Bobin Chen

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.

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.

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

PURPOSE To investigate clinical characteristic and prognostic factors for chronic myelomonocytic leukemia (CMML). METHODS A 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. RESULTS Forty-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. CONCLUSION CMML 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.

Synergistic Effect and Molecular Mechanism of Homoharringtonine and Bortezomib on SKM-1 Cell Apoptosis

Background Myelodysplastic syndromes (MDS) are clonal marrow stem-cell disorders with a high risk of progression to acute myeloid leukemia (AML). Treatment options are limited and targeted therapies are not available for MDS. In the present study, we investigated the cytotoxicity and the molecular mechanism of Homoharringtonine (HHT) and Bortezomib towards high-risk MDS cell line SKM-1 in vitro and the role of miR-3151 was first evaluated in SKM-1 cells. Methods SKM-1 cells were treated with different concentrations of HHT or Bortezomib, and cell viability was analyzed with CCK-8 assay. The influence on cell proliferation, cell cycle distribution and the percentage of apoptosis cells were analyzed by flow cytometry. Calcusyn software was used to calculate combination index (CI) values. Western blot was used to analysis phosphorylation of Akt and nuclear NF-κB protein expression in SKM-1 cells. Mature miR-3151 level and p53 protein level were detected after HHT or Bortezomib treatment. The cell proliferation and p53 protein level were reassessed in SKM-1 cells infected with lentivirus to overexpress miR-3151. Results Simultaneous exposure to HHT and Bortezomib (10.4:1) resulted in a significant reduction of cell proliferation in SKM-1 cells (P < 0.05). Cell cycle arrest at G0/G1 and G2/M phase was observed (P < 0.05). HHT and Bortezomib synergistically induced cell apoptosis by regulating members of caspase 9, caspase 3 and Bcl-2 family (P < 0.01). The mechanisms of the synergy involved Akt and NF-κB signaling pathway inhibition, downregulation of mature miR-3151 and increment of downstream p53 protein level. Overexpression of miR-3151 promoted cell proliferation and inhibited p53 protein expression in SKM-1 (P < 0.01). Conclusions HHT and Bortezomib synergistically inhibit SKM-1 cell proliferation and induce apoptosis in vitro. Inhibition of Akt and NF-κB pathway signaling contribute to molecular mechanism of HHT and Bortezomib. miR-3151 abundance is implicated in SKM-1 cell viability, cell proliferation and p53 protein expression.

Analysis of clinical characteristics of 516 patients with non-Hodgkin's lymphoma in Shanghai area

Abstract The aim was to determine the clinical and cytogenetic characteristics of non-Hodgkins lymphoma (NHL) in Shanghai. A retrospective analysis was conducted in 516 patients with NHL. Patient clinical data, including age, sex, diagnosis, immunophenotypes, and karyotypes, were collected. The median age was 58 years. There was a male predominance in all NHL, except extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Patients with B cell NHL (1.5%) expressed CD3. T cell NHL patients (11.5%) expressed CD20. Epstein–Barr virus latent integral membrane protein 1, BCL6, CD10, Bcl-2, CD68, myeloperoxidase, CD99, CD30, CD15, and CD43 were present in various types of NHL. Complex karyotypes accounted for 92.3% of the 73.7% patients with abnormal karyotypes. Immunoglobin heavy chain gene translocation was present in 60.3% of B cell and 23.7% of T/NK cell neoplasms. Understanding the complex clinicopathological and molecular features of NHL may help with prognosis and serve as targets for treatments.

Myeloid/NK cell acute leukemia

Myeloid/NK cell leukemia is distinct entity, being different from the myeloid/NK cell precursor acute leukemia and blastic NK cell lymphoma/leukemia in morphology and immunotypes. The entity is a more mature state than the latter. We reported a typical case with presentation, immunology and cytogenetic results. The patient went to see a doctor with leucocytosis, anemia and thrombocytopenia. There are no superficial lymph nodes and splenohepatomegaly. The morphology of leukemia cells in bone marrow was similar to that of acute promyelocytic leukemia. The leukemia cells express CD13, CD33, CD15, and CD56, not expressing CD34, HLA-DR and CD16. No abnormal cytogenetics were found. The patients were given chemotherapy as acute myeloid leukemia, and got complete remission.

Therapy-Related Acute Myeloid Leukemia in A Primary Pulmonary Leiomyosarcoma Patient with Skin Metastasis

Primary pulmonary leiomyosarcoma (LMS) is a very unusual tumor. Although LMS has well-known metastatic potential, cutaneous metastasis is a remarkably uncommon. Exposure to cytotoxic agents could lead to “therapy-related myeloid neoplasm” (t-MN). Starting from 2008, the World Health Organization (WHO) has adopted the term to cover the spectrum of malignant diseases previously known as therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndrome (t-MDS) and therapy-related myelodysplastic/myeloproliferative neoplasm (t-MDS/MPN). We described the onset of t-MDS and progression to t-AML in one case diagnosed as primary pulmonary LMS with cutaneous metastasis. This patient achieved complete remission (CR) after three courses of IA regimen chemotherapy (idarubicin 5 mg/d, d 1–3; cytarabine 100 mg/d, d 1–5) and 1 course of HA chemotherapy regimen (homoharringtonine 3 mg/d, d 1–3; cytarabine 100 mg/d, d 1–7). This case presents the natural course of therapy-related neoplasm and provides therapeutic experience for t-AML.

Methotrexate plus idarubicin improves outcome of patients with primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with poor long-term survival. This study assessed methotrexate (MTX) plus idarubicin (IDA) in treating patients of PCNSL comparing to MTX alone therapy. A total of 100 patients were retrospectively enrolled and subjected to MTX alone (n = 52) and MTX plus IDA (n = 48). The completed response (CR) rate in patients treated with MTX plus IDA was 62.50%, and overall response (OR) rate was 79.17%, which in MTX alone cohort were 42.31% and 63.46% respectively. Median progression-free survival (PFS) of patients treated with MTX plus IDA was significantly better than those treated with MTX alone (18.35 months vs.8.45months, P = 0.000). The MTX plus IDA regimen exhibited a significantly better control of PCNSL. Further studies would be needed to confirm these results.Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with poor long-term survival. This study assessed methotrexate (MTX) plus idarubicin (IDA) in treating patients of PCNSL comparing to MTX alone therapy. A total of 100 patients were retrospectively enrolled and subjected to MTX alone (n = 52) and MTX plus IDA (n = 48). The completed response (CR) rate in patients treated with MTX plus IDA was 62.50%, and overall response (OR) rate was 79.17%, which in MTX alone cohort were 42.31% and 63.46% respectively. Median progression-free survival (PFS) of patients treated with MTX plus IDA was significantly better than those treated with MTX alone (18.35 months vs.8.45months, P = 0.000). The MTX plus IDA regimen exhibited a significantly better control of PCNSL. Further studies would be needed to confirm these results.

SLC7A5 act as a potential leukemic transformation target gene in myelodysplastic syndrome

Objective Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell disorders characterized by increased risk of leukemic transformation. This study identifies microRNAs(miRNA) and miRNA targets that might represent leukemic transformation markers for MDS. Methods Based on our previously established nested case-control study cohort of MDS patients, we chose paired patients to undergo Angilent 8 × 15K human miRNA microarrays. Target prediction analysis was administrated using targetscan 5.1 software. We further investigated the function of target gene in MDS cell line using siRNA method, including cell proliferation, cell apoptosis, cell cycle and electron microscope. Results Finally we screened a subset of 7 miRNAs to be significantly differentially expressed between the case (at the end of follow up with leukemic transformation) and control group (at the end of follow up without leukemic transformation). Target prediction analysis revealed SLC7A5 was the common target gene of these 7 miRNAs. Further study on the function of SLC7A5 gene in SKM-1 cell line showed that downregulation of SLC7A5 inhibited SKM-1 cells proliferation, increased apoptosis and caused cell cycle arrest in the G0/G1 stage. Conclusion Our data indicate that SLC7A5 gene may act as a potential leukemic transformation target gene in MDS.