Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective:To investigate the current status of treatment choice and responses in patients with chronic myeloid leukemia (CML) in China.Methods:From the end of April to mid-May in 2020, a cross-sectional survey, by filling out a survey questionnaire, was conducted to explore the first-line choice of tyrosine kinase inhibitors (TKI) , current medications, drug switch and major molecular responses (MMR) as well as the variables associated with them in patients in China.Results:Data of 2933 respondents with CML from 31 provinces, municipalities, and autonomous regions across the country were included in this study. 1683 respondents (57.4%) were males. Median age was 38 (16-87) years old. 2481 respondents (84.6%) received imatinib as first-line TKI; 1803 (61.5%) , the original new drug (branded drug) . When completing the questionnaire, 1765 respondents (60.2%) were receiving imatinib; 1791 (61.1%) , branded drug. 1185 respondents (40.4%) had experienced TKI switch. With a median follow-up of 45 (3-227) months, 1417 of 1944 (72.9%) respondents with newly diagnosed CML in the chronic phase achieved MMR. Multivariate analysis showed that the respondents with urban household registration ( OR=0.6, 95% CI 0.5-0.8, P<0.001) , ≥ bachelor degree ( OR=0.5, 95% CI 0.4-0.7, P<0.001) , and in the advanced phase at diagnosis ( OR=0.5, 95% CI 0.3-0.8, P=0.001) less preferred Chinese generic TKI, while the respondents from the central region in China more preferred Chinese generic TKI more than those from the eastern region ( OR=1.7, 95% CI 1.4-2.0, P<0.001) . Moreover, the respondents in the advanced phase at diagnosis more preferred second-generation TKI ( OR=5.4, 95% CI 3.6-8.2, P<0.001) ; those ≥60 years old, less preferred second-generation TKI ( OR=0.4, 95% CI 0.2-0.7, P=0.002) . Being in the advanced phase at diagnosis ( OR=2.2, 95% CI 1.6-3.2, P<0.001) , first-line choice of imatinib ( OR=2.0, 95% CI 1.6-2.6, P<0.001) or Chinese generic drugs ( OR=1.3, 95% CI 1.1-1.6, P=0.002) , longer interval from diagnose of CML to starting TKI treatment ( OR=1.2, 95% CI 1.1-1.2, P<0.001) and longer duration of TKI therapy ( OR=1.1, 95% CI 1.0-1.1, P<0.001) were significantly associated with TKI switch; urban household registration ( OR=0.7, 95% CI 0.6-0.8, P<0.001) , ≥MMR ( OR=0.6, 95% CI 0.5-0.8, P<0.001) and unknown response ( OR=0.7, 95% CI 0.6-0.9, P=0.003) , no TKI switch. Female sex ( OR=1.4, 95% CI 1.1-1.7, P=0.003) , urban household registration ( OR=1.6, 95% CI 1.3-2.0, P<0.001) , front-line imatinib therapy ( OR=1.4, 95% CI 1.1-1.9, P=0.016) and longer duration of TKI treatment ( OR=1.2, 95% CI 1.2-1.3, P<0.001) were significantly associated with achieving a MMR or better response; age ≥ 60 years old ( OR=0.7, 95% CI 0.4-1.0, P=0.047) and TKI switch ( OR=0.6, 95% CI 0.5-0.7, P<0.001) , achieving no MMR. Conclusions:By 2020, the majority of Chinese CML patients received imatinib as the fist-line TKI therapy and continue to take it. More than half of TKIs were branded drugs. Socio-demographic characteristics and clinical variables affect their TKI choice, drug switch, and treatment response.

Objective:To evaluate the effect of imatinib on growth impairment in children with chronic myeloid leukemia (CML-CP) in the chronic phase.Methods:From July 2018 to July 2019, questionnaires were distributed to CML children aged <18 years at the time of diagnosis who were receiving imatinib for at least 3 months or to their parents in China. The height-for-age standard deviation score (HtSDS) and the difference of standard deviation integral (△HtSDS) were used to explore the change in height with imatinib therapy.Results:The data of 238 respondents were included; 138 (58.0% ) respondents were men. The median age at the first diagnosis of CML was 11.0 years (range, 1.4-17.9 years) , and 93 (39.0% ) respondents were at the prepuberty stage. At the time of completing the questionnaires, the median age was 15.0 years (range, 2.0-34.0 years) . The median duration of imatinib therapy was 28 months (range, 3-213 months) . Among all the respondents, the mean HtSDS when completing the questionnaires (-0.063±1.361) was significantly lower than that at the time of starting imatinib treatment (0.391±1.244) ( P<0.001) . Total 71.0% respondents showed growth impairment that was more common in those starting imatinib therapy at prepubertal age than in those starting at pubertal age. Multivariate analysis showed that younger at the start of imatinib therapy ( P<0.001) and longer duration of imatinib therapy ( P<0.001) were significantly associated with severe growth impairment on imatinib therapy. Conclusions:Imatinib induced growth impairment in children with CML-CP. Younger the age of initiation and longer the duration of imatinib therapy, more obvious the effect of imatinib on growth impairment.

Objective: To evaluate the clinical characteristics of T-cell acute leukemia/lymphoma (T-ALL) and explore the prognosis significance of early T-cell precursor leukemia/lymphoma. Methods: A cohort of 126 patients diagnosed with T-ALL from 2008 to 2014 in West China Hospital, Sichuan University were enrolled in this study. They were further categorized by immunophenotype according to the expression of T-cell lineage markers CD1a, CD8, CD5 and one or more stem cell or myeloid markers. The laboratory indicators and prognosis factors were also statistically analyzed. Results: Of all patients, the ratio of male to female was 2.5∶1, with the median age of 25 years old (range 14 to 77) . The percentage of ETP-ALL was up to 47.6%. T-ALL patients showed higher ratio in first clinical remission rate (CR₁) than T-LBL ones (64.4% vs 30.8%, P=0.032) . Group with WBC count higher than 50×10⁹/L at presentation showed higher ration of achieving CR₁ than those lower than 50×10⁹/L (78.4% vs 50.9%, P=0.010) . In comparison with the non-ETP-ALL, ETP-ALL patients had older age of onset (P<0.001) , lower WBC count (P<0.001) , lower risk of CNS involvement (10.0% vs 30.2%, P=0.009) and slightly inferior overall survival (P=0.073) . T-cell lineage markers CD1a^-, CD8^- and CD4^- positive patients had higher CR₁ than their corresponding negative ones (P=0.002, P=0.000, P=0.001) , while CD33^- and CD56^- positive patients had lower ratio of achieving CR₁ than their negative ones, respectively (P=0.035, P=0.035) . Conclusion Flow cytometry and associated markers for immunophenotyping was of significance in the diagnosis and prognosis monitoring of T-ALL/LBL. The percentage of ETP-ALL/LBL subtype was high in Chinese adolescent and adult T-ALL patients. ETP-ALL/LBL was a high risk subtype, which needs more precise standard for diagnosis and advanced therapies for better outcome.

Objective To detect the expression of Hedgehog signaling pathway receptor Smoothened (Smo) protein in chronic myeloid leukemia (CML) CD34-positive (CD34+) cells, and to explore the role of Hedgehog signaling pathway in CML stem/progenitor cells. Methods Seventeen chronic phase (CP) and 6 advanced phase (AP) CML patients who were diagnosed in West China Hospital of Sichuan University from September 2010 to March 2011 and 10 People (healthy people and patients without hematologic malignances) as control were included in this study. The expression levels of Smo protein were detected by the protocol of indirect immunofluorescence labeling for cytometry and analyzed statistically. Results The mean of relative fluorescence intensity of Smo protein was 282.5±102.4, 188.8±55.4 and 354.0±297.9 in the CML-CP, CML-AD and control groups, respectively. The difference between CML-CP and CML-AD groups was statistically significant (P= 0.032). However, there were no significant differences between the CML-CP, CML-AD groups and control group (both P>0.05). The percentage of CD34+Smo+cells was (58.9±24.2)％, (42.6±17.6)％and (55.9±29.7) ％ in the CML-CP, CML-AD and control groups, respectively. There were still no significant differences between the CML-CP, CML-AD groups and control group (F= 0.950, P= 0.398). The mean of relative fluorescence intensity of Smo protein in the CML-CP patients with tyrosine kinase inhibitor (TKI) (9 cases) administered and without TKI (8 cases) were 282.3 ±122.6 and 282.6 ±82.4, respectively. There were no significant differences between the two groups(P=0.157). Conclusions Flow cytometry can qualitatively and quantitatively detect the expression level of Smo protein in CML CD34+cells. Smo expression is associated with stage of CML;TKI could not inhibit the activation of the Hedgehog signaling pathway in CML CD34+cells.

Objective: To review the clinical characteristics of a pedigree with inherited hemorrhagic disease to explore its molecular pathogenesis. Methods: The clinical data of the pedigree with inherited hemorrhagic disease were collected. After extracting DNA, next generation sequencing was utilized to detect the potential gene mutation. The changes of RASGRP2 transcript of this proband and his parents were detected using RT-PCR to compare with normal control. Results: The phenotype of the proband in this pedigree with inherited platelet dysfunction and bleeding disorder was similar to variant Glanzmann’s thrombasthenia, the maximum aggregations of platelet in response to the physiological agonists including ADP, epinephrine and arachidonic acid were significantly lower, leading to severe spontaneous mucosal bleeding. Integrin αIIbβ3 gene mutation was not detected, but another gene mutation RASGRP2 IVS3-1 stood out. The mutation was homozygous in the proband and heterozygosis in both of his parents. Two transcript types were detected in the proband, without transcripts coding functional RASGRP2 protein, however, his parents had functional transcripts and abnormal transcripts, with the normal transcripts in the majority. Conclusions The RASGRP2 IVS3-1 gene mutation was responsible for the inherited hemorrhagic disease. The RASGRP2 IVS3-1 gene mutation led to abnormal alternative splicing, without formation of functional RASGRP2 protein. The RASGRP2 protein is at the nexus of calcium-dependent platelet activation and hemostasis after damage of blood vessels. Spontaneous mucosal bleeding was a result of the lack of the functional RASGRP2 protein. This was the first report of RASGRP2 gene mutation resulting in bleeding disorder in China, and also the first report of the mutation type of RASGRP2 IVS3-1.

To explore the potential effects of intrauterine device ( IUD) usage in reproductive ages on women′s postmenopausal reproductive health.Women in Shanghai Minhang district were enrolled and categorized into group Ⅰ( IUD) , groupⅡ( tubal ligation ) and control group ( external ejaculation ).Their data were collected and analyzed retrospectively.A total of 2 744 women during postmenopausal period were enrolled (group Ⅰ=2 253, group Ⅱ=202, control =289).Pearl index of each group was 1.08 (groupⅠ) , 0.00 ( group Ⅱ) and 15.22 ( control ) , respectively.Women with IUD usage in reproductive ages were less likely to develop reproductive benign diseases after menopause (χ2 =67.51, P=0.00, OR=0.44, 95%CI:0.32-0.59).Logistic regression indicated pregnancy history (OR=3.85), child-bearing history ( OR =0.52 ) , IUD usage ( OR =0.48 ) , tubal ligation ( OR =1.74 ) , longer duration using contraceptive methods ( OR =0.99 ) , contraception failure ( OR =1.74 ) and family planning surgical procedures(OR=1.73) were risk factors for reproductive benign diseases after menopause.IUD utility in reproductive ages may reduce the risks of benign diseases in reproductive system for postmenopausal women .

Objective To evaluate the clinical diagnostic contribution of 18 F-FDG PET/CT in giant cell arteritis with initial presentation as fever of unknown origin (FUO).Methods Eight cases with initial presentation as FUO diagnosed with the contribution of PET/CT were retrospectively studied in Peking Union Medical College Hospital.The radiologic manifestations of PET/CT were analyzed.Results Eight patients (4 men and 4 women) with average (63 ± 7) years (range from 55-75 years) were included in our study based on the criteria.Non-specific clinical symptoms were common in these patients,including fatigue,night sweat and weight loss.They all suffered from anemia of chronic disease.Not surprisingly,the inflammatory parameters were elevated significantly in all patients.The medical history,physical examination and routine lab and radiologic examinations couldn't reveal the causes of fever.PET/CT was performed in all of them,which demonstrated intense 18F-FDG uptake in the area of aorta and its major branches with maximal standard uptake value (SUVmax) 2.1-4.6 (3.6 ± 0.9).Immunosuppressive agents were effective to control the inflammation activity.The SUV decreased significantly after treatment in the follow-up PET/CT.Conclusions PET/CT has demonstrated high yield of diagnostic contribution in giant cell arteritis with initial presentation as fever of unknown origin.As to elderly FUO patients presenting with prominent inflammatory reaction,PET/CT may provide potential value to differentiate diagnosis from maligancies.

Objective To evaluate the relationship between plasma imatinib and its effect in the treatment of chronic myeloid leukemia(CML). Methods Fifty-one CML patients were included in this study,who began taking imatinib from July 2005 to February 2008, with 34 cases of male, and 17 cases of female.Nine patients took imatinib at dose of 300 mg/d, 37 patients took imatinib at dose of 400 mg/d, and 5 patients took imatinib at dose of 600 mg/d. High-performance liquid chromatography was used to test imatinib plasma levels. Results The imatinib plasma levels was imatinib dose-related, and the imatinib plasma trough levels significantly varied between individuals[(342-4688)ng/ml]. The imatinib plasma levels was significant lower in 300 mg/d dose group [(1037±514) ng/ml] than 400 mg/d dose group [(2123±1016) ng/ml] (t =2.34, P =0.032),and the effective rate was 66.7 % (6/9) in 300 mg/d dose group, which was lower than 400 mg/d dose group of 89.19 % (33/37) (χ2=7.14, P =0.008). In 300 mg/d and 400 mg/d dose groups, 39 patients achieved effective treatment, and their imatinib plasma levels was significant higher than that of 7 patients who did not achieved effective treatment (t =2.25, P =0.037). The ROC curve results suggested that clinical treatment may be poor when the imatinib plasma level was lower than 1050 ng/ml (sensitivity was 84.6 %, specificity was 71.1 %).Conclusion The imatinib plasma levels was dose-related, and significantly varied between individuals.Clinical treatment effect may be poor when the imatinib plasma level was lower than 1050 ng/ml.

Objective To report the clinical characteristics of prosthetic valve endocarditis (PVE).Methods All 25 cases of definite PVE (Duke criteria) diagnosed at our hospital between January 1992 to December 2008 were retrospectively analyzed. Among them, 7 cases were pathologically confirmed and the others were clinically confirmed with either 2 major criteria or 1 major and ≥3 minor criteria. Their clinical characteristics, underlying heart diseases, previous heart operations, presenting manifestations, causative microbes, echocardiographic findings and prognosis, were studied. Results (1) Although most cases underwent valve transplantations for underlying heart diseases of rheumatic heart diseases and congenital heart diseases, 10 patients were complicated with infectious endocarditis (IE) prior to the operations, 4 of them were PVE. (2) Eleven of them developed PVE within 2 months postoperatively. Fever (100%),major vessel embolism (48%), and anemia (36%) were the most frequently manifestations. Fourteen cases (56%) had positive culture results with 15 causative pathogens, including 5 coagulase-negative Staphylococcus (CNS, 3 were methicillin-resistant coagulase-negative Staphylococcus, MRSCoN), 4 fungi, 2Enterococcus faecalis, 2 Burkholderia cepacia, 1 Stenotrophomonasmal-tophilia, and 1 Streptococcus.(3)Prosthetic valve vegetations, periannular leakage, regurgitation, were the main echocardiographic findings.Transesophageal echocardiography (TEE) revealed 13 PVE who had no positive findings on previous transthoracic echocardiography (TTE). (4) Eighteen PVE (72%) developed peri-annular complications (12 leakage, 3 dehiscence, 2 abscesses, 1 fistula), major vessel embolism, congestive heart failure (16%) were frequently observed, 9 of the 17 patients died in hospital, in spite of intensive managements.Conclusions PVE has a high mortality and is a severe complication for patients who underwent heart surgery. Its causative pathogen spectrum is quite different from that of native valve endocarditis. TTE is not sensitive for some PVE cases.