Hemophagocytic lymphohistiocytosis after autologous stem cell transplantation in angioimmunoblastic T-cell lymphoma: A case report.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL), a unique subtype of peripheral T-cell lymphoma, has relatively poor outcomes. High-dose chemotherapy with autologous stem cell transplantation (ASCT) can achieve complete remission and improve outcomes. Unfortunately, subsequent T-cell lymphoma-triggered hemophagocytic lymphohistiocytosis (HLH) has a worse prognosis than B-cell lymphoma-triggered HLH. CASE SUMMARY: We here report a 50-year-old woman with AITL who achieved a favorable outcome after developing HLH 2 mo after receiving high-dose chemotherapy/ ASCT. The patient was initially admitted to our hospital because of multiple enlarged lymph nodes. The final pathologic diagnosis, made on biopsy of a left axillary lymph node was AITL (Stage IV, Group A). Four cycles of the following chemotherapy regimen were administered: Cyclophosphamide 1.3 g, doxorubicin 86 mg, and vincristine 2 mg on day 1; prednisone 100 mg on days 1-5; and lenalidomide 25 mg on days 1-14. The interval between each cycle was 21 d. The patient received a conditioning regimen (busulfan, cyclophosphamide, and etoposide) followed by peripheral blood stem cell infusion. Unfortunately, she developed sustained fever and a low platelet count 17 d after ACST, leading to a diagnosis of HLH after ASCT. During treatment, she experienced thrombocytopenia and Pneumocystis carinii pneumonia. The patient was successfully treated with etoposide and glucocorticoids. CONCLUSION: It is possible that development of HLH is related to immune reconstitution after ASCT.

Role of five small nucleotide polymorphisms in the VEGF gene on the susceptibility to osteosarcoma and overall survival of patients.

The present study aimed to investigate the association between five common small nucleotide polymorphisms (SNPs) in the VEGF gene and the risk of osteosarcoma. An additional aim was to investigate the role of these five SNPs on the prognosis of osteosarcoma. A total of 186 patients with osteosarcoma and 186 age- and sex-matched healthy controls were enrolled into the present study. A polymerase chain reaction-restriction fragment length polymorphism assay was conducted to determine the incidence of the VEGF-2578 C/A, -1156 G/A, +1612 G/A, +936 C/T and -634 G/C polymorphisms. Conditional logistic regression analyses revealed that individuals carrying the -634 GG genotype possessed a significantly increased risk of osteosarcoma, with an adjusted odds ratio [(95% confidence interval (CI)] of 2.00 (1.07-3.75). In the Cox proportional hazards model, subsequent to adjusting for potential confounding factors, patients with osteosarcoma carrying the -634 GG genotype were found to demonstrate a shorter overall survival time (hazard ratio, 3.10; 95% CI, 1.17-8.38). The VEGF-634 G/C polymorphism may therefore be used as a genetic marker for the prediction of the risk and clinical outcome of osteosarcoma.

Characterization of Th1- and Th2-associated chemokine receptor expression in spleens of patients with immune thrombocytopenia.

PURPOSE: In view of the numerous clinical observations and laboratory studies that suggest a critical role for the spleen in immune thrombocytopenia (ITP) pathophysiology, we aimed to characterize Th1-associated chemokine receptors CXCR3 and CCR5 and Th2-associated chemokine receptor CCR3 in spleens of ITP patients and assess the significance of their differential expression in the clinical setting. METHODS: The histopathology of spleens was observed using hematoxylin-eosin staining (HE), and the positive rate of CXCR3, CCR5 and CCR3 expression in spleens of 24 ITP patients and 12 patients with traumatic splenic rupture as normal controls was detected by immunohistochemistry using the SP method. CXCR3, CCR5 and CCR3 protein expression was analyzed by Western blot and mRNA levels were investigated by real-time polymerase chain reaction (RT-PCR). RESULTS: Reactive hyperplasia could be seen in follicles of the white pulp, the germinal central zone was enlarged and the marginal zone was thickened, the central arteries were thickened and fibrotic, and the density of the capillary vessel was increased in ITP patients. ITP group displayed a higher rate of expression of Th1-associated chemokine receptors CXCR3 and CCR5 (83.3% vs. 75%, 100% vs. 83.3%) but lower rate of expression of Th2-associated chemokine receptor CCR3 (50% vs. 66.7%) compared with the controls (P < 0.05, respectively). Western blot analysis revealed that CXCR3 and CCR5 protein expression was significantly increased in ITP patients while CCR3 was significantly reduced (P < 0.05, respectively). Meanwhile, ITP patients displayed increased mRNA levels of CXCR3 and CCR5 but decreased gene expression of CCR3 (P < 0.05, respectively). CONCLUSION: The data suggested that the abnormal expression of Th1/Th2 chemokine receptors may participate in splenic immune disorder in patients with ITP. Using corresponding inhibitors may inhibit Th1-dominant expression and mitigate the progress of the disease.

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model.

Lymphoma cells mobilize many mechanisms to evade the immune system. There is substantial evidence that CD4(+)CD25(+) regulatory T cells (Tregs) play a key role in the control of immune evasion. Tregs can transfer cyclic adenosine monophosphate (cAMP) to effector T cells, suggesting an association between Tregs' immune-evasion role and the intracellular cAMP pathway. In this study, we used A20 B-cell lymphoma mice as aggressive tumor models to investigate the mechanism of the depletion of Tregs by low-dose cyclophosphamide (CY, 20 mg/kg). The tumor-bearing mice had longer survival times and slower tumor growth rates following treatment with CY, but its effects were temporary. Along with the depletion of Tregs by low-dose CY treatment, the expression of interleukin-2 (IL-2) in T effector cells increased, and intracellular cAMP concentrations in immune cells decreased. Our study demonstrates the ability of low-dose CY to reverse Tregs-mediated immune evasion in a mouse model. The changes in intracellular cAMP concentrations correlated with the upregulation of effector T cells and the downregulation of Tregs, indicating the close association of cAMP analogs and low-dose CY in the immune therapy of B-cell lymphoma.

[Expression of CXCR3 and CCR5 chemokine receptor in spleens of patients with primary immune thrombocytopenia].

OBJECTIVE: To study CXCR3 and CCR5 chemokine receptor expression in spleens of patients with primary immune thrombocytopenia (ITP) and its clinical significance. METHODS: The splenectomy specimens from 10 ITP patients (ITP group) and 8 patients with traumatic splenic rupture (normal control group) were studied. Immunohistochemistry (IHC) was used to study the positive rate of CXCR3 and CCR5. Western blot was performed to detect CXCR3 and CCR5 protein expression, while real-time polymerase chain reaction (RT-PCR) was conducted to analyze their mRNA expression. RESULTS: The positive rate of CXCR3 and CCR5 were both higher in ITP group (90% and 100%, respectively) than those in control group (75% and 87.5%, respectively)(P < 0.05). The differences were statistically significant (P < 0.05). Protein and mRNA level of CXCR3 in ITP group were 3.0 and 3.5 times as high as those in control group, respectively. Those of CCR5 in ITP group were 1.2 and 1.7 times as high as those in control group, respectively. CONCLUSION: High expression of CXCR3 and CCR5 may play a part in the splenic immune disorders in patients with ITP.

[In vitro activation of bone marrow natural killer T cells of aplastic anemia patients].

OBJECTIVE: To investigate the quantitative and qualitative changes of TCRVα24(+)Vß11(+) natural killer T (NKT) cells from bone marrow (BM) of aplastic anemia (AA) after in vitro stimulation of α-galactosylceramide (α-Galcer). METHODS: NKT cells in the bone marrow mononuclear cells (BMMNCs) from either AA patients or healthy controls were enumerated with flow cytometry. BMMNCs were cultured in RPMI1640 medium supplemented with either α-Galcer and rhIL-2 or α-Galcer, rhIL-2 and rhG-CSF. The proliferative capacity of NKT cells was determined by NKT cell numbers before and after in vitro culture. Expression of intracellular IFNγ and IL-4 in activated NKT cells was analyzed with flow cytometry. RESULTS: In AA group, the percentage of NKT cells in BMMNCs was (0.19 ± 0.09)%. Addition of rhG-CSF into the α-Galcer/rhIL-2 culture medium resulted in significantly reduced expansion of NKT cells (67.45 ± 29.42-fold vs 79.91 ± 40.56 fold, P < 0.05). Meanwhile, addition of rhG-CSF reduced IFNγ positive NKT cells \[(37.45 ± 7.89)% vs (62.31 ± 14.67)%, P < 0.01\] and increased IL-4 positive NKT cells \[(55.11 ± 12.13)% vs (27.03 ± 9.88)%, P < 0.01\]. In healthy control group, the percentage of NKT cells in BMMNCs was (0.25 ± 0.12)%. Addition of rhG-CSF into the α-Galcer/rhIL-2 culture medium also significantly reduced expansion of NKT cells (97.91 ± 53.22-fold vs 119.58 ± 60.49-fold, P < 0.05), reduced IFNγ positive NKT cells \[(28.65 ± 10.63)% vs (50.87 ± 12.66)%, P < 0.01\], and increased IL-4 positive NKT cells \[(66.53 ± 14.96)% vs (31.11 ± 10.07)%, P < 0.01\]. CONCLUSION: Compared to those from healthy controls, BMMNCs from AA patiants have a reduced fraction of NKT cells, which possesses a decreased potential to expand in vitro in response to α-Galcer stimulation, and produce more IFNγ(+) NKT1 cells. rhG-CSF, in combination with α-Galcer, confers polarization of NKT cells towards IL-4(+) NKT2 subpopulation.

Predictors of hepatic steatosis in HBeAg-negative chronic hepatitis B patients and their diagnostic values in hepatic fibrosis.

OBJECTIVE: To investigate predictors of hepatic steatosis in HBeAg-negative chronic hepatitis B (CHB) patients and their diagnostic values in hepatic inflammation and fibrosis. METHODS: A total of 106 HBeAg-negative CHB patients with clinically and pathologically proven steatosis and 98 patients without steatosis were recruited into this study. The levels of fasting blood glucose (FBG), fasting insulin (FINS), triglyceride (TG), cholesterol (CHOL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (Alb), globulin (Glb), HBV DNA, body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR) and pathological changes of the liver in inflammation, fibrosis and fatty deposition were examined in all patients. RESULTS: The levels of BMI, HOMA-IR, FBG, insulin, TG, and CHOL were significantly higher in patients with steatosis than those without steatosis (all P<0.05). But ALT, AST and HBV DNA levels were significantly lower in patients with steatosis (all P<0.05). Logistic regression analysis showed that only FINS was a significant predictor for hepatic steatosis (P<0.05); FINS and Glb were significant predictors for hepatic inflammation (all P<0.05); BMI and TC were significant predictors for hepatic fibrosis (all P<0.05). CONCLUSIONS: Hepatic steatosis, a common disease in HBeAg-negative CHB patients, was positively associated with BMI, FBG, FINS, TG, TC, GGT, ALP and HOMA-IR. In these patients, the prevalence of hepatic inflammation and fibrosis was also increased.

Cyclic adenosine monophosphate signal pathway in targeted therapy of lymphoma.

OBJECTIVE: To review the role of cyclic adenosine monophosphate (cAMP) signal pathway in the pathogenesis of lymphoma and explore a potential lymphoma therapy targeted on this signaling pathway. DATA SOURCES: The data cited in this review were mainly obtained from the articles listed in Medline and PubMed, published from January 1995 to June 2009. The search terms were "cAMP" and "lymphoma". STUDY SELECTION: Articles regarding the role of the cAMP pathway in apoptosis of lymphoma and associated cells and its potential role in targeted therapy of lymphoma. RESULTS: In the transformation of lymphocytic malignancies, several signal pathways are involved. Among of them, the cAMP pathway has attracted increasing attention because of its apoptosis-inducing role in several lymphoma cells. cAMP pathway impairment is found to influence the prognosis of lymphoma. Targeted therapy to the cAMP pathway seems to be a new direction for lymphoma treatment, aiming at restoring the cAMP function. CONCLUSIONS: cAMP signal pathway has different effects on various lymphoma cells. cAMP analogues and phosphodiesterase 4B (PDE4B) inhibitors have potential clinical significance. However, many challenges remain in understanding the various roles of such agents.

[Effects of PML-RARalpha on cAMP-induced AML cell differentiation].

To explore the molecular mechanisms of acute promyelocytic leukemia cell differentiation induced by cAMP combined with low-dose As2O3, the PR9 cell line, which was stably transfected by PML-RARa fusion gene, was used as in vitro model. The effects of PML-RARa on cAMP-induced AML cell differentiation were evaluated according to cell growth, cell morphology, cell surface antigen as well as luciferase reporter gene assay, in the cells before and after the treatment with cAMP and/or As2O3. The results showed that cAMP alone could slightly increase the expression of CD11b in the PR9 cells expressing the PML-RARa fusion protein, but could not induce these cells to differentiate. The cells presented the terminal differentiation morphology and significantly increased CD11b expression only under the treatment of cAMP combined with As2O3. In addition, PML-RARa had strong inhibitory activity on the transcription of the reporter gene containing cAMP response elements. In conclusions, the PML-RARa fusion protein could dramatically block the signaling pathway of cAMP during the AML cell differentiation.

[Expression of specific antibodies against platelet glycoproteins in patients with mds and its significance].

The aim of this study was to find platelet specific autoantibodies against glycoproteins in myelodysplastic syndrome (MDS) and to explore its role in pathogenesis of MDS. The plasma autoantibodies against GP IIb/IIIa and GP Ib/IX were measured by using a modified monoclonal antibody specific immobolization platelet antigens assay (MAIPA). Absorbance greater than mean value plus tripled standard deviation recorded from the normal controls were regarded as positive. The results indicated that the total positive rate in patients with MDS was 16.67% (5/30), the total positive rate in patients with ITP was 46.67% (14/30), the difference between MDS group and ITP group was significant (P < 0.05). It is concluded that partial patients with MDS have plasma specific autoantibodies against platelet GP II b/III a and GP Ib/IX, indicating correlation of thrombocytopenia of patients with immune factors and the autoantibody-mediated platelet destruction may be involved in the pathogenesis of MDS. It provides a new basis for immunosuppression therapy for MDS.

RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins.

The RIG-G gene, originally isolated from an acute promyelocytic leukemia cell line NB4, codes for a 60-kDa cytoplasmic protein that is induced by all-trans retinoic acid (ATRA) treatment along with the induction of morphological differentiation of NB4 cells. Here, we provide evidence that ectopic expression of Rig-G in U937 cells can lead to a significant accumulation of cells at G(1)/S transition. Growth arrest seems to occur by modulating several major cell cycle regulatory players. Interestingly, Rig-G alters JAB1 cellular distribution through interacting with this protein and increases the intracellular level of p27 by preventing it from the JAB-1-dependent and ubiquitin/proteasome-mediated degradation. Furthermore, we demonstrate a role of Rig-G for c-myc down-regulation that results in an up-regulation of p21, tightly associated with cell cycle arrest. In addition, our studies reveal that Rig-G is a direct target of STAT1, a key transcription factor in regulating IFN responses, and may be one of the first experimentally proven molecular mediators for the antiproliferative effect of IFN-alpha. Considering that IFN-alpha and ATRA synergistically inhibit growth along the intracellular pathways triggered by the two compounds in many cell types, we suggest that Rig-G may also represent one of the key molecular nodes of signaling cross-talk between ATRA and IFN-alpha.

[Activation of adenylate cyclase influences the sensitivity of acute promyelocytic leukemia cell lines to ATRA].

OBJECTIVE: To explore the molecular mechanism of APL cell resistance to ATRA. METHODS: The ATRA sensitive and resistant APL cell lines, NB4 and NB4-R1, were used as in vitro models. The effects of specific inhibitors and activators of adenylate cyclase (AC) and phosphodiesterase (PDE) on ATRA-induced differentiation was evaluated by cell morphology, cell surface antigen expression and nitroblue-tetrazolium (NBT) reduction assays. RESULTS: SQ22536, a specific antagonist of AC, could dramatically block ATRA-induced NB4 cell differentiation. When ATRA + SQ22536 group compared with ATRA group, the positivity of CD11b decreased from (95.9 +/- 2.5)% to (60.3 +/- 7.1)%, while the A(540) in NBT reduction assay decreased from 0.585 +/- 0.092 to 0.170 +/- 0.028 (P < 0.05). Forskolin, an agonist of AC, could overcome the resistance of NB4-R1 cells to ATRA. When ATRA + forskolin group compared with ATRA group, the positivity of CD11b increased from (34.3 +/- 5.3)% to (94.6 +/- 2.4)%, while the A(540) in NBT reduction assay increased from 0.110 +/- 0.028 to 0.395 +/- 0.049 (P < 0.05). In contrast, the specific antagonist and agonist of PDE, 3-isobutyl-1-methylxanthine (IBMX) and calmodulin, exerted little impact on ATRA treatment. CONCLUSIONS: The defaults in the initiation of AC activation may contribute to the resistance to ATRA in some APL cells.