Xiaoping Xu

Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis

Abstract The impact of rituximab (R) on the incidence of central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is unclear. We performed a meta-analysis to explore the risk factors and assess the association between R-chemotherapy (R-chemo) and CNS relapse. We searched MEDLINE, PubMed, EMBASE and OVID for eligible studies. Published group statistics were extracted from each study for analysis; individual patient data from each study were not accessed. Fixed- or random-effects models were used to estimate the odds ratio (OR) with a 95% confidence interval (CI). Eight studies were identified. The OR for R-chemo compared with identical chemotherapy was 0.70 (95% CI 0.54–0.91). Stage III/IV (OR 2.25, 95% CI 1.64–3.08), International Prognostic Index (IPI) > 1 (OR 2.62, 95% CI 1.59–4.33), performance status (PS) > 1 (OR 1.67, 95% CI 1.23–2.27), elevated lactate dehydrogenase (LDH) (OR 2.23, 95% CI 1.54–3.22), bone marrow involvement (OR 2.85, 95% CI 1.99–4.07), more than one extranodal involvement (OR 2.61, 95% CI 1.93–3.54), presence of B symptoms (OR 1.87, 95% CI 1.37–2.56) and testicular involvement (OR 3.83, 95% CI 1.84–7.97) were associated with increased risks of CNS relapse. This meta-analysis demonstrated a lower incidence of CNS relapse of DLBCL in the rituximab era. The risk of CNS relapse can be assessed by stage, IPI, PS, LDH, presence of B symptoms, number of extranodal sites, bone marrow and testicular involvement.

ID4 methylation predicts high risk of leukemic transformation in patients with myelodysplastic syndrome

Epigenetic gene silencing due to promoter methylation is observed in human cancers like acute myeloid leukemia (AML). Little is known about aberrant methylation in myelodysplastic syndrome (MDS), a heterogeneous clonal stem cell disorder with a approximately 30% risk of transformation into secondary AML. Recent evidence demonstrated that ID4, a negative regulator of transcription, may act as a tumor-suppressor gene. To clarify the role of ID4 in MDS, we employed methylation-specific PCR (MSP) to examine the methylation status of ID4 in 144 adult de novo MDS patients. We found that ID4 methylation was present in 35.4% (n=51) of these MDS patients and methylaiton was correlated significantly with World Health Organization (WHO) subtypes and International Prognostic Scoring System (IPSS) risk groups. Patients with advanced stages of WHO subtypes (45.8% vs. 21.3%, P=0.002) and higher risk IPSS subgroups (45.7% vs. 26.0%, P=0.014) exhibited a significantly higher frequency of ID4 methylation. The median survival of patients with ID4 methylation was shorter than patients without ID4 methylation (12.2 months vs. 26.9 months, P=0.005). Multivariate analysis indicated that ID4 methylation status was the independent factor that impacted leukemia-free survival (LFS). Disease in patients with ID4 methylation progressed more rapidly than those without ID4 methylation (P=0.047, HR=2.11). Our results suggest that ID4 may be a therapeutic target in MDS.

Cytogenetic evolution correlates with poor prognosis in myelodysplastic syndrome

Clonal chromosomal abnormalities are observed in 30-50% of primary myelodysplastic syndrome (MDS) patients. Although the prognostic relevance of cytogenetics is generally appreciated, the prognostic value of cytogenetic evolution has rarely been evaluated. In this study, we retrospectively analyzed cytogenetic features at diagnosis and during follow-up in 85 patients with primary MDS. Cytogenetic evolution occurred in 18 of the 85 patients (21%), with chromosomes 8, 5, and 1 most often involved. Patients with higher levels of marrow blasts (P = 0.034), more advanced stages of World Health Organization (WHO) subtypes (44% vs. 16%, P = 0.035), and higher risk International Prognostic Scoring System (IPSS) subgroups (47% vs. 16%, P = 0.021) had higher incidences of developing cytogenetic evolution. Furthermore, the median survival of patients in the group with cytogenetic evolution was 25.8 months, compared with 45.4 months for patients in the group without cytogenetic evolution (P = 0.01). The same result was also found for time to progression: patients with cytogenetic evolution progressed more rapidly than those without cytogenetic evolution (P = 0.007). Knowledge of cytogenetic evolution offers useful information for clinicians to make more accurate prognostic assessments for patients with MDS.

Cytogenetic features and prognosis analysis in Chinese patients with myelodysplastic syndrome: a multicenter study

It has been suggested that Asian and Western myelodysplastic syndrome (MDS) patients have different cytogenetic and prognostic features. In this study, we retrospectively analyzed clinical and cytogenetic data from 435 Chinese adult primary MDS patients. In addition, we evaluated the prognostic value of the World Health Organization classification as well as six prognostic scoring systems in these patients. The median follow-up time was 25.1xa0months (5.5–53.2). Of the 435 patients, 186 (42.8%) had died and 40 (9.2%) had progressed to acute myeloid leukemia. Multivariate analysis identified older age, higher percent of marrow blasts, and poor-risk IPSS cytogenetics as characteristics associated with worse survival and higher risk of leukemia transformation. Low platelets, hemoglobin, and mean corpuscular volume were independent factors associated only with worse survival. Among the 424 patients in whom the results of cytogenetic analyses were available, 164 (38.7%) showed karyotypic abnormalities. Incidence of trisomy 8 was common but sole del(5q) was rare in Chinese MDS patients. For predicting survival, most scoring systems were meaningful for stratifying patients into different subgroups, with the exception of the WPSS scoring system. For predicting leukemia evolution, the Spanish scoring system was most effective. Patients with RAEB-2 showed different prognoses from those with RAEB-1. However, there was no significant difference in prognoses between patients with refractory cytopenia with multilineage dysplasia (RCMD) from RA or RARS. In summary, this analysis indicated the presence of a different cytogenetic pattern as well as prognostic features in Chinese MDS patients.

Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma

BackgroundExtranodal NK/T-cell lymphoma (ENKL) is an aggressive hematological malignancy associated with Epstein–Barr virus (EBV) infection. It is often resistant to conventional chemotherapy and has a poor prognosis. Icaritin, a compound derived from Chinese herbal medicine, Herba Epimedii, has been reported to exert antitumor effects on a variety of cancer cell lines. In the present study, we investigated the cytotoxic effects of Icaritin on the two EBV-positive ENKL cell lines SNK-10 and SNT-8, along with the underlying molecular mechanisms.MethodsENKL cell lines SNK-10 and SNT-8 were exposed to different concentrations of Icaritin for the indicated time. Treated cells were analyzed for cell proliferation, cell cycle, and cell apoptosis. Phosphorylation of Stat3 and Akt proteins in signaling pathways and the EBV-encoded LMP1 proteins were measured by Western blot. Expression of EBV genes was assessed by Real-Time PCR.ResultsOur results showed that Icaritin dose-dependently inhibits ENKL cell proliferation and induces apoptosis and cell cycle arrest at G2/M phase. Additionally, Icaritin upregulates Bax, downregulates Bcl-2 and pBad, and activates caspase-3 and caspase-9. The anti-proliferative and pro-apoptotic effects of Icaritin are likely mediated by inhibition of Stat3 and Akt pathways through LMP1 downregulation. Importantly, Icaritin induces EBV lytic gene expression in ENKL cells, and the combination of Icaritin and the antiviral drug ganciclovir (GCV) is more effective in inducing ENKL cells apoptosis than Icaritin or GCV alone.ConclusionsThese findings indicate that EBV-targeted approaches may have significant therapeutic potential for ENKL treatment.

Prevalence and prognostic significance of FLT3 gene mutations in patients with acute leukaemia: analysis of patients from the Shanghai Leukaemia Co-operative Group.

This study was designed to evaluate the prevalence of fms-like tyrosine kinase-3 (FLT3) gene mutations in the World Health Organization classified subtypes of acute leukaemia (AL), and their prognostic significance in terms of complete remission (CR), leukaemia-free survival (LFS) and overall survival (OS). Of 468 patients, 374 (79.9%) had acute myeloid leukaemia (AML) and 83 (17.7%) had acute lymphoblastic leukaemia (ALL). Among the AML patients, a FLT3 internal tandem duplication (FLT3/ITD) mutation was present in 59 cases (15.8%), whereas a FLT3/D835 mutation was detected in 15 cases (4.0%). Conversely, in the ALL patients, no FLT3/ITD mutations were detected and a FLT3/D835 mutation was found in only two cases (2.4%). The FLT3/ITD mutation was associated with a lower CR rate compared with those with no mutations (52.3% versus 71.1%) and with a shorter median OS (9 versus 18 months) in AML patients. In conclusion, the FLT3/ITD mutation occurred frequently in AML and was associated with a lower CR and shorter median OS. In contrast, FLT3/D835 mutations were not of prognostic value.

Lentiviral vector-mediate ATG3 overexpression inhibits growth and promotes apoptosis of human SKM-1 cells

Based on the nested case–control study cohort and gene expression profile, we have picked up a subset of six genes to distinguish the leukemia group and control group stably. ATG3 is the only down regulated gene. This research is to investigate the effect of ATG3 gene over expression by lentivirus on SKM-1 cell line and myelodysplastic syndrome to leukemic transformation. Human SKM-1 cells were transfected with ATG3–GFP recombinant lentiviral vectors and compared with cells transfected with GFP lentiviral vectors. Western blot was performed to detect the ATG3 protein. Cell proliferation was assessed by cell counting kit-8. Cell vitality was tested by Trypan Blue. Cell apoptosis was determined by Annexin V Apoptosis Detection Kit APC. Observe and compare the changes on growth curve, cell vitality and cell apoptosis. After 72xa0h of transfection, satisfactory transfection efficiency (> 90xa0%) was observed. SKM-1 cell line showed a statistically significant (Pxa0<xa00.05) overexpression of ATG3, parallel to significantly (Pxa0<xa00.05) inhibited cell proliferation. The cell vitality of ATG3 overexpression was significantly (Pxa0<xa00.05) lower than negative control. Cell apoptosis analysis by flow cytometer demonstrated decreased proportion of early apoptosis and increased that of late apoptosis and death (Pxa0<xa00.05). Over expressed ATG3 gene and protein, the SKM-1 cell line was inhibited in proliferation and cell vitality. It was promoted from early apoptosis to late apoptosis and death. The malignancy of SKM-1 cell line was decreased after transfection. ATG3 gene and its gene family may play an important role in transformation of myelodysplastic syndrome.

Prospective nested case-control study of feature genes related to leukemic evolution of myelodysplastic syndrome

We established a nested case–control study cohort of myelodysplastic syndrome patients (nxa0=xa0435). And 41 patients had conditions progressing to leukemia (case groupxa0=xa041), 342 patients had no leukemic transformation (control groupxa0=xa0342), and 52 patients died. Bone marrow mononuclear cell of the patients in the case group and after the evolution were analyzed for the gene expression microarray test (self-control study), whereas the bone marrow mononuclear cell of the paired patients extracted at diagnosis were analyzed for the gene expression microarray test (case–control study). By incorporating the results of above two studies, we identified the genes related to the transformation of myelodysplastic syndrome to acute leukemia. A total of 958 deregulated genes were identified via bioinformatics analysis. Further analyses identified a subset of six genes that help distinguish between the case and control groups. These genes are TUBB, PSMD1, SLC7A5, ATG3, TUBB2C, and TIMM10. The combined gene expression microarray test and nested case–control study method identified a subset of six genes that help distinguish between the case and control groups. The six genes may play critical roles in the evolution of myelodysplastic syndrome to acute leukemia.

Analyses on clinical characteristic and prognoses of 41 patients with chronic myelomonocytic leukemia in China.

PURPOSEnTo investigate clinical characteristic and prognostic factors for chronic myelomonocytic leukemia (CMML).nnnMETHODSnA retrospective cohort study was used in the research. We investigated clinical and laboratory characteristics of CMML patients and survival status. Patients were followed up regularly through out the course of the research.nnnRESULTSnForty-one cases were diagnosed as CMML, including 27 male and 14 female patients. Median WBC was 13.7 x 10(9)/L. Five patients had leukocytopenia (1.92-3.46 x 10(9)/L). Median monocyte count in the peripheral blood was 2.13 x 10(9)/L. All patients presented with bone marrow dysplasia, and most showed hyperplasia, except 3 cases. Abnormal chromosome was detected in 34% cases. Median survival time for CMML-1 and CMML-2 was 20 and 12 months, respectively, but there were no statistical significance of survival duration between them. Univariable analysis showed that age (>60 years), neutrophil count (<2.0 x 10(9)/L), lymphocyte count (<1.0 x 10(9)/L), mature monocyte count (>or=5 x 10(9)/L) and anemia (Hb<60 g/L) were associated with poor prognosis for CMML. There was no statistical significance in LDH, gender, and abnormal chromosome for survival time. Only lymphocyte count and neutrophil count in peripheral blood were independent prognostic factors for CMML after multivariate analysis.nnnCONCLUSIONnCMML mainly occurs in elderly patients. Although most patients have leukocytosis and monocytosis at diagnosis, few cases show leucopenia and monocytopenia. Age, neutrophil, lymphopenia, monocytosis, and severe anemia are associated with inferior prognosis of CMML. Lymphocyte<1.0 x 10(9)/L and neutrophil count<2.0 x 10(9)/L are adversely independent prognostic factors for CMML.

Myeloid/natural killer cell precursor acute leukemia with multiple subcutaneous nodules as the initial presentation: a case report and literature review

Myeloid/natural killer (NK) cell precursor acute leukemia is a rare neoplasm, which is characterized by high incidence of extramedullary infiltration, especially in the mediastinum and lymph nodes, an aggressive course and poor prognosis. As coexpressing myeloid and NK-cell antigens, myeloid/NK-cell precursor acute leukemia (MNKL) may pose diagnostic difficulty. Because the developmental pathway of normal NK cells is not well understood, neoplams of NK-cell origin are not clearly identified. To our knowledge, there have been only about 30 cases with this disease published previously. In the current paper, we present a case of a 21-year-old male patient whose initial presentation showed numerous subcutaneous nodules without bone marrow involvement. A diagnosis of MNKL was finally made by skin biopsy, bone marrow immunohistochemistry and immunophenotypic analysis. Although bone marrow achieved complete remission using DA chemotherapeutic regimen, the skin nodules did not regress. However, FLAG chemotherapeutic regimen, including fludarabine, cytarabine and G-CSF, was effective for both bone marrow and skin involvement. To the best of our knowledge, this study is the first to describe the effect of FLAG regimen for the treatment of this disease, indicating that it may be effective against the skin involvement of MNKL.