The efficacy and safety of Bruton tyrosine kinase inhibitors as monotherapy in the treatment of newly diagnosed patients with Waldenström macroglobulinemia / 中华血液学杂志

Objective: To investigate the efficacy and safety of Bruton tyrosine kinase inhibitors (BTKi) ibrutinib or zanubrutinib monotherapy in newly diagnosed patients with Waldenström macroglobulinemia (WM) . Methods: The efficacy and adverse effects of 58 patients with newly diagnosed WM receiving BTKi monotherapy in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were analyzed retrospectively from January 2018 to August 2022. Results: The response of 55 patients may be examined. Forty patients received ibrutinib monotherapy for a median of 15 months, with an overall response rate (ORR) of 85%, a main remission rate (MRR) of 70%, and a very good partial remission (VGPR) rate of 10%. Fifteen patients received zanubrutinib monotherapy for a median of 13 months, with an ORR of 93%, an MRR of 73%, and a VGPR rate of 0%. For various reasons, 10 patients were converted from ibrutinib to zanubrutinib. Ibrutinib treatment lasted an average of 7.5 months before conversion. The median duration of zanubrutinib therapy after conversion was 3.5 months. The ORRs before and after conversion were 90% and 100%, MRRs were 80% and 80%, and VGPR rates were 10% and 50%, respectively. After a median of 16 months, the 24-month progression-free survival (PFS) rate of patients who received both BTKi was 86%. PFS did not differ statistically across individuals with low, medium, and high-risk ISS scores (P=0.998). All of the patients survived. The most common side effects of BTKi were neutropenia and thrombocytopenia, which occurred in 12% and 10% of all patients, respectively. Ibrutinib accounts for 5% of atrial fibrillation, and zanubrutinib has a 7% risk of bleeding. Conclusions: In treating WM, ibrutinib or zanubrutinib provides good efficacy and tolerable adverse effects.

Clinicopathologic characteristics and prognostic analysis of testicular diffuse large B-cell lymphoma / 中华血液学杂志

Objective: To analyze the clinicopathologic characteristics and prognosis of testicular diffuse large B-cell lymphoma (DLBCL) . Methods: A retrospective analysis was performed on 68 patients with testicular DLBCL admitted to Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October 2001 to April 2020. The gene mutation profile was evaluated by targeted sequencing (55 lymphoma-related genes) , and prognostic factors were analyzed. Results: A total of 68 patients were included, of whom 45 (66.2% ) had primary testicular DLBCL and 23 (33.8% ) had secondary testicular DLBCL. The proportion of secondary testicular DLBCL patients with Ann Arbor stage Ⅲ-Ⅳ (P<0.001) , elevated LDH (P<0.001) , ECOG score ≥ 2 points (P=0.005) , and IPI score 3-5 points (P<0.001) is higher than that of primary testicular DLBCL patients. Sixty-two (91% ) patients received rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) -based first-line regimen, whereas 54 cases (79% ) underwent orchiectomy prior to chemotherapy. Patients with secondary testicular DLBCL had a lower estimated 5-year progression-free survival (PFS) rate (16.5% vs 68.1% , P<0.001) and 5-year overall survival (OS) rate (63.4% vs 74.9% , P=0.008) than those with primary testicular DLBCL, and their complete remission rate (57% vs 91% , P=0.003) was also lower than that of primary testicular DLBCL. The ECOG scores of ≥2 (PFS: P=0.018; OS: P<0.001) , Ann Arbor stages Ⅲ-Ⅳ (PFS: P<0.001; OS: P=0.018) , increased LDH levels (PFS: P=0.015; OS: P=0.006) , and multiple extra-nodal involvements (PFS: P<0.001; OS: P=0.013) were poor prognostic factors in testicular DLBCL. Targeted sequencing data in 20 patients with testicular DLBCL showed that the mutation frequencies of ≥20% were PIM1 (12 cases, 60% ) , MYD88 (11 cases, 55% ) , CD79B (9 cases, 45% ) , CREBBP (5 cases, 25% ) , KMT2D (5 cases, 25% ) , ATM (4 cases, 20% ) , and BTG2 (4 cases, 20% ) . The frequency of mutations in KMT2D in patients with secondary testicular DLBCL was higher than that in patients with primary testicular DLBCL (66.7% vs 7.1% , P=0.014) and was associated with a lower 5-year PFS rate in patients with testicular DLBCL (P=0.019) . Conclusion: Patients with secondary testicular DLBCL had worse PFS and OS than those with primary testicular DLBCL. The ECOG scores of ≥2, Ann Arbor stages Ⅲ-Ⅳ, increased LDH levels, and multiple extra-nodal involvements were poor prognostic factors in testicular DLBCL. PIM1, MYD88, CD79B, CREBBP, KMT2D, ATM, and BTG2 were commonly mutated genes in testicular DLBCL, and the prognosis of patients with KMT2D mutations was poor.

Clinical characteristics and prognosis of primary and secondary diffuse large B-cell lymphoma of the pancreas / 中华血液学杂志

Objective: To analyze the clinical characteristics and prognosis of primary and secondary pancreatic diffuse large B-cell lymphoma (DLBCL) . Methods: Clinical data of patients with pancreatic DLBCL admitted at Shanghai Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine from April 2003 to June 2020 were analyzed. Gene mutation profiles were evaluated by targeted sequencing (55 lymphoma-related genes). Univariate and multivariate Cox regression models were used to evaluate the prognostic factors of overall survival (OS) and progression-free survival (PFS) . Results: Overall, 80 patients were included; 12 patients had primary pancreatic DLBCL (PPDLBCL), and 68 patients had secondary pancreatic DLBCL (SPDLBCL). Compared with those with PPDLBCL, patients with SPDLBCL had a higher number of affected extranodal sites (P<0.001) and had higher IPI scores (P=0.013). There was no significant difference in the OS (P=0.120) and PFS (P=0.067) between the two groups. Multivariate analysis indicated that IPI intermediate-high/high risk (P=0.025) and double expressor (DE) (P=0.017) were independent adverse prognostic factors of OS in patients with pancreatic DLBCL. IPI intermediate-high/high risk (P=0.021) was an independent adverse prognostic factor of PFS in patients with pancreatic DLBCL. Targeted sequencing of 29 patients showed that the mutation frequency of PIM1, SGK1, BTG2, FAS, MYC, and MYD88 in patients with pancreatic DLBCL were all >20%. PIM1 (P=0.006 for OS, P=0.032 for PFS) and MYD88 (P=0.001 for OS, P=0.017 for PFS) mutations were associated with poor OS and PFS in patients with SPDLBCL. Conclusion: There was no significant difference in the OS and PFS between patients with PPDLBCL and those with SPDLBCL. IPI intermediate-high/high risk and DE were adverse prognostic factors of pancreatic DLBCL. PIM1, SGK1, BTG2, FAS, MYC, and MYD88 were common mutations in pancreatic DLBCL. PIM1 and MYD88 mutations indicated worse prognosis.

Exploring the detection of MYD88 mutation in patients with Waldenström macroglobulinemia by different methods and specimens / 中华血液学杂志

Objective: To improve the positivity rate and accuracy of MYD88 mutation detection in patients with Waldenström macroglobulinemia (WM) . Methods: MYD88 mutation status was retrospectively evaluated in 66 patients diagnosed with WM in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from June 2017 to June 2021. The positivity rate and accuracy of the different methods and specimens for MYD88 mutation detection were analyzed. Results: MYD88 mutations were detected in 51 of 66 patients with WM, with an overall positivity rate of 77%. The positivity rate of the next-generation sequencing (NGS) or allele-specific polymerase chain reaction (AS-PCR) was significantly higher than that of the first-generation Sanger sequencing (84% vs 71% vs 46%, P<0.05) . For the different specimens, the positivity rate for the lymph nodes or bone marrow was significantly higher than that of peripheral blood (79% vs 84% vs 52%, P<0.05) . The positivity rate of the MYD88 mutation in the lymph nodes, bone marrow, and peripheral blood determined by NGS was 86%, 90%, and 67%, respectively. The positivity rate in the lymph nodes, bone marrow, and peripheral blood detected by AS-PCR was 78%, 81%, and 53%, respectively. Thirty-nine patients with WM underwent ≥ 2 MYD88 mutation detections. The final MYD88 mutational status for each patient was used as the standard to determine the accuracy of the different methods and in different specimens. The accuracy of MYD88 mutation detection in the lymph nodes (n=18) and bone marrow (n=13) by NGS was significantly higher than that in the peripheral blood (n=4) (100% vs 100% vs 75%, P<0.05) . There was no statistically significant difference in the accuracy of MYD88 mutation detection by AS-PCR in the lymph nodes (n=15) , bone marrow (n=11) , or peripheral blood (n=16) (93% vs 91% vs 88%, P>0.05) . Conclusions: In the detection of the MYD88 mutation in patients diagnosed with WM, NGS or AS-PCR is more sensitive than Sanger sequencing. Lymph nodes and bone marrow specimens are better than peripheral blood specimens.

In vivo fate study of drug nanocarriers: the applications of environment-responsive fluorescent dyes / 药学学报

The in vivo fate is a crucial factor that governs the successful translation of nanoformulations. However, one of the current biggest challenges is with the real-time monitoring of the body of the nanoparticles themselves. Conventional radioactive or fluorescent probes give signals even after they are disassociated from the particle matrix, generating interference to bioimaging and leading to misjudgment of results. Environment-responsive fluorescent dyes are regarded as promising tools due to signal switching in response to the changes in the environment. Currently, there are three categories of dyes in bioimaging of nanoparticles based on Förster resonance energy transfer (FRET), aggregation-induced emission (AIE) and aggregation-caused quenching (ACQ). They have similar characteristics that strong fluorescence is emitted when they are embedded in the matrix of nanocarriers, whereas the fluorescence quenches upon release from the matrix due to dissociation of nanocarriers. The fluorescence switching reflects the existing status of the nanocarriers and therefore helps to interpret the in vivo behaviors. FRET and AIE probes have been widely used in elucidating the interactions between nanoparticles and cell models. However, they show intrinsic defects in studying in vivo fate of nanoparticles. ACQ-based dyes are sensitive to water, a universal factor in the biological environment. Therefore, with the help of bioimaging equipment, the in vivo trafficking process of nanoparticles can be unraveled. This review article tends to provide an overview on the rationale, pros and cons and applications of the three categories of environment-responsive fluorescent dyes in the investigation of the in vivo fate of nanocarriers.

Clinical Characteristics and Outcome of 66 Cases of Mantle Cell Lymphomas / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analyze the clinical features and prognostic factors of patients with mantle cell lymphoma(MCL).</p><p><b>METHODS</b>The clinical data of 66 MCL patients were collected from the Department of Hematology of Shanghai Ruijin Hospital, Shanghai Jiaotong University Medical School from January 2000 to December 2014. The clinical characteristics, treatment efficiency and survival rate were analyzed retrospectively.</p><p><b>RESULTS</b>The sex ratio of male to female in these 66 MCL patients was 3.71:1, the nosopoietic median age was 59 years old, and most cases were diagnosed as MCL in Ann Arbor stage III-IV(90.9%). "R-HperCVAD" regimen had the highest CR-rate reached to 55.6%, and CR rate of "R-CHOP" reached to 44.4%. The total prospective 5-year overall survival and progress-free survival rates were 35.5%±11.5% and 8.8%±5.6%, respectively. Leukocyte count abnormality(>10×10/L or <4×10/L), B symptom, LDH level, bone marrow involvement, Ki-67 and high risk group of MIPI scores, and therapy combined with or without rituximab were the independent prognostic factors.</p><p><b>CONCLUSION</b>The prognosis of MCL patients is poor, and the incidence is higher in men. The extranodal sites of bone marrow and gastrointestinal tract are involved more easily. The treatment combined with rituximab can increase survival rate for these patients.</p>

Prognostic Significance of Follicular Lymphoma International Prognostic Index 2 (FLIPI2) in Follicular Lymphoma Patients Treated with Rituximab Maintenance / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the prognostic significance of Follicular Lymphoma International Prognostic Index 2 (FLIPI2) in FL patients treated with rituximab maintenance.</p><p><b>METHODS</b>A tatol of 140 newly diagnosed FL patients who received Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy in our department were retrospectively analyzed from December 2002 to December 2014. Among 140 patients with FL 122 patients achieved response, from them 56 patients received R maintenance (RM) every 2 months for median 8 times (RM group) while the rest 66 patients did not receive further anti-lymphoma treatment (non-RM group).</p><p><b>RESULTS</b>There was no statistical difference in age, sex, pathologic grading, staging, FLIPI or FLIPI2 between RM and non-RM groups. The 2-year progression-free survival (PFS) of RM and non-RM groups were 89.7% and 77.6% (P=0.043) while the 2-year overall survival were 100% and 98.6% (P=0.131). FLIPI2 is a significant prognostic model either in the total cohort, RM or non-RM groups (P<0.001 all). In subgroup analysis, RM was able to decrease disease progression in low and intermediate-risk group of FLIPI2, while the 2-year PFS of RM and non-RM groups in high-risk group were similar (55.6% vs 46.9%)(P=0.920).</p><p><b>CONCLUSION</b>FLIPI2 presents robust prognostic significance either in RM or OBS patients, the patients in FLIPI2 low and intermediate-risk group may benefite from RM, but the role of RM in high-risk patients should be further to investigate.</p>

The retrospective study of serum aspergillus galactomannan (GM) antigen assay in invasive aspergillosis on hematological diseases / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the relationship between the optical density index of serum aspergillus galactomannan (GM) assay and invasive aspergillosis (IA).</p><p><b>METHODS</b>From Jan 2008 to Dec 2011, 825 hematological diseases patients with neutrophil count <0.5×10⁹/L⁹ by continuous blood count tests were admitted into our hospital. The optical density index of GM assay was ≥0.5 at least once. Of 825 patients, 247 cases were manifested as fever during hospitalization. The optical density index of GM antigen was detected by enzyme-linked immunosorbent assay, and the sensitivity and specificity of optical density ranged in 0.5-1.5.</p><p><b>RESULTS</b>In this study, the sensitivity and specificity of GM assay with continuous twice samples (73% and 93%, respectively) were higher than single sample (66% and 80%, respectively) when optical density index ≥1.0. 69 cases were diagnosed as proven IA with the incidence rate of 8.36%.</p><p><b>CONCLUSION</b>The cut-off level for serum GM antigen assay should be decided as optical density index in two continuous samples of ≥1.0.</p>

Prognostic analysis of non-cytogenetic factors in elderly adults with acute myeloid leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the prognostic factors in elderly patients with acute myeloid leukemia (AML).</p><p><b>METHODS</b>The clinical data of 211 AML patients with age 55 years or over and treated in Shanghai Jiaotong University Medical School affiliated Ruijin Hospital from 2007 to 2011 were collected and analyzed. Multivariate and univariate analysis of clinical data were performed using a Cox regression model and log-rank test, including age, subtype, performance status, white blood cell count, serum LDH and albumin level, and treatment strategy.</p><p><b>RESULTS</b>Acute promyelocytic leukemia (APL) patients had longer survival than other subtypes. To rule out the impact of APL on the prognostic analysis, we conducted multivariate and univariate analysis excluding APL patients. The significant parameters of the univariate analysis were age (P = 0.003), achieving remission (P < 0.01), performance status (P < 0.01), organ dysfunction (P < 0.01), increased WBC counts (P = 0.022), increased LDH level (P = 0.006) and low albumin level (P < 0.01). Multivariate analysis showed that only failure of achieving remission (P < 0.01), poor performance status (ECOG 3-4) (P < 0.01) and increased WBC counts (P < 0.01) were independent prognostic factors. The patients aged 70 years or over had poor overall survival, and no significant difference of OS was observed among patients with age between 55 and 69 years. For patients aged 55 - 69 years received either DA/IA or CAG treatments had longer survival than those with palliative treatments. For those aged 70 years or over, only patients with CAG treatment had significantly longer survival than palliative treatment. For the patients with age less than 70 years and achieving complete remission after induction, intermediate-dose cytarabine consolidation might not improve survival.</p><p><b>CONCLUSION</b>Elderly AML patients should be treated individually. The intermediate-dose cytarabine consolidation might not improve survival of elderly AML patients.</p>

Study of prognostic related factors of elderly patients with T/NK cell lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the prognostic related factors of elderly patients with T/NK cell lymphoma.</p><p><b>METHODS</b>The clinical data of 62 T/NK cell lymphoma patients with age over 60 years and treated in Shanghai Jiaotong University Medical School affiliated Ruijin Hospital from 1999 to 2011 were collected and analyzed. Multivariate and univariate analysis of clinical data were performed using a COX regression model, including stage, performance status, extranodal infiltration, bone marrow involvement and LDH level. According to IPI or PIT systems, survival functions were estimated using the Kaplan-Meier method and compared by the log-rank test.</p><p><b>RESULTS</b>Using the IPI system, the CR rate of the low risk (IPI = 1, n = 7), intermediate-low risk (IPI = 2, n = 22), intermediate-high risk (IPI = 3, n = 13) and high risk (IPI = 4-5, n = 20) groups were 85.7%, 59.1%, 0% and 5.0%, with the median overall survival (OS) of 90.0, 63.9, 10.1 and 5.0 months, respectively. The patients with IPI = 1-2 had significant longer OS than those with IPI = 3-5 (P < 0.01), but no significant difference of OS was observed between IPI = 1 and IPI = 2 (P = 0.3647). As for the PIT system, CR rate of patients with PIT = 1 (n = 18), PIT = 2 (n = 18) and PIT = 3-4 (n = 26) were 61.1%, 44.4% and 3.8%, with the median survival of 90.0, 46.9 and 5.0 months, respectively. Significant difference of OS was found among groups of PIT = 1, PIT = 2 and PIT = 3-4 (P < 0.01). Therefore, PIT index was more effective than IPI in predicting prognosis of elderly T/NK cell lymphoma patients. The significant parameters of the univariate analysis were B symptom (P = 0.025), increased LDH level (P = 0.004), bone marrow infiltration (P = 0.023) and extranodal involvements (P = 0.033). Multivariate analysis showed that only increased LDH level (P = 0.007) and bone marrow involvement (P = 0.016) were the two independent prognostic factors of survival. These two factors were included in PIT index.</p><p><b>CONCLUSIONS</b>PIT is more effective than IPI to predict outcomes of elderly T/NK lymphoma patients.</p>

Mechanism of inhibiting the cell growth in diffuse large B-cell lymphoma by valproic acid combined with temsirolimus / 中国实验血液学杂志

The aim of this study was to illustrate the mechanism of inhibiting the cell growth in diffuse large B-cell lymphoma by histone deacetylase inhibitor valproic acid (VPA) combined with mTOR inhibitor temsirolimus (TEM). MTT assay and Wright's stain were used to assess cell growth inhibition and to detect the cell morphological changes respectively. The cell apoptosis, cell cycle and cell autophagy were determined by flow cytometry. Ultrastructure changes were confirmed by electron microscopy. Protein changes were detected by Western blot. The results showed that both VPA and TEM alone inhibited cell proliferation and the effect was more obvious in the combination group. VPA combined with TEM induced cell arrest in G0/G1 phase and upregulated the expression of autophagy-related protein LC3, without cell apoptosis. Moreover, typical autophagosomes were observed, further confirming the presence of autophagy. Western blot showed the changes of proteins involved in autophagy signaling pathway. VPA decreased HDAC1 and HDAC3 expression and increased histone acetylation, suggesting that VPA also affected lymphoma cell proliferation through epigenetic modification. It is concluded that the combined treatment of VPA and TEM induces cell cycle arrest and cell autophagy, which provides a new clue for their clinical application in diffuse large B-cell lymphoma.

Prognostic significance of EBMT score system for hematological malignancies with allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the impact of EBMT score system in patients with hematological malignancies received allogeneic hematopoietic stem cell transplantation (allo-HSCT).</p><p><b>METHODS</b>A total of 144 consecutive patients were analyzed retrospectively. According to the EBMT score system, including age, disease status before transplantation, interval between diagnoses to transplantation, donor/recipient sex match and donor type, patients were divided into 3 risk groups: low risk (score 0-1), intermediate risk (score 2-3) and high risk (score 4-7).</p><p><b>RESULTS</b>The median follow-up duration were 413 (10-1827) days for all patients and 837 (166-1827) days for alive patients. The estimated 4-year overall survival (OS), transplant-related mortality (TRM) and relapse rate (RR) were (57.5±4.6)%, (21.6±3.7)% and (42.7±6.1)%, respectively. The 4-year OS, TRM and RR were (72.2±9.0)%, (8.1±4.5)% and (27.3±8.7)% in the low-risk group, significantly superior to both intermediate-risk group [(57.7±6.0)%, (23.1±5.1)% and (44.9±8.3)%] and high-risk group [(36.9±10.2)%, (33.5±9.2)% and (51.5±11.8)%] (P<0.01, 0.02 and 0.009 for OS, TRM and RR respectively).</p><p><b>CONCLUSION</b>The EBMT score system provides prognostic significance for OS, TRM and RR in patients with hematological malignancies received allo-HSCT.</p>

Clinical features and prognostic analysis of mantle cell lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the clinical features, therapeutic effects, survival time and prognostic factors of patents with mantle cell lymphoma (MCL).</p><p><b>METHODS</b>Clinical data of 47 MCL patients admitted from January 2002 to December 2011 were retrospectively analyzed.</p><p><b>RESULTS</b>Of all patients, median age was 58 year-old and male to female ratio was 3.3:1. Forty-two cases (89.4%) were in Ann Arbor stage III-IV, 13 cases (27.7%) with bone marrow involvement, 6 cases (12.8%) with lymphocytosis, 18 cases (38.3%) with elevated LDH, and 28 cases (59.6%) with elevated β(2)-MG. Age, bone marrow involvement, increased LDH level and treatment without rituximab were poor prognostic factors. The efficiency and complete remission rate of rituximab combined with chemotherapy were 91.4% and 48.6%, which were superior to those of CHOP regimen (41.7% and 16.7%). As compared to CHOP regimen, rituximab combined with chemotherapy induced longer progression-free survival and overall survival.</p><p><b>CONCLUSION</b>Most patients with MCL were older adults with a male predominance and usually had bone marrow involvement and poor prognosis. Rituximab combined with chemotherapy could significantly improve patient outcome.</p>

Eeffects of Coptis Chinensis on vasoconstrictive activity of isolated thoracic aorta of normoxic and chronic intermittent hypobaric hypoxic rats / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To observe the effects of Coptis Chinensis on vasoconstrictive activity of isolated thoracic aorta rings of normoxic and chronic intermittent hypobaric hypoxic (CIHH) rats, and to investigate the underlying mechanisms.</p><p><b>METHODS</b>Young male Sprague-Dawley rats were randomly divided into normoxic group and CIHH group: the fonnrmer were not given any special treatment; the latter were exposed to hypoxia in a hypobaric chamber simulating 5000 m altitude (PB = 404 mmHg, PO2 = 84 mmHg, 11.1% O2), 6 hours daily for 28 days. The isolated thoracic aorta rings of rats were prepared and perfused in thermostat, and the effects of Coptis on vasoconstrictive activity of aorta rings were recorded, the mechanisms were investigated simultaneouly.</p><p><b>RESULTS</b>Coptis Chinensis significantly decreased NE and KC-induced vasoconstriction of normoxic and CIHH rats' isolated aortic rings, but the inhibitive effects had no obvious discrepancy between the two groups. The contractive amplitude had no marked change after the removal of endothelium. When calculated by Logit Loglinear analysis, IC50 of NE and KCl-induced contractive amplitude in normoxic group were respectively 2.99 g/L and 6.14 g/L, while they were 3.45 g/L and 5.81 g/L in CIHH group. The inhibitive effect of Coptis on vasoconstrictive activity of both groups could be partly decreased by Glibenclamide and nitro-L-arginine methyl ester; Indomethacin suppressed the effect on normoxic group as well. Also Coptis significantly inhibited NE-induced both intracellular and extracellular calciumion-depended vasoconstriction.</p><p><b>CONCLUSION</b>Coptis Chinensis obviously relaxes isolated thoracic aorta rings of normoxic and CIHH rats, but the effects are endothelium-independent and have no marked discrepancy between the two groups. The mechanisms of the effects may be related to the opening of ATP-sensitive K+ channel, raise of nitric oxide concentration in both groups, and the increasing of PGI2 in normoxic group. Besides, Coptis may inhibit sarcoplasmic reticulum releasing Ca2+ and decrease the inflow of extracellular Ca2+ via cell membrane.</p>

Prognostic significance of EBMT score for chronic myeloid leukemia patients in allogeneic stem cell transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the risk factors of allogeneic stem cell transplantation (allo-SCT) for chronic myeloid leukemia (CML) in an attempt to avoid transplant risks.</p><p><b>METHODS</b>A total of 121 CML patients received allo-SCT were analyzed retrospectively. The risk analysis was based on the EBMT score (gratwohl score) which included donor type, age of patients, disease status before transplantation, donor/recipient sex match and time interval between diagnosis to allo-SCT. Patients were divided into 3 risk groups based on their EBMT score: low risk (score 0-2), intermediate risk (3-4) and high-risk (5).</p><p><b>RESULTS</b>The median follow-up duration was 37 (1 - 126) months. The estimated 5-year overall survival (5 y-OS), non-relapse mortality (5 y-NRM) and relapse rate (5 y-RR) were (56.8 ± 5.0)%, (35.6 ± 4.9)% and (12.9 ± 3.7)%, respectively. The 5y-OS, NRM and RR were (66.0 ± 6.1)%, (28.8 ± 6.0)% and (7.8 ± 3.3)% in the low risk group being significantly superior to both intermediate-risk \[(47.2 ± 8.7)%, (43.6 ± 8.5)% and (18.7 ± 8.1)%\] and high-risk group \[(16.8 ± 15.2)%, (66.7 ± 25.5)% and (50.0 ± 25.0)%\] (P = 0.0015, 0.045 and 0.0053 for OS, NRM and RR respectively).</p><p><b>CONCLUSION</b>The EBMT risk score can effectively predict the overall outcome, relapse and transplant-related mortality of allo-SCT for CML patients.</p>

Treatment options and prognosis in newly diagnosed multiple myeloma patients / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the effect of treatment option on the response and outcomes in multiple myeloma (MM) patients suitable for autologous hematopoietic stem cell transplantation (auto-HSCT).</p><p><b>METHODS</b>A total of 71 newly-diagnosed MM patients less than 65 years admitted to RuiJin Hospital from June 2005 to December 2009 were analyzed retrospectively. Among them, 21 received auto-HSCT (HSCT group) with standard conditioning of melphalan 200 mg/m(2), 30 received conventional chemotherapy (conventional group) and 20 received Bortezomib-based therapy (Bortezomib group). The responses and outcomes of different treatments were analyzed.</p><p><b>RESULTS</b>The median follow-up duration for all patients was 18 (1 - 58) months with estimated 3-year overall survival (3-yr OS) of (79.8 ± 6.3)% and progression-free survival (3-yr PFS) of (54.8 ± 9.0)%. Thirty-four patients achieved complete remission (CR) or very good partial remission (VGPR) on induction therapy, which were 80% for the Bortezomib group, 33.3% for the conventional group and 38.3% for the HSCT group. After auto-HSCT the CR + VGPR rate was increased to 76.1% for the HSCT group. Overall, the 3-yr PFS was (26.3 ± 13.8)% (median 21 months), (40.5 ± 20.1)% (median 25 months) and (93.8 ± 6.1)%(median not reached, P = 0.025) for conventional, Bortezomib and HSCT groups respectively. Univariate analysis demonstrated that CR/VGPR after induction (P = 0.020), best response of CR/VGPR (P < 0.01), autoHSCT (P = 0.002) and maintenance therapy after CR/VGPR (P = 0.0005) were associated with improved PFS and that CR/VGPR after induction (P = 0.009), best response with CR/VGPR (P < 0.01), maintenance therapy for any patients (P = 0.035) and maintenance therapy for patients with CR/VGPR (P = 0.031) were associated with OS. In multivariate analysis, only auto-HSCT (P = 0.039) and best response of CR/VGPR (P = 0.009) were independent prognostic factors for PFS and the best response of CR/VGPR was the only independent prognostic factor for OS (P = 0.005). The estimated 3-yr OS was (62.4 ± 13.7)%, (94.1 ± 5.7)% and (87.9 ± 8.3)% respectively for 3 groups.</p><p><b>CONCLUSIONS</b>For newly-diagnosed MM younger than 65 are suitable for auto-HSCT, the best response of CR/VGPR was associated with OS and PFS. Auto-HSCT is also important prognostic factor for PFS. Induction therapy with Bortezomib can achieve rapid CR/VGPR while auto-HSCT as a crucial consolidation therapy and maintenance therapy maybe also important for improvement of long-term outcome.</p>

Genetic susceptibility of single nucleotide polymorphism in MGMT to non-Hodgkin lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the relationship between five single nucleotide polymorphism loci in the MGMT, XPA, XPD and XPG genes and the prevalence of non-Hodgkin's lymphoma.</p><p><b>METHODS</b>A case-control study of 73 lymphoma cases and 500 healthy controls was conducted and the Mass-ARRAY method was applied for detection of MGMT L84F, MGMT K178R, XPA TSS+62, XPD K751Q and XPG TSS+372.</p><p><b>RESULTS</b>MGMT L84F (T allele) was associated with an increased risk of non-Hodgkin lymphoma (OR=2.085, 95%CI=1.069-4.068, P=0.029), mainly in B-cell lymphoma, of which the risk increased by 2.403-fold (OR=2.403, 95%CI=1.103-5.235, P=0.024). No statistically significance was found for MGMT K178R, XPA TSS+62, XPD K751Q and XPG TSS+372.</p><p><b>CONCLUSION</b>Single nucleotide polymorphism in the MGMT gene may closely related to the occurrence of non-Hodgkin lymphoma, especially of B-cell subtype.</p>

Application of SNP-arrays in hematological malignancies - review / 中国实验血液学杂志

Single Nucleotide Polymorphism (SNP) is a DNA sequence variation caused by the mutation at the level of genomic nucleotides. It has been reported as the third generation of genetic markers. The SNP-arrays, based on the principle of SNP, plays an important role in disease research mainly for genomic detection of predisposing genes. As a convenient, confident, sensitive and efficient technique, SNP arrays could be applicable for the multiple-point interaction analysis of candidate genes, making it a promising and powerful method for DNA analysis. Hematological malignancies consist of various categories and their incidence is rising significantly. A multiple-point gene interaction has been reported as the essential pathogenetic mechanism of these diseases. This review illustrates the process of SNP-arrays in genome-wide assay and the application of this technique to the pathogenesis, clinical manifestation, therapeutic response and the prognosis of the hematological malignancies, including leukemia, malignant lymphoma, juvenile myelo-monocytic leukemia, myelodysplastic syndrome, multiple myeloma and so on.

Synergistic effects of proteasome inhibitor and histone deacetylase inhibitor on apoptosis and aggresome formation in T lymphoma cells / 中国实验血液学杂志

The aim of the study was to explore the synergistic effect of the proteasome inhibitor bortezomib (bor) and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) on apoptosis of T lymphoma cell lines Jurkat and Hut78, and on the formation of aggresome. Jurkat and Hut78 cells were treated with bor (10 nmol/L) or bor (10 nmol/L) combined with SAHA (2 micromol/L) respectively. Cell growth inhibition was estimated by trypan blue dye exclusion test. Cell morphology was evaluated by light microscopy with Wright's staining of cytocentrifuge preparations. Cell apoptosis was analyzed by flow cytometry. Ultrastructure of cell apoptosis and aggresome were observed by transmission electron microscopy. The results showed that proliferation of both Jurkat and Hut78 cells was significantly inhibited in the bor+SAHA group, as compared with the control group and the bor alone group. Flow cytometric analysis confirmed that the percentage of apoptosis in Jurkat and Hut78 cells in the bor+SAHA group (41.8+/-4.7% and 72.7+/-11.7% respectively) was remarkably higher than those in the control group (3.6+/-1.3% and 7.0+/-1.9% respectively) and the bor alone group (6.3+/-2.3% and 18.7+/-9.2% respectively) (p<0.01). Ultrastructure examination revealed that typical aggresomes in cells could be observed in bor alone group. The combination of bor and SAHA diminished both the amount and density of aggresomes, or even eliminated them, accompanied by the increased rate of apoptosis. It is concluded that proteasome inhibitor combined with histone deacetylase inhibitor synergically induces T lymphoma cell apoptosis. Bortezomib stimulates the formation of aggresome, while SAHA destroys this aggresome structure, which may be one of the mechanisms underlying the enhancement of bortezomib-induced apoptosis.

FIP1L1-PDGFRalpha alone or with other genetic abnormalities reveals disease progression in chronic eosinophilic leukemia but good response to imatinib / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The FIP1L1-PDGFRalpha fusion gene plays an important role in the pathogenesis of chronic eosinophilic leukemia (CEL) and is a direct therapeutic target of the tyrosine kinase inhibitor imatinib mesylate.</p><p><b>METHODS</b>In 24 hypereosinophilic syndromes (HES) patients, using reverse transcriptase-polymerase chain reaction (RT-PCR), nested PCR and sequence analysis, we investigated the frequency of FIP1L1-PDGFRalpha and other abnormalities of tyrosine kinase family genes like PDGFRalpha, PDGFRbeta, C-KIT, FGFR1, ABL and FLT3 as well as gene mutation "hotspots", like MPL515 and JAK2V617F, frequently involved in myeloproliferative diseases. Fluorescence in situ hybridization was used to confirm the 4q12 deletion.</p><p><b>RESULTS</b>The FIP1L1-PDGFRalpha fusion transcript was found in 8 (33%) of 24 patients with HES, corresponding to the chromosome 4q12 deletion identified by FISH. The FIP1L1-PDGFRalpha-associated patients diagnosed with CEL, frequently had hepatosplenomegaly, eosinophil-related tissue damage, anemia, thrombocytopenia, myelofibrosis and a short overall survival time. Nevertheless, imatinib mesylate induced rapid and complete hematological responses in treated FIP1L1-PDGFRalpha cases, followed by molecular remission and reversal of myelofibrosis. FIP1L1-PDGFRalpha fusion could co-exist with other mutations of tyrosine kinase family genes, like FLT3 or PDGFRbeta. We also demonstrated that the SNPs of PDGFRbeta were associated with selective splicing of exon 19 in case 20.</p><p><b>CONCLUSIONS</b>Correlating the CEL genotype with phenotype, FIP1L1-PDGFRalpha emerges as a relatively homogeneous clinicobiological entity that co-exists with other abnormalities of tyrosine kinase family genes. It reflects the disease progression and there is a good response to imatinib. Detection of the FIP1L1-PDGFRalpha fusion gene is valid for both CEL diagnosis and therapy surveillance.</p>