[Clinical and genetic characteristics of young patients with myeloproliferative neoplasms].

Objectives: To investigate the clinical and genetic features of young Chinese patients with myeloproliferative neoplasms (MPN). Methods: In this cross-sectional study, anonymous questionnaires were distributed to patients with MPN patients nationwide. The respondents were divided into 3 groups based on their age at diagnosis: young (≤40 years) , middle-aged (41-60 years) , and elderly (>60 years) . We compared the clinical and genetic characteristics of three groups of MPN patients. Results: 1727 assessable questionnaires were collected. There were 453 (26.2%) young respondents with MPNs, including 274 with essential thrombocythemia (ET) , 80 with polycythemia vera (PV) , and 99 with myelofibrosis. Among the young group, 178 (39.3%) were male, and the median age was 31 (18-40) years. In comparison to middle-aged and elderly respondents, young respondents with MPN were more likely to present with a higher proportion of unmarried status (all P<0.001) , a higher education level (all P<0.001) , less comorbidity (ies) , fewer medications (all P<0.001) , and low-risk stratification (all P<0.001) . Younger respondents experienced headache (ET, P<0.001; PV, P=0.007; MF, P=0.001) at diagnosis, had splenomegaly at diagnosis (PV, P<0.001) , and survey (ET, P=0.052; PV, P=0.063) . Younger respondents had fewer thrombotic events at diagnosis (ET, P<0.001; PV, P=0.011) and during the survey (ET, P<0.001; PV, P=0.003) . JAK2 mutations were found in fewer young people (ET, P<0.001; PV, P<0.001; MF, P=0.013) ; however, CALR mutations were found in more young people (ET, P<0.001; MF, P=0.015) . Furthermore, mutations in non-driver genes (ET, P=0.042; PV, P=0.043; MF, P=0.004) and high-molecular risk mutations (ET, P=0.024; PV, P=0.023; MF, P=0.001) were found in fewer young respondents. Conclusion: Compared with middle-aged and elderly patients, young patients with MPN had unique clinical and genetic characteristics.

[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.

[Analysis of verification results of protective effects of hearing protectors in different industries].

Objective: To get insight into the current practice of noise reduction effect of workers as they wore hearing protectors in different domestic enterprises and the possible affected factors. Methods: From October 2020 to April 2021, using a random sampling method, 1197 workers exposed to noise in petrochemical factories, textile factories, and parts manufacturing factories were selected as the study subjects. The noise reduction effect of hearing protectors worn by workers in daily use was tested using a hearing protector suitability testing system. The personal sound attenuation level (PAR) was compared among workers in three enterprises, Targeted intervention and repetitive testing were conducted for workers who did not meet the noise reduction effect required by the enterprise, and the changes in PAR of workers before and after the intervention were compared. The comparison of baseline PARs between two or more groups was performed using the Mann Whitney test, the comparison of baseline PARs with post intervention PARs was performed using the Wilcoxon signed rank sum test, and the comparison of qualitative data between two or more groups was performed using the Chi square test. Results: The median baseline PAR for all workers was 15 dB. Men, age<30 years old, education level at or above college level, working experience of 5 to 15 years, and those who used hearing protectors for 5 to 15 years had higher PARs, with statistically significant differences (P<0.05). The median difference in baseline PAR among workers from three enterprises was statistically significant (H=175.06, P<0.01). The median PAR of subjects who did not pass the baseline increased from 3 dB to 21 dB after intervention (Z=-27.92, P<0.01) . Conclusion: Some workers wearing hearing protectors do not meet the required PAR, and low PARs may be related to incorrect wearing methods and incorrect selection of hearing protectors. As a tool for testing, training, and assisting in selection, the hearing protector suitability testing system is of great significance for worker hearing protection.

[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.

[Risk assessment on noise-induced hearing loss of 488 workers in a petrochemical plant].

Objective: To assess the risk of noise-induced hearing loss in workers from a petrochemical plant. Methods: In October 2020, 488 male workers exposed to noise in a petrochemical plant in Guangdong Province were selected by cluster sampling. Acoustics-Estimation of Noise-Induced Hearing Loss (ISO 1999: 2013) was used to assess the risk of noise-induced hearing loss of workers, and individual fit testing was used to evaluate the sound attenuation obtained by the workers. The risk assessment results and fitness test results of workers with different hearing levels were compared. Results: The average noise exposure equivalent sound level of the workers in the petrochemical plant was 86.7 dB (A) . The median of PARs (personal attenuation ratings) was 16 (4, 23) dB. There were statistically significant differences in age and service years among workers with different hearing results (P<0.05) , but no statistically significant differences in noise intensity and PARs (P>0.05) . According to risk assessment results of ISO 1999: 2013, the current risk of high-frequency hearing loss in 488 workers were negligible risk and acceptable risk. The risk of noise-induced deafness weredivided into three levels: negligible risk in 452 workers (92.7%) , medium risk in 27 workers (5.5%) and high risk in 9 workers (1.8%) . The risk of high-frequency hearing loss in next 5 to 15 years for workers with noise exposure level of >94 to 97 dB and >97 dB or above would be medium risk or above. The risk of noise-induced deafness in next 5 to 15 years for workers exposed to noise withlevel of 91 to 94 dB would be medium risk or above. Conclusion: The risk of noise-induced hearing loss in workers from the petrochemical plant is high in next 5 to 15 years, and noise prevention and control measures need to be strengthened. ISO1999: 2013 assessment method may underestimate the risk of hearing loss among workers.

[Effect of perioperative accelerated rehabilitation management program for children with congenital spinal deformity].

Objective: To explore the perioperative therapeutic effect of enhanced recovery after surgery (ERAS) in children with congenital spinal deformity and summarize the clinical experience. Methods: Fifty-nine pediatric patients with congenital spinal deformities admitted to Beijing Children's Hospital from May 2020 to January 2021 were included in this study, and all patients underwent posterior spinal osteotomy orthopedic implant fusion with internal fixation. There were 22 males and 37 females, aged (7.4±4.1) years. Patients were divided into ERAS group (n=29) and control group (n=30) according to the management model. Patients in the ERAS group were managed with an accelerated recovery management model during the perioperative period, which mainly included: high protein diet, shortened fasting time, optimized anesthesia protocol, and multimodal analgesia. Patients in the control group received the traditional perioperative management model. The indexes of surgery, diet, pain score and laboratory tests were compared between the two groups. Results: All patients completed the surgery successfully. The mean temperature and pain scores of patients in the ERAS group were lower than those in the control group at 3 days postoperatively (P<0.05). The time to exhaustion and defecation in the ERAS group was (1.0±0.8) d and (2.5±0.9) d postoperatively, both significantly earlier than those in the control group ((3.4±0.8) d and (4.0±1.1) d) (both P<0.05). C-reactive protein was 38(8,46) mg/L in patients of the ERAS group on the day 3 postoperatively, which was significantly lower than that in the control group 47(22,93) mg/L (P=0.023). The hemoglobin level on postoperative day 3 was (110.7±9.6) g/L in the ERAS group, which was significantly higher than that in the control group ((104.5±11.4) g/L) (P=0.029). Postoperative complications occurred in 8(27.6%) and 9(30.0%) patients in the ERAS and control groups, respectively (P=1.000), with mild abdominal pain and bloating being the most common complications in both groups, most of which were not treated specifically. Conclusion: ERAS is a safe and effective perioperative management mode for children with congenital spinal deformity. Compared with the traditional method, it can significantly improve the treatment efficiency and deserve clinical application.

Elevated expression of CDT1 in childhood acute lymphoblastic leukemia promotes cell proliferation, invasion and migration through activation of EMT.

Acute lymphoblastic leukemia (ALL) is a malignant disease of the hematopoietic system. At present, the mechanism and pathogenesis of ALL have not been fully clarified. This study aimed to illustrate the roles of Cdc10 protein-dependent transcript 1 (CDT1) in ALL. Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) was performed to examine serum levels of CDT1 in childhood ALL patients and healthy volunteers. The interaction between CDT1 expression and prognosis of childhood ALL was analyzed. Meanwhile, expressions of CDT1 in ALL cell lines were determined. Furthermore, CDT1 knockdown model was constructed in ALL cells, and Cell Counting Kit-8 (CCK-8), and Transwell assays were conducted to analyze the effect of CDT1 on the biological functions of ALL cells. Potential mechanism was further explored through detecting the expressions of Epithelial-to-mesenchymal transition (EMT)-related genes. RT-qPCR results indicated that serum level of CDT1 in childhood ALL patients was remarkably higher than that of healthy volunteers. Childhood ALL patients with high expression of CDT1 had lower overall survival rate compared with those expressing low expression of CDT1. CDT1 knockdown remarkably decreased the proliferation and metastasis abilities of pediatric ALL cells. Results of western blot showed that CDT1 might contribute to the malignant progression of childhood ALL via activating EMT. The findings showed that elevated CDT1 facilitated ALL metastasis by promoting EMT, suggesting that CDT1 played a pivotal role in ALL metastasis and may serve as a novel prognostic biomarker and therapeutic target.

[Relationship between insulin resistance, serum VCAM-1, FGF19, IGF-1 and colorectal polyps].

Objective: To explore the relationship between insulin resistance, glucose and lipid metabolism related molecules and colorectal polyps. Methods: A total of 262 healthy people who underwent colonoscopy in Shandong cancer hospital from June 2019 to September 2020 were selected. The levels of serum vascular cell adhesion molecule-1 (VCAM-1), fibroblast growth factor 19 (FGF19), insulin like growth factor (IGF-1), fasting blood glucose and fasting blood insulin were detected by enzyme-linked immunosorbent assay (ELISA). Insulin resistance index (HOMA-IR) was calculated, and the influencing factors of occurrence, pathological type, size and number of polyps were analyzed. Results: Among 262 cases, 116 cases were polyp free, 113 cases were adenomatous polyp and 33 cases were inflammatory polyp. HOMA-IR, VCAM-1 and FGF19 in polyp group were 2.904±1.754, (334.415±139.573) ng/ml and (135.865±98.470) pg/ml, respectively, which were higher than 2.369±1.306, (302.480±99.946) ng/ml and(110.694±76.044) ng/ml in non-polyp group, respectively (P<0.05). Multivariate Logistic regression analysis showed that the gender (OR=4.269, 95%CI: 1.963-9.405) and FGF19 (77.0-131.4 pg/ml: OR=2.385, 95%CI: 1.155-4.926) were independent factors of colorectal polyps. The gender (OR=3.799, 95%CI: 1.650-8.748) and FGF19 (77.0-131.4 pg/ml: OR=2.290, 95%CI: 1.072-4.891) were independent factors of colorectal adenomatous polyps. The gender(OR=6.725, 95%CI: 1.853-24.410) and fasting plasma glucose (≥6.5 mmol/L: OR=0.047, 95%CI: 0.009-0.245) were independent factors of colorectal inflammatory polyps. The gender (OR=3.539, 95% CI: 1.293-9.689) was an independent factor for the occurrence of single polyp. The gender (OR=5.063, 95% CI: 2.048-12.515), FGF19 (77.0-131.4 pg/ml: OR=2.502, 95%CI: 1.102-5.681), fasting plasma glucose (≥6.5 mmol/L: OR=0.282, 95%CI: 0.095-0.839) were independent factors of multiple polyps. The gender (OR=3.416, 95% CI: 1.134-10.289) and fasting insulin (≥9.4 µU/ml: OR=9.480, 95% CI: 1.485-60.521) were independent risk factors for colorectal polyps<0.5 cm. The gender (OR=3.151, 95%CI: 1.244-7.984) and fasting plasma glucose (≥6.5 mmol/L: OR=0.310, 95%CI: 0.102-0.941) were independent risk factors for colorectal polyps with the size of 0.5-0.9 cm. The gender (OR=22.649, 95%CI: 4.154-123.485), age (55 to 64 years old: OR=4.473, 95%CI: 1.070-18.704; ≥65 years old: OR=5.815, 95%CI: 1.300-26.009), BMI (≥28 kg/m(2): OR=5.310, 95%CI: 1.224-23.032) and FGF19 (77.0-131.4 pg/ml: OR=7.474, 95%CI: 1.903-29.351) were independent factors for colorectal polyps with size ≥ 1.0 cm. Gender stratification analysis showed that FGF19 was an independent factor for the occurrence of male polyps (77.0-131.4 pg/ml: OR=6.109, 95%CI: 1.688-22.104) and adenomas (77.0-131.4 pg/ml: OR=6.401, 95%CI: 1.717-23.864). The age (55 to 64 years old: OR=3.783, 95%CI: 1.052-13.611) and VCAM-1 (≥352.8 ng/ml: OR=4.341, 95%CI: 1.142-16.493) were independent risk factors of female polyps. The age (55 to 64 years old: OR=5.743, 95%CI: 1.205-27.362, ≥65 years old: OR=6.885, 95%CI: 1.143-41.467), VCAM-1 (≥352.8 ng/ml: OR=6.313, 95%CI: 1.415-28.159) and IGF-1 (≥7.6 ng/ml: OR=5.621, 95%CI: 1.069-29.543) were independent factors of female adenoma. Conclusions: The occurrences of colorectal polyps and adenomatous polyps are related to insulin resistance and glucose and lipid metabolism. Serum FGF19 is an independent influencing factor for the occurrence of colorectal polyps and adenomatous polyps, and is a potential serological diagnostic marker and therapeutic target for colorectal polyps and adenomatous polyps.

[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.

[Characteristics of esophageal motility and clinical presentation in gastroesophageal reflux disease patients of different age groups].

Objective: To explore the characteristics of esophageal motility and clinical presentation in gastroesophageal reflux disease (GERD) patients of different age groups. Methods: This was a case-control study. Confirmed GERD patients in the Department of Gastroenterology of Peking Union Medical College Hospital from January 2015 to September 2018 were enrolled and divided into two groups: elderly group (≥60 years old) and young and middle-aged group (<60 years old). Characteristics of gender, disease course, clinical symptoms, esophageal motility, gastroscopic manifestations and esophageal hiatus function of patients in the two groups were analyzed. Results: A total of 250 patients met the inclusion criteria, with 61 patients in elderly group and 189 in young and middle-aged group. There were no significant differences in gender ((male/female: 24/37 vs 78/111, P>0.05) and disease course((4.9±4.2) years vs(4.5±3.8)years, P>0.05) between the two groups. However, there were significant differences in typical symptoms (acid regurgitation and heartburn) and atypical symptoms (chest pain, cough, foreign body sensation in pharynx, etc.) (typical/atypical symptoms: 35/26 vs 146/43, P<0.01) between the two groups. Compared with young and middle-aged group, upper esophageal sphincter (UES) resting pressure was lower ((65±28) mmHg (1 mmHg=0.133 kPa)vs (74±28) mmHg, P<0.05), but the percentage of ineffective esophageal motility (IEM) (78.7%(48/61) vs 65.1%(123/189),P<0.05) and DeMeester score (16.3(6.0,36.3) vs 6.4(2.5,18.0), P<0.05) were higher in elderly group. There were no significant differences in lower esophageal sphincter (LES) resting pressure and distal contractile integral (DCI) between the two groups. Higher proportion of grade C and D reflux esophagitis,and grade C and D reflux esophagitis complicated with esophageal hiatus dysfunction was observed in elderly group compared with young and middle-aged group (2.04%(8/49) vs 0.65%(1/155); 14.29%(7/49) vs 0(0/155); both P<0.01). Pearson correlation analysis showed that there was a negative correlation between UES resting pressure and age(r=-0.145, P<0.05), while there was a positive correlation between the LES length and age (r=0.129, P<0.05). Conclusion: Compared with young and middle-aged GERD patients, the atypical symptoms, lower LES resting pressure, increased incidence of ineffective esophageal motility and acid exposure were more prominent in the elderly. Considering that anti-reflux function was weakened, long-term acid suppressants may be needed in elderly patients.

[Health-related quality of life and its associated variables in Chinese patients with Philadelphia-negative myeloproliferative neoplasms].

Objectives: To explore health-related quality of life (HRQoL) and identify its associated variables in Chinese patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) . Methods: In this cross-sectional study, anonymous questionnaires were distributed to adult patients with MPNs to assess symptom burden measured by MPN-10 and HRQoL measured by Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) . Results: The data from 1405 respondents with MPNs, including 645 (45.9%) with essential thrombocythemia (ET) , 297 (21.1%) with polycythemia vera (PV) , and 463 (33.0%) with myelofibrosis (MF) , were analyzed. 646 (46.0%) respondents were male. The median age was 56 (range, 18-99) years. The mean MPN-10 scores were 13.0±12.7, 15.0±14.7, and 21.0±16.6 (P<0.001) , and the physical component summary (PCS) and mental component summary (MCS) scores were 48.0±8.5, 47.0±9.0, and 42.0±10.0 (P<0.001) and 51.0±11.0, 50.0±10.8, and 49.0±11.1 (P=0.002) for respondents with ET, PV, and MF, respectively. Respondents with MF reported the lowest score of physical functioning, role functioning, emotional functioning, cognitive functioning, social function, and global health status (all P<0.01) and the highest score of fatigue, pain, dyspnea, appetite loss, diarrhea, and financial problems (all P<0.05) in EORTC QLQ-C30. Multivariate analyses revealed that higher MPN-10 scores were significantly associated with lower PCS (-0.220 to -0.277, P<0.001) and MCS (-0.244 to -0.329, P<0.001) scores; increasing age (-1.923 to -4.869; all P<0.05) , lower PCS score. Additionally, comorbidity (ies) , symptom at diagnosis, splenomegaly, anemia, unknown driver gene, and higher annual out-of-pocket cost were significantly associated with lower PCS and/or MCS scores. However, age ≥ 60 years, urban household registration, concomitant medication, and receiving ruxolitinib therapy in respondents with MF were associated with higher MCS scores. Weak correlations were found between MPN-10 score (except the subscale of appetite loss and constipation) and EORTC QLQ-C30 score in majority of subscales in respondents with ET (|r| = 0.193-0.457, all P<0.001) , PV (|r| = 0.192-0.529, all P<0.01) , and MF (|r| = 0.180-0.488, all P<0.001) , respectively. Conclusions: HRQoL in patients with MPN was significantly reduced, especially in patients with MF. Sociodemographic and clinical variables were significantly associated with the HRQoL in patients with MPNs.

[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.

[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

[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.

[Comparison of the efficacy and safety of Chinese generic imatinib and branded imatinib in patients with chronic myeloid leukemia in consideration of demographic characteristics].

Objectives: To compare the efficacy and safety of Chinese generic imatinib with branded imatinib as frontline therapy in adults with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) (Frontline group) , and to explore the efficacy and safety of Chinese generic imatinib in CML-CP patients switching from branded imatinib (Switching group) . Methods: Frontline group: Data of adults with newly diagnosed CML-CP receiving Chinese generic imatinib (Xinwei(®)) or branded imatinib (Glivec(®)) between October 2013 and August 2018 were retrospectively collected and analyzed. Switching group: Data of adults diagnosed with CML-CP who received branded imatinib and then switched to Chinese generic imatinib after achieving at least complete cytogenetic response (CCyR) were retrospectively collected and analyzed. Results: Frontline group: In total, 409 adult patients receiving Chinese generic imatinib (n=201) or Glivec (n=208) were included in this study. Median age was 42 years (range, 18-83 years) . Comparison of baseline showed significant difference on demographic characteristics among two cohorts: lower education level (P<0.001) , and divorced or widowed status (P=0.004) and rural household registration (P<0.001) were more common in the generic imatinib cohort than those in the Glivec cohort. There was no significant difference on age, gender, Sokal risk score, WBC and HGB between the 2 cohorts. With a median follow-up of 25 months (range, 3-62 months) , there was no significant difference on the 3-year cumulative incidence of achieving CCyR (97.5% vs 94.5%, P=0.592) , major molecular response (MMR) (84.3% vs 93.1%, P=0.208) , molecular response(4.0) (MR(4.0)) (42.7% vs 41.7%, P=0.277) , molecular response(4.5) (MR(4.5)) (25.4% vs 33.0%, P=0.306) as well as the 3-year probabilities of failure free survival (FFS) (76.7% vs 81.0%, P=0.448) , progression free survival (PFS) (91.8% vs 96.3%, P=0.325) and overall survival (OS) (95.8% vs 98.5%, P=0.167) between the generic and branded imatinib cohorts. Multivariate analysis showed the type of imatinib was not associated with treatment responses and outcomes. The incidences of adverse effects were comparable in the 2 cohorts. Switching group: In total, 39 patients switching from branded imatinib to Chinese generic imatinib after achieving at least CCyR were included in this study. Median age was 42 years (range, 23-80 years) . With a median follow-up of 39 months (range, 6-63 months) , molecular responses were maintained in 23 (58.9%) patients and improved in 12 (39.8%) patients. Adverse effects were tolerable. Conclusion: Demographic characteristics might influence the choice of the type of TKI used in CML-CP patients. There was a comparable efficacy and safety between the Chinese generic imatinib and the branded imatinib in adults with newly diagnosed CML-CP under standard management and closely monitoring. Patients could safely switch from the branded imatinib to the Chinese generic imatinib.

[Observation on the efficacy of consolidation chemotherapy combined with allogeneic natural killer cell infusion in the treatment of low and moderate risk acute myeloid leukemia].

Objective: To evaluate the efficacy of consolidation chemotherapy combined with allogeneic natural killer (NK) cell infusion in the treatment of low or intermediate-risk (LIR) acute myeloid leukemia (AML) . Methods: A cohort of 23 LIR AML patients at hematologic complete remission (CR) received NK cell transfusion combined with consolidation chemotherapy after 3 consolidation courses from January 2014 to June 2019 were reviewed. Control group cases were concurrent patients from Department of Hematology, and their gender, age, diagnosis, risk stratification of prognosis, CR and the number of courses of consolidate chemotherapy before NK cell transfusion were matched with LIR AML patients. Results: A total of 45 times of NK cells were injected into 23 LIR AML patients during 4 to 7 courses of chemotherapy. The median NK cell infusion quantity was 7.5 (6.6-8.6) ×10(9)/L, and the median survival rate of NK cells was 95.4% (93.9%-96.9%) . Among them, the median CD3(-)CD56(+) cell number was 5.0 (1.4-6.4) ×10(9)/L, accounting for 76.8% (30.8%-82.9%) ; The number of CD3(+) CD56(+) cells was 0.55 (0.24-1.74) ×10(9)/L, accounting for 8.8% (4.9%-20.9%) . Before NK cell infusion, the number of patients with positive MRD in the treatment and control groups were 9/23 (39.1%) and 19/46 (41.3%) (χ(2)=0.030, P=0.862) respectively. After NK infusion, There was no significant difference in terms of MRD that went from negative to positive between the treatment and the control groups (14.3% vs 22.2%, χ(2)=0.037, P=0.847) . In the treatment group, 66.7% (6/9) of the MRD were converted from positive to negative, which was significantly higher than that in the control group (10.5%, 2/19) (χ(2)=6.811, P=0.009) . Morphological recurrence occurred in 1 case of MRD negative in the treatment group and 2 cases of MRD positive in the control group. By the end of follow-up, the median follow-up was 35 (10-59) months, the number of patients with morphological recurrence in the treatment group was 30.4% (7/23) , which was significantly lower than that in the control group (50.2%, 24/46) (χ(2)=2.929, P=0.087) , although there was no statistically significant difference between the two groups. There was no significant difference on MRD-negative between the treatment and the control groups (43.5% vs 43.5%, χ(2)=1.045, P=0.307) . The 3-year leukemia-free survival was better in the treatment group [ (65.1±11.1) %] than that in the control group [ (50.0±7.4) %] (P=0.047) . The 3-year overall survival in the treatment and control groups were (78.1±10.2) % and (65.8±8.0) % (P=0.212) , respectively. Conclusion: The consolidation of chemotherapy combined with allogeneic NK cell infusion contributed to the further remission of patients with LMR AML and the reduction of long-term recurrence.

[Severe hematologic toxicity and its impact on treatment response in newly diagnosed patients with chronic myeloid leukemia receiving tyrosine kinase-inhibitor therapy].

Objectives: To explore the incidence and factors of severe leukopenia and/or thrombocytopenia in newly diagnosed patients with chronic myeloid leukemia (CML) to probe their impacts on cytogenetic and molecular responses, progression free survival (PFS) and overall survival (OS) . Methods: Data of newly diagnosed patients with CML in the chronic phase (CP) and/or accelerated phase (AP) were retrospectively collected and analyzed. Results: 855 CML patients [including 744 (87%) in the CP and 111 (13.0%) in the AP] were included in this study. 523 (61.2%) patients were male with a median age of 39 years (range, 14-87 years) . 749 (87.6%) patients received imatinib, 93 (10.9%) nilotinib, and 13 (1.5%) dasatinib, respectively as front-line therapy. At a median treatment of 1 month (range, 0.1-7.0 months) , 137 (16.0%) developed ≥grade 3 leukopenia and/or thrombocytopenia and recovered 0.6 month (range, 0.3-6.5 months) . Multivariate analysis showed that female gender (OR=1.5, 95%CI 1.0-2.2, P=0.033) , WBC ≥100×109/L (OR=1.9, 95%CI 1.3-2.8, P=0.001) , CP in Sokal high-risk (OR=2.2, 95%CI 1.2-3.9, P=0.005) , AP with ≥15% blast cells in blood or bone marrow (OR=5.1, 95%CI 1.9-13.3, P=0.001) were factors associated with higher incidence of ≥grade 3 leukopenia and/or thrombocytopenia. Severe leukopenia and/or thrombocytopenia with time of drug discontinuance >2 weeks was associated with lower probabilities of achieving complete cytogenetic (OR=0.4, 95%CI 0.3-0.6, P<0.001) , severe leukopenia and/or thrombocytopenia, no matter the time of drug discontinuance >2 weeks or ≤2 weeks, were associated with lower probabilities of achieving major molecular responses (OR=0.3, 95%CI 0.2-0.5, P<0.001; OR=0.7, 95%CI 0.5-1.0, P=0.036) and MR4.5 (OR=0.2, 95%CI 0.1-0.5, P=0.002; OR=0.7, 95%CI 0.4-1.1, P=0.110) ; however, those had no impacts on PFS and OS. Conclusions: Severe leukopenia and/or thrombocytopenia were common adverse events during TKI therapy. Female patients, WBC ≥100×109/L at diagnosed, CP in Sokal high-risk, CML-AP with ≥15% blast cells in blood or bone marrow were at high risk for higher incidence of severe leukopenia and/or thrombocytopenia. Those severe adverse events had impacts on lower cytogenetic and molecular response.