Serum-soluble fas level determines clinical symptoms and outcome of patients with aggressive non-Hodgkin's lymphoma

Soluble Fas (sFas) blocks apoptosis induced by Fas ligand in vitro. The serum concentration of sFas is elevated in lympho-proliferative diseases. We hypothesized that higher levels of sFas worsen the clinical symptoms and outcome of patients with aggressive non-Hodgkin's lymphoma (NHL). We prospectively measured the serum concentrations of sFas in 67 consecutive patients with aggressive NHL (59 with diffuse large cell lymphoma and 8 with diffuse small cleaved cell lymphoma). sFas was significantly elevated in patients with aggressive NHL compared to healthy controls (N = 36, P< 0.005), while sFas in patients with B symptoms (4.20 +/- 2.12 microg/l) was significantly higher than in those without B symptoms (2.66 +/- 1.08 microg/l, P < 0.005). No significant difference was observed between B-cell lymphoma and T-cell lymphoma or between patients with clinical stage I or II and those with clinical stage III or IV. Significant correlations were found between sFas concentration and both soluble interleukin-2 receptor (R = 0.400, P < 0.001) and C-reactive protein (R = 0.340, P < 0.01) levels in patients with aggressive NHL. No correlation was observed between sFas and either white blood cell count or lactate dehydrogenase. Generalized Wilcoxon analysis revealed that NHL patients with sFas less than 4 microg/l had better overall survival than those with sFas above 4 microg/l (P < 0.001). The serum concentration of sFas might be associated with clinical symptoms and the prognosis of patients with aggressive NHL.     

Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma

Angiogenesis is a crucial process in the progression of multiple myeloma (MM). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are multifunctional cytokines that potently stimulate angiogenesis including tumour neovascularization. Serum levels of VEGF and HGF were measured in 52 patients with MM by enzyme-linked immunosorbent assay (ELISA). Serum levels of VEGF and HGF were elevated in MM patients compared with healthy controls (VEGF: mean 0.31 ng/ml and 0.08 ng/ml respectively, P < 0.01; HGF: mean 2.17 ng/ml and 0.45 ng/ml, respectively, P < 0.001). In serial samples taken after chemotherapy, serum VEGF and HGF levels were correlated with M-protein levels. Serum levels of VEGF were higher in patients with extramedullary plasmacytomas than in patients without them (P < 0.05). They were also significantly higher in a group of patients who showed poor response to chemotherapy (P < 0.01). Serum levels of HGF were higher in patients with complications such as anaemia, hypercalcaemia and amyloidosis than in patients without these complications (P < 0.01, P < 0.05, P < 0.05 respectively). Both serum VEGF and HGF levels were significant predictors of mortality (P = 0.01, P = 0.02, respectively, log-rank test). The present study demonstrated that serum levels of VEGF and HGF are significantly elevated and dependent on the severity of MM, suggesting that measurement of VEGF and HGF may be useful for assessing disease progression and for predicting the response to chemotherapy in MM patients.     

Hepatocyte growth factor in myeloma patients treated with high-dose chemotherapy

Hepatocyte growth factor (HGF) is a cytokine produced by myeloma cells. We examined serum HGF levels in a population of young myeloma patients (median age 52 years) treated with high-dose chemotherapy. Sera from 128 myeloma patients at diagnosis and serial samples from 16 patients were analysed. Compared with 62 healthy controls, HGF was elevated at diagnosis in 25% of patients (median 0.48 and 1.08 ng/ml respectively; P < 0.0001). The 95 patients who completed therapy were analysed for the impact of HGF on survival. Median survival was not reached after 77 months in the patient group with normal HGF values (< 1.7 ng/ml, n = 69). In the group with elevated HGF (>/= 1.7 ng/ml, n = 26), median survival was 63 months (P = 0.08). In 16 patients, serum was drawn at diagnosis and at the time of expected disease remission (6 weeks to 3 months after chemotherapy). HGF values declined after treatment in 14 of these patients, from a median of 0.9 ng/ml (0.49-1.65) to 0.42 ng/ml (0.32-0.73) (P = 0.005). Our results show that in young myeloma patients HGF is elevated, and that patients with higher levels had a trend towards poorer prognosis. Treatment with high-dose chemotherapy reduced HGF in the serum of the majority of patients.     

High prevalence of occult hepatitis B virus infection in patients with B cell non-Hodgkin’s lymphoma

Several reports recently found that patients with B cell non-Hodgkin's lymphoma (NHL) had a higher carrier rate of hepatitis B surface antigen (HBsAg). The current study aimed to examine the hepatitis B virus (HBV) infection status of NHL patients in Taiwan, an HBV-endemic area. Serum HBV and serum hepatitis C virus were measured in 471 NHL patients and 1,013 non-lymphoma cancer patients enrolled between February 2000 and March 2007. Furthermore, nested polymerase chain reaction of HBV-DNA was used to examine the sera from selected patients in these two populations and healthy volunteers for the presence of occult HBV infection. The infection rates (as indicated by the rates of HBsAg and occult HBV) were compared between different groups. There was a higher incidence of HBV infection in B cell NHL patients (23.5%), especially patients with diffuse large B lymphoma, than solid tumor patients (15.6%, P = 0.001). Among HbsAg-negative patients, those with B cell NHL had a higher prevalence of occult HBV infection (6%) than those with non-lymphoma solid tumors and healthy volunteers, 0% and 0.9%, respectively (P = 0.005). B cell NHL patients, even HBsAg-negative B cell NHL patients, but not T cell NHL patients, have a higher incidence of HBV infection than patients with solid tumors. Our findings support the etiologic role of HBV infection in B cell NHL.     

Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma

Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL-6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I-III (p=0.02) and were significantly elevated in stage II-III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post-treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo-therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.     

非霍奇金淋巴瘤患者sVEGF和sbFGF水平的变化及临床意义

目的:研究非霍奇金淋巴瘤(NHL)患者血清血管内皮生长因子(sVEGF)及血清碱性成纤维细胞生长因子(sbFGF)水平与临床特征的关系,探索其临床意义.方法:ELISA法检测36例不同病期NHL患者sVEGF、sbFGF水平,并收集临床资料,进行统计分析.结果:NHL患者sVEGF、sbFGF水平明显高于对照组(均P＜...     

Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) is a common hepatic malignancy worldwide. Its nature of rapid growth results in a grave prognosis. Hepatocyte growth factor (HGF) is a mitogen for hepatocytes, responsible for their proliferation. The aim of the present study was to investigate the prognostic roles of serum HGF in untreated HCC patients.Methods Fifty-five patients with inoperable HCC were studied. The diagnosis of HCC was based on either liver histopathology or imaging evidence of a liver mass, together with elevated serum alpha-fetoprotein. Serum HGF levels of the patients, at the time of diagnosis, were compared to those of 28 healthy controls. All patients received only palliative treatments and were followed up until they died. Comparison of survival curves between patients with a serum HGF level of 1.0ng/ml or more and those with lower serum HGF was performed, using the log-rank test. Data values are expressed as means and SD.Results Fifty-one men and four women with inoperable HCC were recruited. The mean age was 54.15 ± 15.34 years. The serum HGF levels in the inoperable HCC patients were significantly higher than those in the controls (0.58 ± 0.43 vs 0.14 ± 0.04ng/ml; P < 0.001). The patients mean survival time was 5.28 ± 6.73 months (range, 0.1–33 months). Serum HGF levels exhibited a negative correlation with the survival time (P = 0.032). In addition, HCC patients with serum HGF levels of 1.0ng/ml or more had a shorter survival time than the other HCC patients (P = 0.0025).Conclusions Patients with inoperable HCC had higher levels of serum HGF than the healthy controls, and serum HGF was negatively correlated with the survival time. Serum HGF levels of 1.0ng/ml or more in HCC patients are suggestive of a grave prognosis, indicating that HGF plays important and active roles in the disease progression. The detailed mechanisms need to be further investigated.     

Prognostic value of serum IL-10 and soluble IL-2 receptor levels in aggressive non-Hodgkin's lymphoma

Summary We investigated the prognostic significance of interleukin-10 (IL-10) and soluble interleuckin-2 receptor (sIl-2r) levles in the pretreatment serum of 105 individuals with newly-diagnosed aggressive non-Hodgkin's lymphoma (NHL). Commercially available enzyem-linked immunoassay kits were used for cytokine and receptor measurements. Detectable levels of IL-10 were found in 42 (40%) patients at diagnosis, with no correlation with clinico-haematological parameters, but in no control samples (P < 0.001).
Pretreatment concentrations of sIL-2r were markedly increased in individuals with NHL when compared to controls (2614 ± 893 U/ml v 219 ± 65U/ml, P < 0.001), patients with stage III/IV presenting higher values than those with stage II disase (3885 ± 1196U/ml v 1732 ± 646U/ml, P < 0.001). No single parameter was associated with the achiveement of complete remission, but the combination of elevated IL-10 and of sIL-2r greater than 3000U/ml selected a subset of patients with a high probability of failing induction therapy (P < 0.001). Lifetable analysis also indicated thatj patients with these characteristics have a significantly shorter event-free survival. In a multivariate analysis the combination of IL-10 with sIL-2r was found to have greater predictive strength than the combination of IL-10 with β₂-micro-globulin. We conclude that IL-10 and sIL-2r measurements can be expected to improve existing methods of risk assignment in aggressive NHL.     

Prognostic significance of hepatocyte growth factor and c-MET expression in patients with diffuse large B-cell lymphoma

The expression and prognostic significance of hepatocyte growth factor (HGF) and its receptor c-MET (MET proto-oncogene) was analysed in 96 cases of diffuse large B-cell lymphoma (DLBCL). Tissue sections were immunohistochemically stained for HGF and c-Met. The prognosis of HGF-positive and c-Met-positive cases was significantly worse than negative cases (HGF: P = 0.0036; c-Met: P = 0.0002). In addition, in the low-risk international prognostic index group, HGF-negative and c-Met-negative cases had a significantly better prognosis than positive cases (HGF: P = 0.0009; c-Met: P < 0.0001). Our results suggest that HGF/c-MET is a useful clinical marker of prognosis for patients with DLBCL.     

非霍奇金淋巴瘤患者血清LDH与β2-MG检测及其临床意义

目的探讨非霍奇金淋巴瘤（NHL）患者血清乳酸脱氢酶（LDH）及β2-微球蛋白（β2-MG）水平检测与临床诊断、分期及治疗效果的关系。方法筛选32例初诊为NHL患者为观察组,其中Ⅰ期5例,Ⅱ期7例,Ⅲ期9例,Ⅳ期11例。以35名健康体检者为正常对照组。全部入组对象均采集清晨空腹静脉血检测LDH、β2-MG值。结果 （1）NHL血清LDH及β2-MG水平明显高于对照组（P〈0.01）;（2）Ⅲ＋Ⅳ期患者血清LDH及β2-MG水平明显高于Ⅰ＋Ⅱ期患者（P〈0.01）;（3）化疗2个疗程后,其血清LDH及β2-MG水平较治疗前明显降低（P〈0.01）。结论血清LDH及β2-MG水平检测可作为NHL诊断、分期、疗效评估的参考指标。     

Clinical significance of serum neuron-specific enolase in patients with adult T-cell leukemia

The present study examines the clinical significance of serum neuron-specific enolase (NSE) in patients with adult T cell-leukemia (ATL). Serum NSE values were measured using a radioimmunoassay in 35 patients (acute type, n = 15; lymphoma type, n = 10; chronic type, n = 10) and in 7 controls carrying T lymphotropic virus type-1 (HTLV-1). Serum NSE values >10 ng/mL were detected in 9 of 15 patients with acute type (60%), 5 of 10 with lymphoma type (50%), and in one of 10 patients with chronic type (10%) ATL, but in none of the HTLV-1 carriers. Contrary to previous findings demonstrating that 20% of patients with non-Hodgkin's lymphoma (NHL) had positive serum NSE, the frequency of a high NSE value in patients with acute and lymphoma type ATL was much higher (60% and 50%, respectively). The serum NSE value positively correlated with serum thymidine kinase activity (TK) and serum soluble interleukin-2 receptor (sIL-2R) levels (P < 0.04 and P < 0.01, respectively). Serum NSE values at the initial diagnosis were adversely related to overall survival time according to the log-rank test (P < 0.02). Pathological examinations demonstrated that both patients with anaplastic large cell lymphoma type ATL had cytoplasmic NSE and CD30 markers on cell membranes. These findings suggest that serum NSE is partially produced by ATL cells and that ATL tumor cells seem preferentially produce NSE compared with other NHL cells. Serum NSE may be a novel marker of disease aggressiveness as well as a prognostic factor for ATL.     

Detection of membrane and soluble interleukin-6 receptor in lymphoid malignancies

Summary. We studied the membrane expression of the gp80 chain of IL-6 receptor (IL-6R) by quantitative flow cytometry in chronic lymphocytic leukaemia (CLL) and leukaemic centrocytic lymphoma using a panel of seven monoclonal antibodies. IL-6R was detected in 18/26 CLL cases and 4/7 lymphoma cases, with a mean antigen density <3000 molecules/cell. Multiple labelling experiments confirmed the IL-6R expression by neoplastic cells. Specific mRNA was found by RT-PCR in neoplastic cells. A specific ELISA test was designed using two anti-IL-6 receptor MAbs to measure the serum soluble IL-6R (sIL-6R) in CLL (n = 48), B-cell non-Hodgkin's lymphoma (NHL; n = 40), and monoclonal gammopathy (MG; n = 32). SIL-6R was higher in CLL (170±12.6ng/ml) in NHL (160 ± 12ng/ml) and MG patients (183±23ng/ml) than in age-matched controls (100 ±5.6 ng/ml; P < 0.001) and higher in high-grade than low-grade NHL. No correlation was noted with a previous treatment. Among CLL cases the patients classified as stage B according to the Binet's staging of the disease had the highest sIL-6R values, thus suggesting a link with tumour cell mass.     

Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkin's lymphoma

Therapeutic approaches for non-Hodgkin's lymphoma (NHL) are currently based on the International Prognostic Index (IPI). Research on biological prognostic factors has been actively pursued in recent years, with serum vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) being identified as prognostic factors for NHL. Here, we determined that serum VEGF and IL-6 levels are independent prognostic factors for aggressive lymphoma. Compared with normal controls, serum VEGF and IL-6 levels were significantly higher in patients with aggressive lymphoma or adult T-cell leukemia/lymphoma. Furthermore, overall and disease-free survival rates for patients with high levels of VEGF or IL-6 were significantly poorer than for patients with low levels. In addition, the prognosis for patients with high levels of both serum VEGF and IL-6 was significantly poorer than that for patients with high levels of either VEGF or IL-6 or with low levels of both VEGF and IL-6. Multivariate analyses of a variety of prognostic factors, including the five IPI factors, revealed that serum VEGF and IL-6 were both independent prognostic factors for overall survival of aggressive lymphoma. Therefore, a combination of VEGF and IL-6 represents a useful prognostic factor for aggressive lymphoma.     

脑梗死急性期患者血清肝细胞生长因子含量的动态变化

目的探讨肝细胞生长因子(HGF)在老年急性脑梗死患者血清中的含量变化及临床意义。方法选择72例急性脑梗死患者为脑梗死组,根据梗死灶体积大小又分为3个亚组:小梗死灶组(22例)、中梗死灶组(30例)和大梗死灶组(20例);根据神经功能缺损程度分为轻型21例、中型31例和重型20例。另选择同期健康体检者20例为对照组。采用ELISA法测定脑梗死组患者发病第1、3、7、10天血清中HGF的水平,对照组第1天采血测定。结果脑梗死组患者血清HGF水平在发病第1天即升高,第7天最高,各时间点水平均高于对照组(P<0.01);HGF水平在轻、中、重型之间及小、中、大梗死灶各亚组之间比较,差异均有统计学意义(P<0.05)。结论脑缺血后HGF在大脑的表达上调,HGF作为神经营养因子可能参与了脑缺血后脑损伤的修复过程。     

Circulating levels of TNF alpha and TNF receptor superfamily members in lymphoid neoplasia

We have correlated the serum levels of TNF alpha and soluble TNF receptor superfamily members with clinico-pathologic parameters in patients of Hodgkin's disease (HD, N = 26) and non-Hodgkin's lymphoma (NHLs, N = 35). HD patients had significantly higher levels of TNF alpha, sTNFRI, and sTNFRII in serum while NHL patients had significantly higher levels of sTNFRI, sTNFRII, sCD27, and sFas as compared to controls. In NHL patients the levels of sCD27 correlated directly and significantly with the high-stage disease, bone marrow involvement, lymph nodal presentation, and serum LDH levels. Similarly in NHL patients, levels of sFas also correlated directly and significantly with the presence of high stage disease. HD patients with B symptoms had significantly higher levels of sTNFRII.     

多种血液肿瘤中NK细胞受体表达差异的临床意义

目的：检测几种血液肿瘤患者中自然杀伤（NK）细胞受体变化，以探究NK细胞功能状态。方法：收集多发性骨髓瘤（MM）患者38例，其中IgG-k型18例、IgG-λ型10例、IgA-k型4例、IgA-λ型6例；非霍奇金淋巴瘤（NHL）患者27例，其中弥漫性大B细胞淋巴瘤18例、边缘区淋巴瘤3例、滤泡性淋巴瘤1例、套细胞淋巴瘤2例、免疫母性T细胞淋巴瘤1例、外周T细胞淋巴瘤2例；慢性髓系细胞白血病（CML）患者10例；30例健康志愿者为正常对照组。通过流式细胞术测定外周血中NK细胞占有核细胞比例，用实时荧光定量聚合酶链反应（RT-qPCR)方法检测NK细胞表面抑制性受体（PD-1）及活化性受体（CD69、NKG2D）的基因表达水平。结果：与正常对照组比较，MM、NHL患者外周血NK细胞占有核细胞比例比较，差异无统计学意义（P均＞0.05）；而CML患者NK细胞占有核细胞数显著减少（P＜0.05）；MM、NHL及CML患者的NK细胞表面活化性受体（CD69、NKG2D）水平较正常对照组明显降低，NK细胞表面抑制性受体（PD-1）表达显著高于正常对照组（P均＜0.05）；MM、NHL及CML患者间受体(PD-1、CD69、NKG2D)表达比较，差异无统计学意义（P均＞0.05）。结论：MM、NHL及CML患者外周血NK细胞表面活化性受体（CD69、NKG2D）水平明显降低，抑制性受体（如PD-1）表达明显增高，提示NK细胞功能耗竭。     

Hepatitis C virus in non-Hodgkin's lymphoma. A reappraisal after a prospective case-control study of 300 patients. Lombart Study Group of HCV-Lymphoma

It is widely thought, but not yet explained, that there might be a pathogenetic link between the infection of hepatitis C virus (HCV) and the onset of B non-Hodgkin's lymphoma (NHL). We studied the prevalence of serum anti-HCV antibodies among 300 NHL comparing it with the prevalence among 600 age- and sex-matched non-neoplastic subjects as controls, 247 patients with non-lymphomatous neoplasm, and 122 patients treated with immunosuppressive agents. We found a prevalence of 0.16 among NHL and 0.085 among controls and non-lymphomatous patients. Although the difference was statistically significant (P < 0.001), the odds ratio was 2.049 and its confidence intervals included the equality. The HCV prevalence was independent of NHL subset, and the genotypes distribution was the same among NHL and controls. We disclosed a HBsAg prevalence of 0.077 in NHL versus 0.008 in controls (P < 0.001) with an odds ratio of 9.9. We do not believe that these findings support the hypothesis of an HCV pathogenetic role in lymphomagenesis because (i) the risk of previous infection is marginally higher in NHL than in controls, (ii) a typical genotype distribution is lacking, as is a NHL clinico-histological feature associated with HCV, and (iii) the higher prevalence of viral infection is not specific as witnessed by the high HBsAg prevalence.