Effects of extramedullary disease on patients with newly diagnosed multiple myeloma / 中华血液学杂志

Objective: To summarize the characteristics of patients with newly diagnosed multiple myeloma (NDMM) admitted at Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine. We compared the clinical characteristics and prognoses among patients with non-extramedullary disease (EMD), bone-related extramedullary (EM-B) disease, and extraosseous extramedullary (EM-E) disease and further explored the effects of autologous hematopoietic stem cell transplantation (ASCT) for EMD. Methods: From January 2015 to January 2022, data of 114 patients (22%) with EMD out of 515 patients with NDMM were retrospectively analyzed; 91 (18%) and 23 (4%) patients comprised the EM-B and EM-E groups, respectively. The clinical characteristics of patients in all groups were compared with the Chi-square test. Progression-free survival (PFS) and overall survival (OS) of patients were analyzed by the Kaplan-Meier method. Independent prognostic factors were determined using multivariate Cox proportional hazard model. Results: There were no significant differences in age, gender, ISS stage, light chain, creatinine clearance, cytogenetic risk, 17p deletion, ASCT, and induction regimens among the three groups. Overall, 13% of EM-E patients had IgD-type M protein, which was significantly higher than that in EM-B patients (P=0.021). The median PFS of patients in the non-EMD, EM-B, and EM-E groups was 27.4, 23.1, and 14.0 months; the median OS was not reached, 76.8 months, and 25.6 months, respectively. The PFS (vs non-EMD, P=0.004; vs EM-B, P=0.036) and OS (vs non-EMD, P<0.001; vs EM-B, P=0.002) were significantly worse in patients with EM-E, while those were not significantly different between patients with EM-B and those with non-EMD. In the multivariate analysis, EM-E was an independent prognostic factor for OS in patients with NDMM (HR=8.779, P<0.001) and negatively impacted PFS (HR=1.874, P=0.050). In those who did not undergo ASCT, patients with EM-B had significantly worse OS than those with non-EMD (median 76.8 months vs. not reached, P=0.029). However, no significant difference was observed in the PFS and OS of patients with EM-B and those with non-EMD who underwent ASCT. Conclusions: Compared to patients with either non-EMD or EM-B, those with EM-E had the worst prognosis. EM-E was an independent risk factor for OS in patients with NDMM. ASCT can overcome the poor prognosis of EM-B.

Cytotoxicity and its mechanism of zinc oxide nanoparticles on human leukemic monocyte lymphoma cell line U937 / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate the cytotoxicity and its mechanism of ZnO nanoparticles on human leukemic monocyte lymphoma cell line U937.</p><p><b>METHODS</b>Four different size ZnO (10, 30, 60, 500 nm) were carefully characterized. The survival rate and viability were measured by trypan blue assay and MTT assay for each size ZnO particles at different concentrations (12, 120, 240, 600, 1200 µmol/L). The zinc probe, Fluozin-3, was used to detect the intracellular free zinc. Transmission electron microscopy was adopted to observe the cellular ultrastructure and the uptake of ZnO.</p><p><b>RESULTS</b>All four kinds of ZnO were rod shape, with a purity of > 99.9 wt%, and they were classified as zincite phase crystal and their surface areas were in accordance with the sizes. The viability (ZnO-n10: (97 ± 19)%, (91 ± 4)%, (24 ± 4)%, (15 ± 2)%; ZnO-n30: (111 ± 4)%, (81 ± 3)%, (24 ± 2)%, (27 ± 8)%; ZnO-n60: (105 ± 11)%, (73 ± 20)%, (43 ± 11)%, (28 ± 14)%; ZnO-µm: (88 ± 16)%, (62 ± 7)%, (22 ± 4)%, (13 ± 5)%) of cells exposed to ZnO decreased with the increasing of the concentration of ZnO from 12 to 600 µmol/L (r values were 0.965, 0.979, 0.998, 0.992, and the t values were 19.8, 25.3, 76.3, 40.9, respectively, P < 0.05). The liability (ZnO-n10: (98 ± 1)%, (67 ± 2)%, (59 ± 7)%, (13 ± 13)%, (5 ± 4)%; ZnO-n30: (98 ± 1)%, (97 ± 2)%, (50 ± 3)%, (20 ± 14)%, (7 ± 2)%; ZnO-n60: (97 ± 2)%, (88 ± 5)%, (48 ± 10)%, (12 ± 5)%, (4 ± 1)%; ZnO-µm: (96 ± 1)%, (76 ± 3)%, (58 ± 3)%, (19 ± 5)%, (20 ± 10)%) of cells exposed to ZnO decreased with the increasing of the concentration of ZnO from 12 to 600 µmol/L (r valued at 0.982, 0.956, 0.972, 0.980, and the t valued at 19.3, 12.1, 15.6, 18.5, respectively, P < 0.05). The increase of the zinc concentration showed by the zinc fluorescence probe was 121 ± 11, which was similar to the fluorescence of cells treated with ZnAc(2) (132 ± 14, F = 0.6, P > 0.05) at the Zn-equivalent concentration. There was no statistic difference for the percents of high zinc content cells in total cells exposed to ZnO-n30 (87.6 ± 2.6)% and these exposed to ZnAc(2) (86.9 ± 3.2)% (F = 1.5, P > 0.05).</p><p><b>CONCLUSION</b>ZnO nanoparticles are highly cytotoxic to U937 cells and the solubilization of ZnO is the main toxicological mechanism.</p>

Comparisons of conventional and normalized calculation of quantitative real-time RT-PCR detecting PML-RAR alpha fusion gene in patients with acute promyelocytic leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To optimize the calculation of quantitative real time RT-PCR (Q-RT-PCR) of PML-RARalpha in patients with acute promyelocytic leukemia (APL) for molecular monitoring of minimal residual disease (MRD).</p><p><b>METHODS</b>By using both regular reverse transcription polymerase chain reaction (RT-PCR) and Q-RT-PCR, the expression levels of PML-RARalpha transcripts were measured before and after treatment. The conventional Q-RT-PCR calculation was directly compared the post-treatment transcript level with the respective pre-treatment one (DoseN) in the individual patient while the standardized calculation was based on the calculation of standardized pre-treatment DoseN of all patients.</p><p><b>RESULTS</b>In 181 samples from 31 patients, the results of log-reduction of PML-RARa after induction, at the end of consolidation and during maintenance by conventional method were (1.9 +/- 1.9), (4.8 +/- 1.3) and (5.7 +/- 0.4), respectively, while by standardized method were (2.0 +/- 1.9), (4.9 +/- 1.4) and (5.7 +/- 0.1), respectively. Of notice, the result was with significant less variation of the latter methods during maintenance therapy. Moreover, with defined criteria of molecular response (3.0-4.9 log-reduction as minor and > or = 5.0 log-reduction as major molecular response), the standardized method was validated in clinical settings.</p><p><b>CONCLUSION</b>The standardized method is superior to the conventional method for calculation of Q-RT-PCR results. The new method can reduce the individual variation in monitoring the MRD and is feasible even for patients with unavailable pre-treatment samples.</p>

FLT3 internal tandem duplication in patients with acute promyelocytic leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the mutation of FLT3 internal tandem duplication (FLT3-ITD) in bone marrow cells from patients with newly-diagnosed acute promyelocytic leukemia (APL).</p><p><b>METHODS</b>The mutation of FLT3-ITD in bone marrow mononuclear cells (MNCs) from 103 APL patients were screened by polymerase chain reaction (PCR) and the clinical features of ITD positive patients were analyzed.</p><p><b>RESULTS</b>FLT3-ITD mutations were identified in 19.4% (20/103) patients. It was associated with short/variant form of PML-RAR alpha isoforms (P < 0.0001). Among the 20 patients with FLT3-ITD mutation, 16 presented with short, 2 with variant and 2 with long form of PML-RAR alpha isoforms. Patients with FLT3-ITD mutation also presented significantly higher initial peripheral white blood cell count (WBC) (P < 0.01), especially in those with short/variant PML-RAR alpha isoforms (P = 0.015). For patients with long form PML-RAR alpha, there was no significant difference in initial WBC. Out of FLT3-ITD positive patients, 18/20 (90%) obtained complete remission and 16 evaluable patients (2 lost follow-up) remained in first remission in a median follow-up of 26 (11-47) months.</p><p><b>CONCLUSION</b>FLT3-ITDs are frequently identified in patients with newly diagnosed APL. FLT3-ITD mutation is associated with short/variant form of PML-RAR alpha fusion gene and higher initial WBC. No significant impact on treatment outcome was observed with a limited follow-up.</p>

Bio-effects of water soluble taurine multi-wall carbon nanotubes on lungs of mice / 中华预防医学杂志

<p><b>OBJECTIVE</b>To track the translocation of water soluble taurine multi-wall carbon nanotubes (14C-tau-MWCNTs) in lungs of the Kunming mice and evaluate the acute lung toxicity of intratracheally instilled tau-MWCNTs in Kunming mice.</p><p><b>METHODS</b>Healthy adult Kunming mice were randomly grouped by their body weight (5 mice in each group). The lungs of mice were intratracheally instilled with 0.125, 0.25, 0.5 and 1 mg/kg of water soluble tau-MWCNTs and phosphate-buffered saline (PBS) as negative control. After exposure of 1, 7, 14 and 28 days, the blood and lung tissue were collected. Blood were assessed by using biochemical biomarkers of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and angiotensin converting enzyme (ACE). Lung tissues were assessed by histopathology. The intratracheal instillation of 14C-tau-MWCNTs was conducted in the same way, after 1, 3, 7, 14, 21, 28 days, 14C-activity of the samples was counted in several organs, tissues, blood and feces etc.</p><p><b>RESULTS</b>14C-activities were detected only in lungs, and with the exposure time proceeding the radioactivity descending from (80 +/- 7.7)% of the 1st day to (22 +/- 6.9)% of the 28th day. Activity of all groups of ALP and LDH went to the highest level on the 7th day postexposure, and back to the control level on the 28th day post-exposure, but LDH of 1 mg/kg group[(14.18 +/- 1.70) micromol x s(-1) x L(-1)] was still higher than that of control [(10.95 +/- 3.51) micromol x s(-1) x L(-1)] after 28 days' exposure. There was no significant changes observed in the activity of ACE. Histopathology found that lungs of all groups presented significant increase in pulmonary inflammation, lung cell proliferation. Many tau-MWCNTs were clearly found in some alveolar macrophages and bronchial epithelial cells.</p><p><b>CONCLUSION</b>Intratracheal instillation of water soluble tau-MWCNTs could induce slight bio-effects on lungs of Kunming mice.</p>

Clinical observation of the short-term efficacy of the treatment with combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) in newly diagnosed acute promyelocytic leukemia (APL) / 中华血液学杂志

<p><b>OBJECTIVE</b>To study whether all-trans retinoic acid (ATRA) combined with arsenic trioxide (As(2)O(3)) in acute promyelocytic leukemia (APL) treatment could further improve the clinical and molecular remission rate.</p><p><b>METHOD</b>Thirty one newly-diagnosed APL patients of whom 15 were males, 16 females and median age 35.4 years entered into the study. They were treated with ATRA 25 mg x m(-2) x d(-1) combined with As(2)O(3) 0.16 mg x kg(-1) x d(-1) until complete remission (CR). The doses were adjusted according to white blood cell (WBC) counts, occurrence of RA syndrome and the status of liver function. CR rate, time of reaching clinical and molecular remission and side effects were observed.</p><p><b>RESULT</b>Two patients died 2 approximately 3 days after the treatment due to intracranial hemorrhage, and 29 (93.5%) achieved CR. The average time for achieving CR was 25.1 +/- 3.9 days. Hyperleukocytosis emerged in 66.5% and hepatic damages in 65.5% of the patients, they were ameliorated within one week after reduction of the As(2)O(3) dose or its suspension. The PML/RAR alpha fusion gene that was positive in all 29 patients before treatment turned negative only in 3 cases (10.3%) after obtaining CR (CR1) and in 10/13 cases (77%) after consolidation treatment. Up to now (1-8 months follow-up), all 29 patients remain in CR1.</p><p><b>CONCLUSION</b>ATRA combined with As(2)O(3) in de novo APL treatment can yield a high CR rate without intolerable side effects. Long term effect needs further observation.</p>