Prediction of cardiovascular adverse events in newly diagnosed multiple myeloma: Development and validation of a risk score prognostic model.

Background: Multiple myeloma (MM) is the second most common hematological malignancy, and the treatments markedly elevate the survival rate of the patients in recent years. However, the prevalence of cardiovascular adverse events (CVAEs) in MM had been increasing recently. CVAEs in MM patients are an important problem that we should focus on. Clinical tools for prognostication and risk-stratification are needed. Patients and methods: This is a retrospective study that included patients who were newly diagnosed with multiple myeloma (NDMM) in Shanghai Changzheng Hospital and Affiliated Jinhua Hospital, Zhejiang University School of Medicine from June 2018 to July 2020. A total of 253 patients from two medical centers were divided into training cohort and validation cohort randomly. Univariable analysis of the baseline factors was performed using CVAEs endpoints. Multivariable analysis identified three factors for a prognostic model that was validated in internal validation cohorts. Results: Factors independently associated with CVAEs in NDMM were as follows: age>61 years old, high level of baseline office blood pressure, and left ventricular hypertrophy (LVH). Age contributed 2 points, and the other two factors contributed 1 point to a prognostic model. The model distinguished the patients into three groups: 3-4 points, high risk; 2 points, intermediate risk; 0-1 point, low risk. These groups had significant difference in CVAEs during follow-up days in both training cohort (p<0.0001) and validation cohort (p=0.0018). In addition, the model had good calibration. The C-indexes for the prediction of overall survival of CVAEs in the training and validation cohorts were 0.73 (95% CI, 0.67-0.79) and 0.66 (95% CI, 0.51-0.81), respectively. The areas under the receiver operating characteristic curve (AUROCs) of the 1-year CVAEs probability in the training and validation cohorts were 0.738 and 0.673, respectively. The AUROCs of the 2-year CVAE probability in the training and validation cohorts were 0.722 and 0.742, respectively. The decision-curve analysis indicated that the prediction model provided greater net benefit than the default strategies of providing assessment or not providing assessment for all patients. Conclusion: A prognostic risk prediction model for predicting CVAEs risk of NDMM patients was developed and internally validated. Patients at increased risk of CVAEs can be identified at treatment initiation and be more focused on cardiovascular protection in the treatment plan.

Related donor platelet transfusion improves platelet transfusion refractoriness in hematological patients.

Objective: Transfusion of HLA-matched platelets can reduce the effect of alloimmune responses on platelet transfusion efficacy; however, finding HLA-matched platelets in the population is nearly impossible. Almost all HLA-matched platelets from related are half-matched, but the hemostatic efficacy of related donor platelets is unclear. Our goal was to compare the hemostatic effect of related donated platelets and unrelated donors platelets. Methods: In this retrospective cohort study, we included acute leukemia and myelodysplastic syndrome patients with thrombocytopenia after chemotherapy. These patients were all transfused with platelets. This study excluded patients younger than 16 years and older than 65 years, or patients with abnormal coagulation parameters during platelet transfusion. We compared the hemostatic effect of related donated platelets and unrelated donors platelet. The primary outcome was transfusion efficacy after platelet transfusion, and the number of platelet counts and corrected count increments at 24 h after platelet transfusion. Result: We analyzed 31 patients who received platelet transfusions from related donors (Treatment group) and 35 patients who received platelet transfusions from unrelated donors (Comparator group). Except for the relatively small proportion of patients with myelodysplastic syndrome in the treatment group, baseline clinical and laboratory characteristics were similar between the two groups. Hemostasis and prevention of bleeding in the treatment group showed significant superiority; the number of platelets increased 24 h after platelet transfusion in the treatment group was significantly higher than that in the comparator group. After 24 h, the corrected count increments treatment group was also higher than the comparator group; in the treatment group, the transfusion effect was better when the three sites of HLA-A, B, and C were identical, and the different blood types of platelet donors and recipients did not affect the transfusion effect. Conclusion: Related donated platelets have better hemostasis and prevention effects, and no increase in adverse blood transfusion reactions. It may be a better transfusion strategy for platelet refractoriness patients in emergency situations.

[Chloroquine Enhances BIIB021-induced Apoptosis in Chronic Myeloid Leukemia Cells Bearing T315I Mutation].

OBJECTIVE: To explore the combined pro-apoptosis effect of HSP90 inhibitor BIIB021 and chloroquine (CQ) in chronic myeloid leukemia (CML) cells bearing T315I mutation and its mechanism. METHODS: The p210-T315I cells were divided into 4 groups by different treatment: control, BIIB021, CQ, and BIIB021 + CQ. After treated with BIIB021 or/and CQ for 24 hours, Annexin V/PI binding assay was used to detect apoptosis rates of CML cells. DAPI staining was used to observe nuclear fragmentation, and Western blot was used to detect the expression of caspase 3, PARP (apoptosis related proteins) and p62, LC3-I/II (autophagy related proteins). P210-T315I cells were inoculated subcutaneously into mice and CML mouse models were established. The mice in treatment groups were injected with BIIB021 and/or CQ while mice in control group were treated with PBS and normal saline. The tumor volume of mice was measured every 4 days, and protein level of cleaved-caspase 3 and LC3-II in tumor tissue were detected by immunohistochemistry. RESULTS: The results showed that BIIB021 induced apoptosis of CML cells in a dose-dependent manner ( r=0.91). CQ could enhance the apoptosis-inducing effect of BIIB021. Flow cytometry analysis results showed that the apoptosis rate of p210-T315I cells in combination group was higher than that in BIIB021 or CQ only group (P<0.05). DAPI staining showed nuclear fragmentation in combination group could be observed more obviously. Western blot analysis showed that BIIB021 could induce LC3-I to convert to LC3-II and decrease p62 protein levels (P<0.05). Moreover, the combination group had higher expression of LC3-II, p62 (P<0.05), activated PARP and activated caspase 3 than BIIB021 only group (P<0.05). Besides, experiment in vivo showed the mean tumor volume in co-treatment group was lower than that in single drug group (P<0.01). Immunohistochemistry of tumor tissue also showed the protein level of cleaved-caspase 3 and LC3-II in combined group was higher than that in BIIB021 only group. CONCLUSION: HSP90 inhibitor BIIB021 induced significant apoptosis of CML cells bearing T315I both in vivo and in vitro. CQ can enhance this effect probably by autophagy inhibition.

The novel HLA-DRB1*13:306 allele, identified by sequencing-based typing in a Chinese individual.

HLA-DRB1*13:306 differs from HLA-DRB1*13:02:01:01 in exon 2 in codon 84 by a single coding change.

Early Death and Survival of Patients With Acute Promyelocytic Leukemia in ATRA Plus Arsenic Era: A Population-Based Study.

Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or <5 patients per year, p = 0.12) or age (≥60 or <60 years, p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 109/L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future.

[Identification of the status of individual drug-administration behavior in heroin-withdrawal rats based on FrA EEG].

Objective: To identify the compulsive drug-seeking behavior of the individual in the heroin-addicted rat, a novel analysis method of telemetering electroencephalogram (EEG) in the frontal association cortex (FrA) induced by heroin-dependent position preference in rats. Methods: Thirty clean-grade Wistar rats after implantation of prefrontal cortex electrodes, were randomly divided into the surgical control group (n=10) and heroin-inducing group (n=20). The heroin-induced group was subcutaneously injected with heroin 0.5 mg/(kg.d), and then increased daily by 0.25 mg/kg for seven days. The control group was injected with the same amount of normal saline at the same time. Using the CPP video system combined with electroencephalogram (EEG) wireless telemetry technology, EEG signals in FrA areas of the addicted rats were recorded simultaneously in four behaviors: white-black shuttle, black-white shuttle, black-chamber stay and white-chamber stay. The areas with EMG and other noisy signals in the original EEG were identified, and wavelet decomposition and amplitude threshold denoising pre-processing were used. The sample entropy values of EEG data and wavelet coefficients corresponding to 4 rhythm frequencies under different behavioral states standard deviation were extracted, and support vector machine algorithm (SVM) was used to achieve real-time identification of different behavioral states of heroin-addicted rats. Results: SVM real-time classification recognition rate of 20 heroin abstinence rats, which are staying in black or white chamber of video box, shuttling between black-white chambers or between white - black chambers, was about 80%. Among them, the real-time recognition rate of black-white shuttle, which is closely related to drug-seeking behavior, reached 83.88%. Conclusion: In this paper, the real-time identification method of heroin-induced obsessive-compulsive drug-seeking behavior in rats can be used as an effective method to detect the initiation and occurrence of heroin-seeking drug-seeking behavior in rats. It can be used for the clinical observation of heroin-dependent patients and the prevention of drug-seeking behavior.

[Relationship between Chemotactic Factor CCL5 and Diabet-associated Diffuse Large B Cell Lymphoma].

OBJECTIVE: To explore whether the chemotactic factor CCL5 is the major factor of diffuse large B cell lymphoma (DLBCL) induced by diabetes or not. METHODS: The normal human B cells and DLBCL cells were cultured in vitro; the RT-PCR was used to detect their CCL5 mRNA expression, the human DLBCL cell line and mouse-derived DLBCL cell line A20 were cultured in vitro by using glucose at 5 and 30 mmol/L, respectively, then their CCL5 mRNA expression was detected by PT-PCR; the diabetic mouse model was constructed through peritoneal injection of streptozotocin at low dose in the BALB/c mice; the cell lines with stably high and low expression of CCL5 were established via lentiviral transfection and the cell lines with low and high expression of CCL5 were subcutaneously injected into diabetic mice and mice with normal blood sugar level. According to blood sugar level, the experimental mice were divided into 2 groups: diabetic group (A group) and normal blood sugar group as control (B group); then according to CCL5 expression level, the A group and B group were divided as well into high expression group (A1 group and B1 group) and low expression group (A2 group and B2 group), respectively, the tumor-formation rate, tumor-formation time, tumor size and texture were analyzed, respectively; the CCL5 expression was detected by using HE staining of tumor tissue and immunohistochemical method. RESULTS: The expression of CCL5 mRNA in human DLBCL cell line cultured in vitro was higher than that in normal B cells (P < 0.05); the expressions of CCL5 mRNA in human DLBCL cells cultured in high sugar concentration in vitro and mouse DLBCL cells were higher than those in cells cultured in low sugar concentration (P < 0.05). The tumor-formation rates in diabetic mice injected with high and low expression of CCL5 cell line A20 were 93.3% in A1 group and 60% in A2 group; the their tumor-formation time was 7.0 ± 0.85 days in A1 group and 9.5 ± 2.8 days in A2 group, while the tumor formation rates in mice with normal blood sugar level were 20% in B1 group and 20% in B2 group, and their tumor-formation time was 12 ± 1.3 days and 14 ± 2.5 days respectively; the CCL5 expression level in tumor tissue of diabetic mice was higher than that in tumor tissue of mice with normal blood sugar level. CONCLUSION: The high blood glucose level can casase increase of DLBCL risk and promote the tumor growth; the chemotactic factor CCL5 may play an important role in the growth and migration of DLBCL caused by diabetes mellitus.

[Clinical significance of serum lactate dehydrogenase, ß2-microglobulin and vascular endothelial growth factor level detection in patients with non-Hodgkin's lymphoma].

The study was aimed to investigate the clinical significance of serum lactate dehydrogenase (LDH), ß2-microglobulin (ß2-MG) and vascular endothelial growth factor (VEGF) detection in non-Hodgkin's lymphoma (NHL) patients. 58 newly diagnosed NHL patients from January 2010 to December 2011 in our hospital were selected as the study group (NHL group) and 58 healthy individuals were selected at the same time as a control group. Serum LDH level was determined by a biochemical method, while ß2-MG and VEGF levels were determined by enzyme-linked immunosorbent assay. The results showed that as compared with control group, the LDH, ß2-MG and VEGF levels in NHL group were significantly higher (P < 0.05). In NHL group, the LDH and VEGF levels at different pathological types and clinical stages changed remarkably. Compared with low grade patients, the LDH and VEGF levels of intermediate grade and high grade patients were significantly higher (P < 0.05). As compared with patients at stage I, the LDH and VEGF levels of patients at stage II, III and IV increased significantly (P < 0.05). Out from 58 cases in NHL group, 30 cases (51.72%) showed LDH-positive, 39 cases (67.24%) showed ß2-MG positive and 29 cases (50.00%) showed VEGF-positive. It is concluded that some significant changes of serum LDH, ß2-MG and VEGF appears in NHL patients, detection of these 3 tumor marker levels may be help to clinically grading patients with NHL.