristics, volume assessment and adjustment is an important part of the treatment of right ventricular dysfunction (8) Right ventricular enlargement is the prerequisite for increased cardiac output during reversed fluid resuscitation; Nonetheless, right heart enlargement does not mandate reversed fluid resuscitation.(9)Increased pulmonary vascular resistance induced by a variety of factors could affect right heart function by obstructing the blood flow. (10) When pulmonary hypertension was detected in clinical scenario, the differentiation of critical care-related pulmonary hypertension should be a priority. (11) Attention should be paid to the change of right heart function before and after implementation of mechanical ventilation and adjustment of ventilator parameter. (12) The pulmonary arterial pressure should be monitored timingly when dealing with critical care-related pulmonary hypertension accompanied with circulatory failure.(13) The elevation of pulmonary aterial pressure should be taken into account in critical patients with acute right heart dysfunction. (14) Prone position ventilation is an important measure to reduce pulmonary vascular resistance when treating acute respiratory distress syndrome patients accompanied with acute cor pulmonale. (15) Attention should be paid to right ventricle-pulmonary artery coupling during the management of right heart function. (16) Right ventricular diastolic function is more prone to be affected in critically ill patients, the application of critical ultrasound is more conducive to quantitative assessment of right ventricular diastolic function. (17) As one of the parameters to assess the filling pressure of right heart, central venous pressure can be used to assess right heart diastolic function. (18). The early and prominent manifestation of non-focal cardiac tamponade is right ventricular diastolic involvement, the elevated right atrial pressure should be noticed. (19) The effect of increased intrathoracic pressure on right heart diastolic function should be valued. (20) Ttricuspid annular plane systolic excursion (TAPSE) is an important parameter that reflects right ventricular systolic function, and it is recommended as a general indicator of critically ill patient. (21) Circulation management with right heart protection as the core strategy is the key point of the treatment of acute respiratory distress syndrome. (22) Right heart function involvement after cardiac surgery is very common and should be highly valued. (23) Right ventricular dysfunction should not be considered as a routine excuse for maintaining higher central venous pressure. (24) When left ventricular dilation, attention should be paid to the effect of left ventricle on right ventricular diastolic function. (25) The impact of left ventricular function should be excluded when the contractility of the right ventricle is decreased. (26) When the right heart load increases acutely, the shunt between the left and right heart should be monitored. (27) Attention should be paid to the increase of central venous pressure caused by right ventricular dysfunction and its influence on microcirculation blood flow. (28) When the vasoactive drugs was used to reduce the pressure of pulmonary circulation, different effects on pulmonary and systemic circulation should be evaluated. (29) Right atrial pressure is an important factor affecting venous return. Attention should be paid to the influence of the pressure composition of the right atrium on the venous return. (30) Attention should be paid to the role of the right ventricle in the acute pulmonary edema. (31) Monitoring the difference between the mean systemic filling pressure and the right atrial pressure is helpful to determine whether the infusion increases the venous return. (32) Venous return resistance is often considered to be a insignificant factor that affects venous return, but attention should be paid to the effect of the specific pathophysiological status, such as intrathoracic hypertension, intra-abdominal hypertension and so on. Consensus can promote right heart function management in critically ill patients, optimize hemodynamic therapy, and even affect prognosis.

[Clinical features and early treatment effects in intermediate risk and poor risk acute myeloid leukemia with EVI1 positive].

OBJECTIVE: To investigate the clinical biological characteristics of EVI1 positive acute myeloid leukemia (AML) and its effect on early chemotherapy. METHODS: The clinical and biological cha-racteristics of 33 AML patients with EVI1 positive were retrospectively analyzed in 361 AML patients who were diagnosed and treated in our institute from March 2015 to July 2016, and the clinical and biological features, and rates of the induced remission were compared between the intermediate risk and poor risk with EVI1 positive AML, moreover, the influential factors on complete remission (CR) were analyzed. The expression of EVI1/ABL was tested in 32 healthy donors to confirm the abnormal threshold of EVI1 expression. RESULTS: The definition of EVI1 positive was that the quantitative expression of EVI1/ABL was more than 8.0%. The 33 AML patients with EVI1 positive were found in 361 newly diagnosed AML patients, in which the female and male patients were 17 and 16 respectively, the median age was 45 (18-67) years, with a median follow-up of 6.6 (0.7-13.2) months. Intermediate karyotype was found in 17 patients(including 9 patients with normal karyotypes,1 patient with +8);unfavorable karyotype was found in 14 patients [including 7 patients with -7/7q-,4 patients with t (v;11q23),3 patients with inv(3)/t(3;3), and 2 patients without mitotic figures]. The rate of CR in the first induction chemotherapy was 42.4%, and the rate of total CR was 60.6%. According to the NCCN, 16 intermediate risk patients and poor risk patients were divided, without favorable risk patients. The rate of CR in the first induction chemotherapy were 68.8% and 17.6% (P=0.005) in the intermediate risk and poor risk respectively, that of total CR were 81.3% and 41.2%(P=0.032), and the rates of relapse were 7.7% and 14.3%.Univariable analysis revealed that unfavorable karyotype could affect the rate of CR in the first reduction chemotherapy and that of total CR (P=0.004, 0.029). The poor risk patients had higher mortality (41.2% vs. 6.3%, P=0.039) and lower overall survival (OS)(P=0.012). CONCLUSION: EVI1 may be not an independent prognostic factor for the AML patients considering the appea-rance in the intermediate and poor risk patients. It predicts poor outcome in the EVI1 positive AML patients who have unfavorable karyocytes, such as -7/7q-, t(v;11q23), and inv(3)/t(3;3), and also a low rate of both CR in the first induction chemotherapy and total CR. It also has a low rate of long-term survival and high mortality in the AML patients with EVI1 positive, who may benefit from allogeneic bone marrow transplantation as soon as possible.

CTLA-4 polymorphisms and haplotype correlate with survival in ALL after allogeneic stem cell transplantation from related HLA-haplotype-mismatched donor.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment for patients with hematological malignancies. Disease relapse remains a major cause of transplant failure. T cell homeostasis is critical to determine the potency of the GVT effect. Recent studies have shown the association of the CTLA-4 polymorphisms with the outcome after HLA-identical sibling allogeneic HSCT. METHODS: In this study, we focused on four CTLA-4 polymorphisms, and analyzed the impact of donor genotypes and haplotypes on the conditions of 152 acute leukemia patients (ALL 83) after related HLA-haplotype- mismatched transplantation. The four SNP genotypes (-1661, -318, CT60 and +49) were determined by TaqMan SNP genotyping assays. RESULTS: ALL recipients of donors with +49 GG showed significantly lower OS (67.7 vs. 90.3 %, P = 0.015) than those with GA+AA. Multivariate analyses showed that +49 GG was an independent risk factor for OS (HR: 0.306, 95 % CI 0.111-0.842, P = 0.022) .23 ALL patients receiving mDLI showed significantly lower OS with +49 GG donor than those with GA+AA (30.0 vs. 83.1 %, P = 0.003). The haplotype analysis revealed only three haplotypes in the donor population -1661/-318/CT60/+49 i.e., ACGG, ACAA and GTGA, the frequencies were 64.1, 19.4 and 16.5 %, respectively. Donors with and without the ACGG/ACGG haplotype had the same effect on transplant outcomes as those with +49 GG and +49 GA+AA. CONCLUSION: In summary, the CTLA-4 +49 GG and the haplotype ACGG/ACGG reduced the overall survival in ALL after allo-HSCT from the related HLA-haplotype-mismatched donor, knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for donor selection and individual application of immunosuppressive agents and immunotherapy.

[A comparison of efficacy and safety between Chinese generic imatinib versus branded imatinib in patients with newly-diagnosed chronic myeloid leukemia in the chronic phase: a single-center prospective cohort study].

Objective: To compare the efficacy and safety between Chinese generic imatinib (Xinwei®, Jiansu Hansoh Pharmaceutical Group Co., Ltd.) versus branded imatinib (Glivec®, Novartis) in patients with newly-diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Methods: Patients with newly diagnosed CML-CP were enrolled and assigned to receive either Xinwei or Glivec at an initial dose of 400 mg/d according to patients' financial capability. The efficacy and adverse effects were evaluated. Results: From January 2014 to September 2015, 145 eligible patients were assigned to Xinwei (n=89) or Glivec (n=56) group. All patients were treated and followed up at least 3 months. At 3 months, the complete response rates were 95.5%(85/89) and 100%(56/56), major cytogenetic response rates were 74.2%(66/89) and 80.4%(45/56), and the proportions of achieving BCR-ALBIS≤10% were 76.1%(67/88) and 82.1%(46/56) in Xinwei and Glivec groups respectively (all P>0.05). With a median follow-up of 12 months, 2 patients in each group progressed to accelerate or blast phase. Hematologic and non-hematologic side effects were similar between the 2 groups. Conclusions: Early hematological, cytogenetic and molecular responses between Xinwei and Glivec are comparable in newly-diagnosed CML-CP patients. The progression rate and side effects are also similar between the 2 groups.

Hypothyroidism and first-trimester spontaneous miscarriages.

OBJECTIVE: To evaluate the association between hypothyroidism and first-trimester spontaneous miscarriages and to explain the mechanism. MATERIALS AND METHODS: Patients admitted between October and May 2011 with threatened miscarriage in the first trimester were analyzed and levels of progesterone and thyroid hormones as T3, T4, and thyroid-stimulating hormone (TSH) were estimated. Once hypothyroidism was diagnosed, patients were treated with sodium levothyroxine (LT4) as substitution and outcomes were observed. RESULTS: Measurement of progesterone was useful for predicting the outcome of threatened miscarriage The results showed that progesterone (P) = 14.74 ng/ml is selected as predictive value to judge whether the fetal treatment was successfully or not. When serum P value is above 14.74 ng/ml before treatment, it may favour a miscarriage, if the serum P value is below 14.74 ng/ml, miscarriage is unlikely; its sensitivity and specificity are high. The risk for miscarriage in patients diagnosed with hypothyroidism in which LT4 substitution was similar to the level observed in the controls, and P between the two groups had no distinct difference. The mechanism explaining the risk of miscarriage increased by thyroid disorders remains unclear, which needs advanced research. CONCLUSION: Screening of thyroid disorders has important clinical significance in early pregnancy, and substitution of LT4 to those who are in the early pregnancy with hypothyroidism could reduce the risk of miscarriage.

[Factors influencing severe cytopenia in chronic phase chronic myeloid leukemia patients receiving initial second generation tyrosine kinase inhibitors and its impact on treatment responses and outcomes].

Objective: To explore the influencing covariates of severe neutrophils and/or thrombocytopenia and their effect on treatment response and outcome in patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving initial second-generation tyrosine kinase inhibitors (2G-TKI) . Methods: Data from consecutive patients aged ≥18 years with newly diagnosed CP-CML who received initial 2G-TKI at Peking University People's Hospital from September 2008 to November 2021 were interrogated. Binary logistic regression models and Fine-Gray and Cox regression models were applied. Results: Data from 267 patients who received initial 2G-TKI, including nilotinib (n=239, 89.5% ) and dasatinib (n=28, 10.5% ) , were interrogated. The median age was 36 (range, 18-73) years, and 156 (58.4% ) patients were male. At a median treatment period of 1.0 (0.1-3.0) month, 43 (16.1% ) patients developed grade ≥3 neutrophils and/or thrombocytopenia and recovered within 1.0 (0.1-24.6) month. Male (OR=2.9, 95% CI 1.2-6.8; P=0.018) , age of ≥36 years (OR=3.2, 95% CI 1.4-7.2, P=0.005) , a spleen below a costal margin of ≥7 cm (OR=2.8, 95% CI 1.2-6.6, P=0.020) , and a hemoglobin (HGB) level of <100 g/L (OR=2.9, 95% CI 1.3-6.8, P=0.012) at diagnosis were significantly associated with grade ≥ 3 neutrophils and/or thrombocytopenia. Based on their regression coefficients, male, age of ≥36 years, a spleen below a costal margin of ≥7 cm, and an HGB level of <100 g/L were given 1 point to form a predictive system. All patients were divided into three risk subgroups, and the incidence of severe cytopenia significantly differed among the three groups (P < 0.001) . Grade ≥3 neutrophils and/or thrombocytopenia for >2 weeks was significantly associated with lower cumulative incidences of complete cytogenetic response (CCyR, HR=0.5, 95% CI 0.3-0.7, P<0.001) and major molecular response (MMR, HR=0.4, 95% CI 0.3-0.8, P=0.004) and was not significantly associated with failure, progression, and survival. Conclusion: Male, advanced age, a large spleen, and a low HGB level were significantly associated with severe cytopenia. The four covariates were used to establish a prediction model, in which the incidence of severe cytopenia among different risk groups was significantly different. Severe cytopenia for >2 weeks was a negative factor for responses but not for outcomes.

[Comparison of BCR::ABL (P210) mRNA levels detected by dPCR and qPCR methods in patients with chronic myeloid leukemia].

Objective: To compare digital polymerase chain reaction (dPCR) and real-time quantitative PCR (qPCR) measurements of BCR::ABL (P210) mRNA expression in patients with chronic myeloid leukemia (CML) . Methods: In this non-interventional, cross-sectional study, BCR::ABL (P210) mRNA was simultaneously measured by dPCR and qPCR in peripheral blood samples collected from patients with CML who underwent tyrosine kinase inhibitor therapy and who achieved at least a complete cytogenetic response from September 2021 to February 2023 at Peking University People's Hospital. The difference, correlation, and agreement between the two methods were evaluated using the Wilcoxon signed-rank test, Spearman's correlation, and Bland-Altman analysis, respectively. Results: In total, 459 data pairs for BCR::ABL mRNA expression measured by dPCR and qPCR from 356 patients with CML were analyzed. There was a significant difference in BCR::ABL mRNA expression between the two methods (P<0.001). When analyzed by the depth of the molecular response (MR), a significant difference only existed for patients with ≥MR4.5 (P<0.001). No significant difference was observed for those who did not achieve a major MR (no MMR; P=0.922) or for those who achieved a major MR (MMR; P=0.723) or MR4 (P=0.099). There was a moderate correlation between the BCR::ABL mRNA expression between the two methods (r=0.761, P<0.001). However, the correlation gradually weakened or disappeared as the depth of the MR increased (no MMR: r=0.929, P<0.001; MMR: r=0.815, P<0.001; MR4: r=0.408, P<0.001; MR4.5: r=0.176, P=0.176). In addition, the agreement in BCR::ABL mRNA expression between the two methods in those with MR4.5 was weaker than other groups (no MMR: ▉= 0.042, P=0.846; MMR:▉=0.054, P=0.229; MR4:▉=-0.020, P=0.399; MR4.5:▉=-0.219, P<0.001) . Conclusions: dPCR is more accurate than qPCR for measuring BCR::ABL (P210) mRNA expression in patients with CML who achieve a stable deep MR.

[Combination of socio-demographic and clinical co-variates for predicting treatment responses and outcomes in patients with chronic myeloid leukemia in the chronic phase].

Objective: To explore the impacts of socio-demographic and clinical co-variates on treatment responses and outcomes in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitor (TKI) and identified the predictive models for them. Methods: Data of newly diagnosed adult patients with CML-CP receiving first-line TKI and having complete socio-demographic data and clinical information were reviewed. Cox model was used to identify the independent variables associated with complete cytogenetic response (CCyR) , major molecular response (MMR) , molecular response 4 (MR(4)) and molecular response 4.5 (MR(4.5)) , as well as failure-free survival (FFS) , progression-free survival (PFS) , overall survival (OS) and CML-related OS. Results: A total of 1414 CML-CP patients treated with first-line imatinib (n=1176) , nilotinib (n=170) or dasatinib (n=68) were reviewed. Median age was 40 (18-83) years and 873 patients (61.7% ) were males. Result of the multivariate analysis showed that lower educational level (P<0.001-0.070) and EUTOS long-term survival intermediate or high-risk (P<0.001-0.009) were significantly associated with lower cumulative incidences of CCyR, MMR, MR(4) and MR(4.5), as well as the inferior FFS, PFS, OS and CML-related OS. In addition, those who were males, from rural households, had white blood cells (WBC) ≥120×10(9)/L, hemoglobin (HGB) <115 g/L and treated with first-line imatinib had significantly lower cumulative incidences of cytogenetic and/or molecular responses. Being single, divorced or widowed, having, rural household registration, WBC≥120×10(9)/L, HGB<15 g/L, and comorbidity (ies) was significantly associated with inferior FFS, PFS, OS, and/or CML-related OS. Thereafter, the patients were classified into several subgroups using the socio-demographic characteristics and clinical variables by cytogenetic and molecular responses, treatment failure and disease progression, as well as overall survival and CML-related OS, respectively. There were significant differences in treatment responses and outcomes among the subgroups (P<0.001) . Conclusion: Except for clinical co-variates, socio-demographic co-variates significantly correlated with TKI treatment responses and outcomes in CML-CP patients. Models established by the combination of independent socio-demographic and clinical co-variates could effectively predict the responses and outcome.

[The efficacy and safety of low-dose chemotherapy combined with tyrosine kinase inhibitors in the treatment of Philadelphia-chromosomal-positive acute lymphoblastic leukemia].

Objective: The study aims to explore the efficacy and safety of low-dose chemotherapy combined with tyrosine kinase inhibitor (TKI) as an induction therapy for Philadelphia-chromosomal-positive acute lymphoblastic leukemia (Ph(+) ALL) . Methods: The data of the consecutive newly diagnosed patients with Ph(+) ALL were reviewed. The efficacy and safety of low-dose chemotherapy and conventional-dose chemotherapy combined with TKI were compared. Results: A total of 217 patients with a median age of 38 (10-69) years old were included in this study. 78 patients were in the low-dose chemotherapy group, and 139 patients were in the conventional-dose chemotherapy group. There were no significant differences in the 4-week complete remission (CR) rate (98.7% vs 97.0%, P=0.766) and overall CR rate (100% vs 100%, P=1.000) between the two groups. Multivariate analyses showed that the chemotherapy intensity was not related to the disease-free survival rate and overall survival rate. However, the lower incidence of infection (P=0.017) , the shorter duration of neutropenia (P=0.001) and PLT<20 × 10(9)/L (P=0.057) , and the lower red blood cell transfusion volume (P=0.002) were more common in the low-dose chemotherapy group than in the conventional-dose chemotherapy group. Conclusions: The low-dose chemotherapy is superior to the conventional-dose chemotherapy combined with TKI as induction therapy in Ph(+) ALL with similar efficacy but is safer.

[Clinical characteristics, treatment pattern, and outcomes in newly diagnosed patients with chronic myeloid leukemia in the chronic phase by age].

Objective: To explore the clinical characteristics, treatment patterns, and outcomes in newly diagnosed patients with chronic myeloid leukemia in the chronic phase (CML-CP) by age. Methods: Clinical data of consecutive ≥14 years old newly diagnosed CML-CP patients were retrospectively analyzed. Results: This study included 957 patients. Of the patients, 597 (62.4%) were male. The median age was 40 years (range, 14-83 years) . The patients were stratified into three age groups: <40 years (n=470; 49.1%) , 40-59 years (n=371; 38.8%) , and ≥60 years (n=116; 12.1%) . The proportions of the patients who had splenomegaly (P<0.001) , WBC ≥100 × 10(9)/L (P<0.001) , anemia (P<0.001) , PLT<450 × 10(9)/L (P=0.022) , more blasts in the blood (P=0.010) , and clonal chromosome abnormalities in Philadelphia chromosome-positive cells (P=0.006) at diagnosis significantly decreased with age. However, the proportions of those with comorbidities (P<0.001) , intermediate or high Sokal risk (P<0.001) , and receiving imatinib as front-line therapy (P<0.001) significantly increased with age. No significant differences in gender and the EUTOS Long-Term Survival risks were noted across the three age groups. The multivariate analysis showed that ≥60 years was an adverse predictor for overall survival. However, age was not significantly associated with tyrosine kinase inhibitor (TKI) therapy responses and other outcomes. The incidences of nonhematological toxicity were significantly increased with age during TKI therapy (P<0.001) . However, those of hematological toxicity was similar across the three age groups. The proportions of the patients maintaining imatinib therapy (P=0.026) and receiving low-dose TKI therapy (P<0.001) significantly increased with age at the end of follow-up. Conclusions: Significant differences exist in clinical characteristics, TKI response, overall survival rates, and nonhematological toxicity among newly diagnosed CML-CP patients of different ages.

[Analysis of the clinical characteristics of 24 cases of hematological malignancies with SET-NUP214 fusion gene].

Objective: To investigate the expression of SET-NUP214 fusion gene in hematological malignancies and to analyze its related clinical biological characteristics. Methods: The clinical data of 24 patients with SET-NUP214 fusion gene-positive hematological malignancies were retrospectively analyzed, and the Kaplan-Meier method was used for survival analysis. Results: Among the 24 patients with SET-NUP214 fusion gene, 15 cases of acute lymphoblastic leukemia (ALL) (13 cases of T-ALL and 2 cases of B-ALL) , 7 cases of acute myeloid leukemia (AML) , and 2 cases of T/myeloid mixed acute leukemia have been identified. The immunophenotype of 13 cases of T-ALL was mainly characterized by CD3(+)CD2(-), 73.3% of ALL was characterized by myeloid marker expression, and 85.7% of AML was characterized by CD7 expression. Complete remission (CR) was achieved in 22 patients (91.7%) after induction chemotherapy. All 24 patients received allogeneic hematopoietic stem cell transplantation (HSCT) . With a median follow-up of 24 months, the 3-year relapse free survival (RFS) of AML and ALL was 85.7% and 33.3%, respectively (P=0.128) . Comparing 13 cases of SET-NUP214-positive and 62 cases of SET-NUP214-negative T-ALL, the CR rates of induction chemotherapy were 92.3% and 93.5% (P=0.445) , and the 4-week CR rates of induction chemotherapy were 69.2% and 72.6%, respectively (P=0.187) ; the differences were not statistically significant. After HSCT, the 3-year RFS of SET-NUP214(+)T-ALL and SET-NUP214(-)T-ALL was 38.5% and 66.4%, respectively (P=0.028) , and the difference was statistically significant. Conclusion: The SET-NUP214 fusion gene is mainly detected in T cell-derived hematological malignancies, and the prognosis of SET-NUP214 positive T-ALL is relatively poor.

[Variables associated with BCR-ABL kinase domain mutation in TKI-resistant patients with chronic myeloid leukemia].

Objectives: To explore BCR-ABL kinase domain mutation profiles and clinical variables associated with them in tyrosine kinase inhibitor (TKI) -resistant patients with chronic myeloid leukemia (CML) . Methods: Imatinib-, nilotinib-, and/or dasatinib-resistant patients with CML who screened BCR-ABL mutation (s) in Peking University People's Hospital between June 2001 and September 2019 were retrospectively reviewed. BCR-ABL mutation was analyzed by Sanger sequencing. Binary logistic regression model was built to identify independent clinical variables associated with developing BCR-ABL mutation (s) . Results: Data of 1 093 TKI-resistant cases in 804 patients who experienced resistance to imatinib (n=576, 52.7%) , nilotinib (n=238, 21.8%) , and dasatinib (n=279, 25.5%) were analyzed. In total, 291 (50.5%) imatinib-, 152 (63.9%) nilotinib-, and 160 (57.3%) dasatinib-resistant cases developed BCR-ABL mutation (s) . T315I mutation was the most frequent mutation detected in imatinib-, nilotinib-, and dasatinib-resistant cases, accounting for 12.3%, 27.3%, and 34.1%, respectively. Y253F/H (7.5%) and F359V/C/I (5.6%) were the mutation detected in ≥5% imatinib-resistant cases; F359V/C/I (12.2%) , Y253F/H (11.8%) , and E255K/V (10.5%) in nilotinib-resistant cases; and F317L/V/I/C (11.5%) and E255K/V (5.4%) in dasatinib-resistant cases. In multivariate analyses, no TKI dose reduction or discontinuation of TKI therapy was the common variable associated with developing BCR-ABL mutation (s) . Other variables associated with developing BCR-ABL mutation (s) in imatinib-, nilotinib-, or dasatinib-resistant cases included male gender, younger age, no comorbidity, advanced phase before starting current TKI therapy, longer interval from diagnosis to starting current TKI therapy, acquired resistance, and TKI resistance due to progression to advanced phase or hematologic failure. In addition, interval from TKI failure to BCR-ABL mutation detection, starting initial TKI therapy to TKI failure, and starting current TKI therapy to TKI failure were associated with the frequency of developing BCR-ABL mutation. Dasatinib and nilotinib use and acquired resistance were identified to be associated with the development of T315I mutation in multivariate analyses. Conclusions: More than half of TKI-resistant CML patients developed BCR-ABL mutation (s) by Sanger sequencing. T315I mutation was the most frequently detected. Clinical variables significantly associated with developing BCR-ABL mutation (s) should be used not only as basis for the choice of subsequent TKIs but also the understanding of TKI-resistant mechanisms.

[Dasatinib-related pulmonary adverse events in patients with chronic myeloid leukemia].

Objective: To explore dasatinib-related pulmonary adverse events in patients with chronic myeloid leukemia (CML) . Methods: We retrospectively analyzed the incidence of pleural effusion (PE) and pulmonary arterial hypertension (PAH) in patients with CML treated with dasatinib at Peking University People's Hospital from April 2008 to January 2020. Results: A total of 280 patients were collected. The median dasatinib treatment time was 26 (1-142) months. Ninety (32.1%) patients developed PE, including 40 (44.4%) in grade 1, 44 (48.9%) in grade 2, and 6 (6.7%) in grade 3. The incidence of PE increased gradually with the prolongation of treatment. The multivariate analysis showed that increasing age (every 10 years, HR=1.6; P<0.001) , advanced phase when starting dasatinib therapy (HR=2.2; P=0.008) , and cardiovascular comorbidity (ies) (HR=1.9; P=0.018) were significantly associated with developing PE. The advanced phase when starting dasatinib therapy (HR=3.4; P=0.001) , interval from diagnosis to taking TKI for ≤6 months (HR=2.2; P=0.015) , and dose < 100 mg/d when PE was found (HR=3.1; P=0.001) were associated with more severe PE. PE relieved or disappeared after intervention in half of the patients. Among 60 patients with symptoms of cough, chest tightness, and shortness of breath, 49 underwent ultrasonic cardiography; 8 (16.3%) had high probability of PAH, approximately 3.5% in all patients; and 6 (75.0%) of them had PE. PAH was reversible. There was no difference in the incidences of PE and PAH between branded and Chinese generic dasatinib. Conclusion: PE is a common dasatinib-related pulmonary adverse event, and PAH is rare in patients with CML. The identification of individuals with high risk, close monitoring, and timely intervention may help to alleviate PE and PAH.

[Analysis of the efficacy and influencing factors of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia in the chronic phase and accelerated phase].

Objective: To explore the efficacy and prognosis of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) and accelerated phase (AP) . Methods: From January 2008 to November 2018, the data of CML patients who failed first- or second-line tyrosine kinase inhibitor (TKI) -therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed. Results: A total of 226 patients receiving nilotinib or dastinib as second-line (n=183) and third-line (n=43) therapy were included in this study. With a median follow-up of 21 (range, 1-135) months, the cumulative rates of complete hematological response (CHR) , complete cytogenetic response (CCyR) and major molecular response (MMR) were 80.4%, 56.3%and 38.3%, respectively in those receiving TKI as second-line TKI therapy. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.7%and 93.1%, respectively. Multivariate analyses showed that Sokal high risk, female gender, the best response achieved

Correlations of the ZEB1 expression with the incidence and prognosis of non-small cell lung cancer.

OBJECTIVE: In order to investigate the role of the zinc finger E-box-binding homeobox 1 (ZEB1) expression in the incidence of non-small cell lung cancer (NSCLC), the effects of the ZEB1 expression on the pathogenesis and prognosis of NSCLC were investigated. PATIENTS AND METHODS: Correlations of the expression of ZEB1 in 88 clinical patients with NSCLC with clinicopathological features were determined. The patients were followed up for 60 months to study the correlation between the ZEB1 expression and the prognosis of NSCLC patients. To further explore the role of the ZEB1 expression in the incidence of NSCLC, the expressions of ZEB1 and E-cadherin in three NSCLC cell lines (A549, NCI-H1299 and NCI-H1975) and human normal lung epithelial BESA-2B cell line were measured, and the cell invasion ability was detected. The role of ZEB1 in NSCLC cell invasion was verified through the knockdown of ZEB1 by the short hairpin ribonucleic acids (shRNAs). In addition, its effects on the proliferation and apoptosis of NSCLC cells were confirmed by the overexpression of ZEB1. RESULTS: The expression of ZEB1 in NSCLC tissues was remarkably higher than that in normal tissues, and the expression level of ZEB1 was significantly related to the cancer stage and tumor size. The lower the expression of ZEB1 was, the higher the overall survival rate and the longer the survival time would be. The expression of ZEB1 was negatively correlated with that of E-cadherin in cell lines, and ZEB1-shRNAs markedly reduced the invasion ability of NSCLC cells. The overexpression of ZEB1 resulted in an increase in the proliferation activity and a significant decrease in the apoptosis of A549 cells. CONCLUSIONS: The expression of ZEB1 is closely related to the incidence and prognosis of NSCLC. Increased expression of ZEB1 is helpful for promoting the invasion of NSCLC and enhancing the proliferation activity of NSCLC.

[Fertility and disease outcomes in patients with chronic myeloid leukemia].

Objective: To explore Fertility and disease outcomes in patients with chronic myeloid leukemia (CML) . Methods: Clinical and fertility outcomes of male (from Jul. 1998 to Feb. 2018) and female CML (from Sep. 2009 to Feb. 2018) patients were retrospectively analyzed at Peking University People's Hospital. Results: A total of 49 male CML patients and their spouses were enrolled. Before their spouses conceived, 34 patients were receiving tyrosine kinase inhibitor (TKI) imatinib, 9 with nilotinib, and 6 with dasatinib. At the time of conception, the median age of these male patients was 32 years (range, 25-48 years) , and the median TKI treatment duration was 36 months (range, 0.2-198 months) . One male patient having achieved complete hematologic response yet discontinuing TKI for a year developed a disease progression to blast crisis. The other 48 patients sustained stable disease. The total conception times were 61 and finally 55 infants were born including one with premature birth, two with low birth weight, and one with hypospadias receiving surgery. The other 18 female patients after pregnancy were enrolled. Two patients developed spontaneous abortions. Two received induced abortions. Fourteen gave birth to healthy infants without congenital malformation. The interval from diagnosis of CML to initiation of TKI was 4 months (range, 0.3-16 months) . During a median follow-up of 45 months (range from 7-114 months) , the estimated complete cytogenetic response (CCyR) rate, major molecular response (MMR) rate and molecular response(4.5) (MR(4.5)) rate by 5 years were 88.9%, 85.3% and 35.1%, respectively. The estimated failure-free survival, progression-free survival and overall survival were 64.2%, 90.9% and 90.9%, respectively. All 14 babies developed as normal. Conclusions: It seems that TKIs do not affect pregnancy outcome in the spouses of male CML patients, suggesting that withdrawal of TKIs is not necessary. Female CML patients have good pregnancy and disease outcomes in the TKI era.

[Comparison of nilotinib vs imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase].

Objective: To compare the cytogenetic and molecular responses, outcomes and severe hematologic toxicity of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) . Methods: Newly diagnosed CML-CP patients were consecutively recruited from January 2006 to December 2018 who received nilotinib and imatinib as first-line treatment. Clinical data were retrospectively analyzed. Results: A total of 524 patients were classified into 439 (83.8%) receiving imatinib and 85 (16.2%) receiving nilotinib. Comparing with imatinib group, patients in nilotinib group were much younger (P=0.019) and more with intermediate and high Sokal risks (P<0.001) , WBC ≥100×10(9)/L (P<0.001) , HGB<120 g/L (P<0.001) , blast cells in bone marrow (P=0.026) , splenomegaly (P<0.001) by physical examination at diagnosis, and longer interval from diagnosis to TKI treatment (P=0.003) . With a median TKI duration of 57 (range 3-153) months, the probabilities of complete cytogenetic response (CCyR) (P=0.011) , major molecular response (MMR) (P=0.001) and MR(4.5) (P=0.046) were much higher in nilotinib group than those in imatnib according to each risk group. There is no statistical significance on probabilities of failure free survival (FFS) , progression free survival (PFS) and overall survival (OS) at 6 years between the two groups. Multivariate analyses showed that imatinib was an adverse factor associated with achieving CCyR (OR=0.6, 95% CI 0.5-0.8, P=0.001) , MMR (OR=0.6, 95% CI 0.5-0.9, P=0.032) and MR(4.5) (OR=0.6, 95%CI 0.5-0.9, P=0.032) and poor FFS (OR=1.9, 95%CI 1.0-3.4, P=0.041) . In addition, Sokal score was an independent factor affecting cytogenetic and molecular responses, treatment failure, disease progression and survival. Male, WBC ≥100×10(9)/L or HGB<120 g/L at diagnosis were significantly associated with lower cytogenetic and molecular response rates and/or poor FFS. The severe hematologic adverse events were not associated with different TKIs. Conclusions: Nilotinib reaches to the faster and deeper cytogenetic and molecular responses and significantly improves FFS than imatinib in newly diagnosed patients with CML-CP.

[Philadelphia chromosome-negative myeloid neoplasms in patients with Philadelphia chromosome-positive chronic myeloid leukemia during tyrosine kinase inhibtor-therapy].

Objective: To compare the clinical features between the 2 cohorts developing myelodysplastic syndrome or acute myeIogenous Ieukemia in Philadelphia chromosome-negative cells (Ph(-) MDS/AML) and maintaining disease stable in the patients with Philadelphia chromosome-positive chronic myeloid Ieukemia (Ph(+) CML) who had clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph(-)) during tyrosine kinase inhibtor (TKI) - therapy. Methods: We retrospectively analyzed Ph(+) CML patients who developed CCA/Ph(-) during TKI-therapy from May 2001 to December 2017. Results: Data of CCA/Ph(-) 63 patients, including 7 progressing to Ph(-) MDS/AML and 56 remaining disease stable were collected. Compared with those with stable disease, patients with Ph(-)MDS/AML had lower hemoglobin (P=0.007) and platelet (P=0.006) counts, and higher proportion of peripheral blasts (P<0.001) when the first time CCA/Ph(-) was detected, and more mosonomy 7 abnormality (5/7, 71.4%) when MDS or AML was diagnosed; meanwhile, trisomy 8 (32/56, 57.1%) was more common in those with stable disease. Outcome of the patients with Ph(-) MDS/AML were poor. However, most of those with CCA/Ph(-) and stable disease had optimal response on TKI-therapy. Conclusions: A few patients with Ph(+) CML developed CCA/Ph(-) during TKI-therapy, most of them had stable disease, but very few patients developed Ph(-) MDS/AML with more common occurrence of monosomy 7 or unknown cytopenia. Our data suggested the significance of monitoring of peripheral blood smear, bone marrow morphology and cytogenetic analysis once monosomy 7 or unknown cytopenia occurred.