Lixia Zhu

An effective diagnostic index for lymphoma-associated hemophagocytic syndrome

Background Lymphoma-associated hemophagocytic syndrome (LAHS) is a highly fatal immune disorder. Poor prognosis is partly attributed to under diagnosis or delayed diagnosis. Aim Early identification of LAHS patients based on the laboratory findings could improve the outcomes. Design Retrospective observational cross-sectional study. Methods From January 2011 to June 2016, 282 adult patients with hemophagocytosis in bone marrow were enrolled, and 114 hemophagocytic lymphohistiocytosis (HLH) patients with definite underlying cause were finally included for analysis. The HLH patients were further divided into LAHS (76 out of 114) and non-malignancy-associated HLH (38 out of 114) groups. Results Compared to non-malignancy-associated HLH, LAHS patients had significantly elevated lactate dehydrogenase (LDH) levels, increased thickness of spleen, higher proportion of patients with lymphadenopathy and significantly decreased peripheral blood cell count. In multivariate logistic regression model analysis, thickness of spleen ≥5cm (OR = 17.9, 95%CI 1.35-236.6; P = 0.028), IL-6 level ≥55.1pg/mL (OR = 12.01, 95%CI 1.03-138.9; P = 0.047) and IL-10 level ≥425.9pg/mL (OR = 51.18, 95%CI 2.53-1035.1; P = 0.010) were independent predictors of LAHS diagnosis. Based on the regression parameters, we established a diagnostic index with weighted risk scores of 1 assigned to thickness of spleen and IL-6 level respectively, and a score of 3 assigned to IL-10 level. A diagnostic index ≥ 2 points had the best AUC value (0.889) with 84.2% of sensitivity and 93.7% of specificity for predicting LAHS. Conclusions LAHS can be considered when HLH patients have a diagnostic index ≥2 points, so actively looking for evidence of lymphoma and effective chemotherapy may be necessary.

Clinical features and outcomes in secondary adult hemophagocytic lymphohistiocytosis

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by an infrequent but immune-mediated life-threatening disease, with confusing clinical manifestations, rapidly deteriorating health, high morbidity and mortality and challenging diagnosis. Aim The purpose of this study was to improve the recognition and understanding of HLH. Design Retrospective observational cross-sectional study. Methods Data were collected for all cases of adult patients diagnosed with HLH in a large cohort managed at a single medical center from January 2011 to December 2015. Results The median age was 52 years (range 18-90 years) and 123 (60.0%) were male. Over 95% patients manifested fever, hyperferritinemia and elevated lactate dehydrogenase. Underlying triggers of HLH were as follows: 119 (58.0%) malignancies, 83 (40.5%) infections, 14 (6.8%) unknown triggers and 14 (6.8%) autoimmune disorders. The median overall survival was 55 days. And elderly patients (age ≥60 years) had a markedly worse survival compared with young patients (age <60 years) (median overall survival 24 days vs. 159 days, respectively; P <0.001). In a multivariable analysis, platelet <40 × 109/l (HR = 2.534; 95% CI 1.152-5.573; P = 0.021), PT prolonged >3 s (HR = 1.909; 95% CI 1.127-3.234; P = 0.016) and malignancy (HR = 1.614; 95% CI 1.008-2.582; P = 0.046) were correlated with poor survival. Conclusion HLH adult patients had very complex clinical manifestations as well as underlying diseases. Patients with PLT <40 ×109/l, PT prolonged >3 s and malignancy had inferior survival. It is of great importance to improve our understanding of this syndrome.

Adult onset haemophagocytic lymphohistiocytosis prognosis is affected by underlying disease: analysis of a single-institution series of 174 patients

BACKGROUND Haemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterised by activation of the mononuclear phagocytic system, and often leads to progressive multiple organ failure. The diagnosis of HLH is made late by most physicians. METHODS To confirm the diagnosis of acquired HLH made in a single-institution series of adult patients with HLH-04 criteria, we applied the HScore and evaluated prognostic factors associated with clinical outcome. RESULTS A total of 174 patients with a median age of 51 years (range 17-90) were included. Male/female ratio was 111/63. In 92/174 (52.9%) patients, there were potential haematological diseases (4 acute leukaemia, 1 thrombotic thrombocytopenic purpura, 3 Hodgkins lymphoma [HL], 17 B-cell non-Hodgkins lymphoma [NHL], 67 T-cell NHL including 22 natural killer / T-cell NHL [NK/t-cell NHL). Six (3.4%) patients had autoimmune disease and 76 (43.7%) undiagnosed underlying disease. There were 44 (25.3%) patients with Epstein-Barr virus infection, 11 (6.3%) with cytomegalovirus, 1 (0.5%) syphilis, 9 (5.2%) hepatitis B virus and 3 (1.7%) human immunodeficiency virus. More than 95% of patients had hyperferritinaemia, high lactate dehydrogenase, fever and low albumin, whereas 89.1% of patients had bone marrow phagocytosis. By the HScore, 4/174 patients had a >50% and 16/174 patients had a >90% probability of not having HLH. All 174 patients fulfilled more than five of the HLH-04 diagnostic criteria, but 16 of them had a low probability of HLH by the HScore. In a multivariate analysis, lymphopenia and hypofibrinogenaemia were independent prognostic factors for death. CONCLUSION In our study, viral infection was not an independent prognostic factor. NK/T-cell -NHL was associated with worse prognosis compared with B-cell NHL and T-cell NHL (p = 0.036) and similar to other aetiologies.

Clinical and histological features of primary testicular diffuse large B-cell lymphoma: a single center experience in China

Primary testicular lymphoma (PTL) is a rare and aggressive form of extranodal lymphoma. Approximately 80–98% of PTLs are diffuse large B-cell lymphoma (PT-DLBCL). The prognosis of DLBCL patients has improved with the addition of rituximab to systemic chemotherapy, but outcomes of PT-DLBCL remain poor. This may be explained by the high rate of relapse in the central nervous system (CNS) and contralateral testis. We analyzed 1,132 newly diagnosed DLBCL patients (37 with PT-DLBCL) who were treated at our hospital between January 2009 and December 2014. Twenty-five patients finished follow-up. We analyzed clinical characteristics, response to chemotherapy, overall survival, and relapse in the CNS and contralateral testis. All patients underwent orchiectomy. The median age was 60 (range: 43–82) years. Eleven patients had stage III/IV disease. Five patients experienced CNS relapse, and three experienced relapse in the contralateral testis. Median overall survival (OS) was not reached at the time of reporting. The 3-year OS rate was 57%. None of the nine patients who received radiotherapy to the contralateral testis experienced relapse in that location. Intrathecal prophylaxis did not reduce the risk of CNS relapse. All five patients who experienced CNS relapse had the germinal center B-cell-like subtype of DLBCL.

Blood biomarkers in adults with lymph node enlargement contribute to diagnostic significance of malignancy

Lymph node enlargement is a common presentation and has a possibility of malignancy like lymphoma that requires early diagnosis. This study aims to analyze the clinical characteristics of these patients and finds out useful predictors of malignant diseases. We retrospectively investigated 81 patients with lymph node enlargement between July 2, 2014 and May 17, 2016. The characteristics and laboratory findings were evaluated combining with the final diagnosis. The diagnoses were malignancy in 51 patients and benign lymphadenopathy in 30 patients. Increased beta2-microglobulin (B2M) (P = 0.012) was found to be associated with malignant diseases, and level of 3699.5 μg/L was used as a cut-off value to differentiate the malignancies from benign diseases, offering 63.4% sensitivity and 87.0% specificity. Immunoglobulin G (IgG) (P = 0.038) levels were significantly lower in malignant group, whose receiver operating characteristic curve showed that level of 1121.5 mg/dl had sensitivity and specificity as 58.5% and 82.6%. Moreover, through analysis of cytokines, we found interleukin-10 (IL-10) levels were elevated in malignant group compared with benign group. Serum B2M and IgG levels were concluded to be useful parameters for predicting malignancies. Besides, increased IL-10 levels indicated a higher risk of malignancy in some way.

Mechanisms of inhibiting human leukemia cell lines by serum of rats treated with compound banmao capsule

Compound banmao capsule (CBC) is a traditional Chinese medicinal formula composed of extracts from 11 organisms. The present study investigated the mechanism of CBC on the biological behavior of human leukemia cell lines using seropharmacological methods. CBC-containing rat serum was prepared by intragastrical administration of CBC to rats. The proliferation of human leukemia HL60 and K562 cell lines was assayed by measuring cell viability with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium method, while cell cycle distribution and the rate of apoptosis were evaluated with flow cytometry. The mRNA expression of vascular endothelial growth factor A (VEGF-A) and chemotactic and inflammatory genes in human leukemia cell lines was examined using reverse transcription quantitative-polymerase chain reaction methods. It was revealed that the proliferation of K562 and HL60 cells was significantly inhibited by the CBC-containing rat serum at 72 h. The CBC-containing serum also promoted the apoptosis of K562 and HL60 cell lines. The CBC-containing serum altered the cell cycle progression of K562 and HL60, increasing the proportion of the cells in G1 phase and decreasing the proportion of the cells in S phase. Attenuated expression of VEGF-A and a decreasing trend in the expression of chemotactic and inflammatory genes were identified following treatment with CBC-containing serum in HL60 and K562 cells. In conclusion, CBC-containing serum exerted an inhibitory effect on the growth of K562 and HL60 cells by decreasing cellular proliferation, promoting apoptosis and cell cycle arrest, and decreasing the expression of VEGF-A, and chemotactic and inflammatory genes.

Profiling of microRNAs in AML cells following overexpression or silencing of the VEGF gene.

Acute myeloid leukemia (AML) is a disease of the hematopoietic progenitor cells associated with heterogeneous clonal proliferation. Vascular endothelial growth factor (VEGF) and its receptors play important roles in the regulation of angiogenesis during physiological and pathological processes. It is thought that AML cells have an autocrine VEGF pathway that contributes to the development and progression of AML. In addition, growing evidence has suggested that numerous microRNAs are involved in AML. The present study aimed to investigate the relationship between VEGF dysregulation and microRNA profiles in AML cells and patients. VEGF-overexpressing and VEGF-knockdown leukemia cells were constructed and changes in the patterns of microRNA expression were analyzed using a microRNA array. Subsequently, mononuclear cells from the blood of patients with AML showing high or low expression levels of VEGF were obtained and were used to assess the patterns of microRNA expression by reverse transcription-quantitative polymerase chain reaction. The results of the present study suggested that downregulation of VEGF markedly altered the profile of microRNAs in AML cells, while upregulation of VEGF did not. Examination of clinical samples from patients with AML showed that several microRNAs were closely associated with the expression level of VEGF, including miR-20a, miR-93, miR-16-5p, miR-17-5p, miR-124-5p and miR-17-3p. These results suggested that VEGF may be a pivotal protein that can both receive and initiate signals in leukemia cells.

Risk factors and clinical characteristics of non-promyelocytic acute myeloid leukemia of intracerebral hemorrhage: A single center study in China

BACKGROUND Although high mortality in patients with acute leukemia (AL) is associated with intracranial hemorrhage (ICH), the clinical features and pathogenesis of AL patients with cerebral hemorrhage are not well known. METHODS We diagnosed 90 patients with ICH from a total of 1467 patients with non-promyelocytic AL who had been hospitalized in the First Affiliated Hospital of Medical School of Zhejiang University from January 2010 to October 2015. Moreover, the risk factors of ICH death were evaluated. RESULT Median age at ICH was 51years old, in which men accounted for 52.2%. They also accounted for 85.6% of acute myeloid leukemia. The relative incidence of ICH was the highest in M2 and M5 (60.1%). ICH presented with higher peripheral blood white blood cell count (WBC) (P<0.001), lower peripheral platelet counts (P<0.001), lower albumin (P<0.001), lower fibrous protein (P<0.001) and prolongation of prothrombin time (P<0.001) compared to those observed in the patients of NICH group; multivariate analysis, independent risk factors for death in patients with ICH include: WBC≥30.00×109/l and prothrombin time≥12.91 s. CONCLUSIONS Leukocytosis and coagulation dysfunctions might be the main pathogenesis of acute leukemia complicated with cerebral hemorrhage.

HAG (Homoharringtonine, Cytarabine, G-CSF) Regimen for the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Meta-Analysis with 2,314 Participants.

Background In China, the combination of homoharringtonine, cytarabine, and G-CSF (HAG) has been extensively applied for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods We performed a meta-analysis of 2,314 patients (AML, n = 1754; MDS, n = 560) to determine the overall safety and efficacy of this regimen. Results The complete response (CR) rate of AML patients (53%) was significantly higher than that of MDS/transformed-AML patients (45%; P = 0.007). The CR rate of patients with newly diagnosed AML (62%) was significantly higher than in patients with relapsed/refractory AML (50%; P = 0.001). There were no significant difference in CR rates between elderly AML patients (54%) and all AML patients (P = 0.721). When compared with non-HAG regimens for AML/MDS induction therapy, the CR rate of patients treated with HAG was significantly higher than in treated with intensive chemotherapy (P = 0.000). No significant differences in CR rates were observed between patients treated with HAG and those treated with CAG (cytarabine, aclarubicin, G-CSF) regimens (P = 0.073). HAG regimen was well tolerated, with early death (ED) in 2%, grade IV myelosurrpression in 52% and infection in 50%. Reports of ED and rates of myelosuppression were reduced as compared with intensive chemotherapy (P = 0.000 and P = 0.000, respectively). Conclusion The HAG regimen is an effective and safe regimen for the treatment of AML and MDS, and appears to be more effective and better tolerated than intensive chemotherapy. Future randomized controlled trials and further meta-analyses are strongly needed to confirm its efficacy and safety, especially in comparison with intensive chemotherapy.