Soluble interleukin-6 receptor as a prognostic factor in multiple myeloma

Interleukin-6 (IL-6) is a major growth factor for the clonal malignant plasma cells in multiple myeloma (MM). The effect of IL-6 may be enhanced by soluble IL-6 receptor (sIL-6R). As there is a clinical need for improved stratification of MM patients at diagnosis, we have studied the role of sIL-6R as a prognostic marker in 207 newly diagnosed MM patients. Serum sIL-6R concentration was above the upper reference limit in 47% of the patients at diagnosis. The concentrations of sIL-6R and two other prognostic factors, IL-6 and β-2 microglobulin (β2M), were all significantly higher in the patients who died within 3 years compared with those who survived. However, serum sIL-6R did not show linear correlation with IL-6 or β2M levels. In univariate logistic regression analysis sIL-6R was a significant predictor of 3-year mortality. Kaplan-Meier analysis showed that raised levels of sIL-6R were associated with shorter survival. When the patients were stratified into four groups according to their serum IL-6 and sIL-6R levels, the patients with normal serum levels of both parameters had clear survival benefit. As β2M was the most powerful prognostic factor in the multivariate analysis, the patients were also stratified according to their serum β2M and sIL-6R levels. The patients with raised levels of both β2M and sIL-6R had shorter survival than the patients in the other three groups. Thus, measurement of these parameters at diagnosis would help to stratify MM patients.     

Serum oncostatin M in multiple myeloma: impact on disease severity and prognosis

Since high levels of serum IL-6 predict a poor prognosis of patients with multiple myeloma (MM), we investigated if a related cytokine, oncostatin M (OSM), correlates with clinical or biochemical findings or has prognostic significance in patients with MM. Among 82 newly diagnosed MM patients, OSM was detected in the sera in 45 (55%). Serum OSM had a borderline statistical correlation with serum IL-6 (r = 0.198, p = 0.074) and C-reactive protein (r = 0.199, p = 0.074) concentrations. However, OSM did not have prognostic significance alone or in combination with other factors. The median survival of patients with detectable serum OSM concentration was 41 months (range 2-124 months) and of OSM negative patients 35 months (1-75 months). Serum OSM concentration was not associated with clinical factors or severity of bone disease at diagnosis. We conclude that serum OSM concentration is not a prognostic factor in MM patients.     

Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Finnish Leukemia Group

High serum level of bioactive interleukin-6 (IL-6) is regarded as a predictor of poor prognosis in multiple myeloma (MM). On the other hand, the reported levels of immunoreactive IL-6 have been highly variable, and the prognostic value of immunoreactive IL-6 in MM is not clear. We have analyzed the prognostic significance of serum immunoreactive IL-6, as measured by a sensitive immunosorbent assay, in 210 patients with newly diagnosed MM subsequently treated with intermittent melphalan and prednisone. The serum levels of acute phase proteins C-reactive protein (CRP), alpha 1-antitrypsin (alpha 1AT), and acid alpha 1-glycoprotein (orosomucoid; OM) were evaluated as surrogates for IL-6. Serum IL-6, CRP, alpha 1AT, and OM levels were raised in 42%, 40%, 41%, and 24% of the patients, respectively. There was a significant correlation between the clinical stage of the patients and serum IL-6 (P = .006), alpha 1AT (P = .001), and OM (P = .004) levels at diagnosis. At 3 years, 52% of the patients were alive. Univariate logistic regression analysis showed that high levels of IL-6 (P = .002), CRP (P = .02), alpha 1AT (P < .001), OM (P = .007), beta 2- microglobulin (beta 2M; P < .001), and thymidine kinase (P < .05) were all associated with 3-year mortality. In multivariate regression analysis, beta 2M (P < .0001) and alpha 1AT (P = .01) had independent prognostic significance. The patients with high levels of both beta 2M and alpha 1AT or IL-6 were at very high risk of dying within 3 years from diagnosis (16% and 21% of the patients in these groups were alive, respectively). When the patients were stratified according to the clinical stage, the prognostic significance of serum IL-6 and alpha 1AT was especially evident in stage II patients. When the patients were divided into two groups according to normal or raised serum IL-6 levels, the patients with high IL-6 levels had more frequent osteolytic bone lesions (P = .03) and a more aggressive disease. We conclude that serum immunoreactive IL-6 is a significant prognostic marker in MM.     

Lamina propria and circulating interleukin-6 in newly diagnosed pediatric inflammatory bowel disease patients

OBJECTIVES: Understanding cytokine production patterns in early mucosal lesions of pediatric patients newly diagnosed with inflammatory bowel disease (IBD) may be critical to understanding IBD pathogenesis. Interleukin-6 (IL-6) has a central role in a multitude of immune system reactions; however, inconsistent lamina propria and serum IL-6 has been reported in IBD patients. Newly diagnosed pediatric IBD patients have not previously been evaluated for lamina propria or serum IL-6. METHODS: Serum and intestinal lamina propria biopsy whole organ culture supernatants were evaluated by ELISA for IL-6 obtained from newly diagnosed IBD patients, before initiation of immunomodulatory therapies. RESULTS: Levels of lamina propria IL-6 demonstrated significant correlation with graded severity of histological inflammation (p < 0.001). Log-transformed serum and organ culture IL-6 levels demonstrated significant correlation (p < 0.0001, R2 = 0.6226). Assigning a demarcation level of >400 pg/ml, serum IL-6 concentrations were a superior marker for the presence of microscopic intestinal inflammation than erythrocyte sedimentation rate (ESR), with a sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 82%. When evaluating subtypes of IBD, serum IL-6 levels were correlated more significantly with active disease in ulcerative colitis patients (p = 0.01, R2 = 0.74) than in Crohn's disease patients (p = 0.21, R2 = 0.33). CONCLUSIONS: This study outlines graded production of IL-6 in intestinal lamina propria and serum of newly diagnosed pediatric IBD patients, confirming the presence of IL-6 in early IBD patients. In addition, serum IL-6 may be a good predictor of IBD in pediatric patients with suspected or newly diagnosed IBD.     

Elevated serum concentration of hepatocyte growth factor in patients with multiple myeloma: correlation with markers of disease activity

Hepatocyte growth factor (HGF) has been shown to be involved in angiogenesis, epithelial cell proliferation, and osteoclast activation. HGF and its receptor are expressed on myeloma cell lines and could be involved in the pathogenesis of bone destruction in multiple myeloma (MM). The aim of this study was to examine serum levels of HGF in untreated MM patients and its correlation with bone turnover indices and markers of disease activity. Forty-seven newly diagnosed MM patients and 25 controls were included: 12 patients were of stage I, 13 of stage II, and 22 of stage III (Durie-Salmon classification). Bone lesions were scored from 0 to 3, according to X-ray findings. Serum osteocalcin (OC), interleukin-6 (IL-6), TNF-alpha, beta(2)-microglobulin (beta(2)M), CRP, calcium, and 24-hr urine N-telopeptide cross-links of collagen breakdown (NTx) were determined. HGF levels were significantly higher at stage III compared to stages II and I (medians: 1,990.4 vs. 1,743.8 and 1,432.4 pg/mL, respectively, P < 0.05). Similarly, NTx, IL-6, TNF-alpha, CRP, beta(2)M, and calcium increased significantly with advancing stage (P < 0.01). OC was higher at stage I in comparison to stages II and III (P < 0.01). All parameters were significantly higher in patients than controls. HGF showed a strong correlation with IL-6 and TNF-alpha and less with beta(2)M, CRP, NTx, and OC. We conclude that serum HGF levels are increased in advanced stages of MM disease and extended bone lesions. HGF correlates with IL-6 and TNF-alpha, which are cytokines involved in osteoclast stimulation in MM. However, an independent association of HGF with bone turnover markers was not shown in this study, thus its role in MM bone disease needs to be further clarified.     

Prognostic significance of serum cystatin C in multiple myeloma

Multiple myeloma (MM) is frequently complicated by renal insufficiency, which is associated with an unfavorable prognosis. Serum cystatin C is a new and accurate marker of glomerular filtration rate. Global gene expression analysis has revealed serum cystatin C as one of the most highly upregulated genes in MM. Recent data have shown serum cystatin C as an independent prognostic marker in MM. To further elucidate the prognostic significance of serum cystatin C, we investigated pretreatment serum cystatin C levels in 68 newly diagnosed patients homogeneously treated with high-dose melphalan followed by autologous stem cell transplantation. Median serum cystatin C level in MM patients was significantly higher than in the 66 healthy controls (1.07 vs. 0.74 mg/L [p = 0.002]). Median serum cystatin C levels significantly increased with higher International Staging System (ISS) stages (stage I 0.72 mg/L; stage II 0.89 mg/L; stage III 1.28 mg/L; p < 0.0001). Higher serum cystatin C was positively correlated with higher serum levels of creatinine (r = 0.84; p < 0.0001), β2-microglobulin (r = 0.72; p < 0.0001), LDH (r = 0.43; p = 0.0003), white blood cell counts (r = 0.61; p < 0.0001) and calcium (r = 0.29; p = 0.016), and negatively correlated with lower serum albumin levels (r = 0.44; p < 0.0001) and hemoglobin levels (r = 0.31; p = 0.01). Using ROC analysis, patients with serum cystatin C levels ≥0.95 mg/L (n = 24) had a significantly shorter event-free survival (EFS) and overall survival (OS) than patients with serum cystatin C levels <0.95 mg/L (median EFS: 26 vs. 44 months, p < 0.0001; median OS: 54 vs. 68 months, p = 0.05). Moreover, the combination of serum cystatin C level and genomic aberrations further refined the prognostic information (EFS and OS) provided by either one of the factors. The level of serum cystatin C is not only a sensitive marker of renal function, but also reflects tumor burden and delivers prognostic information in MM.     

Serum and in vitro production of IL-1 receptor antagonist correlate with C-reactive protein levels in newly diagnosed, untreated lupus patients

OBJECTIVE: To examine the correlation between C-reactive protein (CRP) and CRP-inducing cytokines (IL-1 beta, IL-6, TNF-alpha) and IL-1 receptor antagonist (IL-1ra), as well as to study their relationship with systemic lupus erythematosus disease activity (SLEDAI) in newly diagnosed, untreated lupus patients. METHODS: Sera from newly diagnosed untreated lupus and rheumatoid arthritis (RA) patients were examined for CRP and cytokines. Data were compared among patient groups and correlated individually among the lupus group. Lupus monocytes and neutrophils were cultured in vitro to produce IL-1ra and experimental results were related to CRP levels and SLEDAI. RESULTS: Within lupus, serum CRP, IL-6, IL-1 beta and TNF-alpha levels were significantly lower than those of RA (all p values were < 0.005) and generally higher than those in the controls (p = 0.002, < 0.001, > 0.2, and < 0.001, respectively). Except IL-1ra, which was correlated with CRP (p = 0.045), no substantial correlation was discovered between CRP and IL-6, IL-1 beta or TNF-alpha individually. Moreover, excluding IL-1ra (p = 0.024), there was no association between cytokines and SLEDAI. In vitro IL-1ra as secreted by monocytes correlated with serum CRP and SLEDAI. CONCLUSION: In lupus patients, serum IL-1 beta, IL-6 or TNF-alpha levels failed to correlate with low CRP levels. This indicates a complicated CRP production process, which can not be explained solely by single cytokines as reported previously. Both serum and in vitro produced IL-1ra may be applied clinically as a surrogate CRP marker in untreated lupus patients as they are both correlated with serum CRP.     

Clinical significance of sCD105 in angiogenesis and disease activity in multiple myeloma

BackgroundΤhe importance of angiogenesis in malignancies' growth is well recognized. CD105 (Endoglin), a proliferation-associated glycoprotein, is a powerful marker of neovascularization. Elevated amounts of solubleCD105 (sCD105) have been identified in selected solid tumors. The aim of the study was to estimate circulating levels of sCD105 and soluble transforming growth factor-β₁ (sTGF-β₁), in multiple myeloma (MM) patients, to determine their significance in tumor progression and to investigate the correlation between sCD105 and markers of disease activity.MethodsWe studied 50 newly diagnosed MM patients. Twenty-five of them were also investigated in plateauphase. Twenty patients with monoclonal gammopathy of undetermined significance (MGUS) were enrolled in this study. As control group 28 healthy persons were studied. We determined sCD105, sTGF-β₁ and interleukin-6 (IL-6) in the serum, Ki-67 proliferation index (Ki-67 PI) expression and microvascular density(MVD) in bone marrow with immunohistochemistry.ResultsThe mean concentrations of sCD105 and IL-6 were higher in MM and MGUS patients compared to controls, whereas serum levels of sTGF-β₁ were lower in MM patients compared to MGUS patients and controls. sCD105 levels, were significantly different among disease stages, with higher values in advanced stages. It was found that sCD105 correlated with Ki-67 PI, MVD and IL-6.ConclusionsCD105 seems to play an important role in angiogenesis and tumor progression. Circulating levelsof sCD105 could detect patients with more advanced disease and might help in evaluating the response to treatment.     

Serum immunoreactive interleukin-6 and C-reactive protein levels in patients with multiple myeloma at diagnosis

Summary Serum bioactive but not immunoreactive interleukin-6 (IL-6), and serum C-reactive protein (CRP), have been reported to be of prognostic significance in multiple myeloma (MM). We measured serum immunoreactive IL-6 by a sensitive enzyme-linked immunosorbent assay in 30 MM patients at diagnosis. In 30% of the patients serum immuno-reactive IL-6 exceeded the upper reference limit. The concentrations of CRP and IL-6 showed a linear association. Logarithmically transformed IL-6, CRP and β₂-microglobulin were significant variables by univariate survival analysis: by multivariate analysis CRP was a slightly stronger prognostic factor than IL-6 and the only one of independent prognostic significance.     

Clinical Features of Bone Complications and Prognostic Value of Bone Lesions Detected by X-ray Skeletal Survey in Previously Untreated Patients with Multiple Myeloma

Multiple myeloma is usually associated with the presence of lytic bone lesions. We reviewed the clinical and laboratory features of patients with newly diagnosed myeloma bone disease and evaluated the prognostic significance of different X-ray image patterns in symptomatic MM patients. We retrospectively reviewed 260 patients with newly diagnosed MM. X-ray image patterns of patients were correlated with hematologic parameters, therapeutic reaction and patient survival. Patients with the X-ray imaging pattern of grade 2–4 had significantly higher marrow plasma cells levels, marrow CD138⁺ D38⁺ cell percentage, ECOG performance score, and serum IL-6 level than grade 0–1. Univariate analysis demonstrated that skeletal lytic changes associated with rapid progression. There is a high incidence of myeloma bone disease (MBD) in patients of MM in China. Patients of extensive bone lesions have more severe alterations in hematologic parameters than do those without bone lesions and severe bone lesions is an important adverse prognostic factor associated with a short TTP.     

Serum level of interleukin-16 in multiple myeloma patients and its relationship to disease activity

Interleukin-16 (IL-16) is a chemoattractant of CD4+ lymphocytes, and it has been implicated in the pathogenesis of various inflammatory diseases. There is evidence that it may have a role in multiple myeloma (MM). In the present study, we determined the serum level of IL-16 both before and after treatment of MM and related it to inflammatory markers and survival. Forty-eight newly diagnosed MM patients were included in the study. Disease stage was defined using the Durie-Salmon classification system (10 patients were in stage I, 19 in stage II, and 19 in stage III). After standard treatment, 22 patients reached the plateau phase and were re-evaluated. The following serum parameters were measured: IL-16, IL-6, alpha-1 antitrypsin (alpha1AT), and C-reactive protein (CRP). Survival was determined as the number of months elapsed since original diagnosis. The mean +/- SD of serum IL-16 was 343 +/- 195 pg/ml in the pre-treatment MM group and 101 +/- 30 pg/ml in the control group. All measured parameters were higher in the patient group compared to healthy controls. Furthermore, IL-16, IL-6, alpha1AT, and CRP were significantly increased with increasing stage of disease, from stage I to stage III (P<0.01). All parameters decreased significantly following effective chemotherapy (P<0.002). Patients with a high level of IL-16 (>430 pg/ml) displayed an inferior survival time in comparison to those with lower levels of IL-16. In the pre-treatment group, IL-16 correlated with alpha1AT and IL-6 (r=0.374, P<0.01 and r=0.454, P<0.002, respectively). IL-16 may play a role in multiple myeloma; however, further functional studies are required.     

Diagnostic value of serum IL-6 level in monoclonal gammopathies

Summary. The serum level of IL-6 was reported to reflect disease severity in patients with multiple myeloma. We used a specific radioimmunoassay to measure the level of IL-6 in 239 serum samples in which a monoclonal gammopathy was identified for the first time. The same sample was used for the measurement of serum C reactive protein and serum albumin. Then, an inventory of clinical and biological features allowed us to classify these patients into five groups: monoclonal gammopathy of undetermined significance (MGUS: 128), multiple myeloma (MM:66), Waldenström's macroglobulinaemia (WM:27), non-Hodgkin's lymphoma (NHL: 11) and chronic lymphocytic leukaemia (CLL: 7). The number of patients with serum IL-6 (S-IL-6) level >0.335 ng/ml (upper limit in normal sera) was significantly higher in the MM group (35%; Confidence Interval (CI) 23.5–46.5) compared with the MGUS group (15%; CI 8.8–21.2). The distribution of S-IL-6 levels was also significantly different between the groups (Mann-Whitney test: P< 0.01). High S-IL-6 levels were measured in 5/11 patients with NHL and 9/27 patients with WM. The distribution of S-IL-6 levels in these groups was the same as that in MGUS or MM groups. In patients with MM, elevated S-IL-6 levels were associated with haemoglobin level <100 g/l (P< 0.005). bone marrow plasmocytosis >50% (P<0.05) and stages II and III in the Durie & Salmon staging system (P< 0.005). The S-IL-6 level was also related to light chain component excretion in urine (P<0.01) and M component serum level for IgA (P<0.01). In patients with MGUS, the S-IL-6 level correlated with serum CRP level (P<0.05). serum lactate dehydrogenase (P< 0.05) and serum ferritin (P < 0.01). We conclude that the S-IL-6 level is a marker of high tumour burden in multiple myeloma. However, S-IL-6 level can be increased in patients with MGUS in relation to inflammatory parameters. Therefore the S-IL-6 level does not demonstrate high predictive value for the diagnosis of MM in patients with newly identified monoclonal gammopathy.     

Serum levels of interleukin-1β and interleukin-6 in patients with chronic pancreatitis

To investigate the role played by cytokines in chronic pancreatitis, we examined serum levels of interleukin-1β (IL-1β) and interleukin-6 (IL-6) by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) in 33 patients with definitively diagnosed chronic pancreatitis. All the patients, who had received either no treatment or only digestive enzyme products for their chronic pancreatitis, had significantly elevated serum IL-1β levels (38.5±28.8pg/ml, mean ± SD), compared to normal controls (16.0±6.7pg/ml;P<0.01); however they showed no changes in serum IL-6 levels. Changes in IL-1β and IL-6 serum levels were not correlated with the etiological features of pancreatitis or with complications due to liver diseases. Serum IL-1β and IL-6 levels were also not correlated with the activity of any pancreatic enzymes in blood or urine. However, in the patients with chronic pancreatitis, serum IL-6 levels were correlated with C-reactive protein (CRP), whereas serum IL-1β levels were not correlated with CRP or with erythrocyte sedimentation rate. These results suggest that serum IL-1β is involved in the progression and reduction of chronic inflammation of the pancreas, and that the serum IL-1β level may be useful as a marker for chronic pancreastitis.     

Bone marrow megakaryocytes,soluble P-selectin and thrombopoietic cytokines in multiple myeloma patients

Abstract

The expression of adhesion molecules and other cell-surface molecules is substantial in the communication between plasma cells and bone marrow microenvironment, and may lead to increased proliferation of myeloma cells. Many of the cytokines involved in multiple myeloma (MM) pathogenesis, e.g. thrombopoietin (TPO) and interleukin-6 (IL-6), play a pivotal role in different developmental stages of megakaryocytopoiesis and thrombopoiesis. The principal aim of our study was to explore the relationship between thrombopoietic cytokines, megakaryocytes (MKs) and soluble P-selectin (sP-selectin) levels in MM patients before and after anti-angiogenic treatment. Forty-four patients (20 female and 24 male) with a newly diagnosed MM were examined in three groups, following a division based on the International Staging System, ISS. Plasma levels of TPO, IL-6 and soluble P-selectin (human sP-selectin) were measured by means of ELISA. Bone marrow specimens were studied to determine the number of MKs and the so-called “naked nuclei” (NN), as well as the expression of platelet-derived growth factor (PDGF). The comparison revealed a significantly higher concentration of cytokines and sP-selectin in newly diagnosed MM patients compared to healthy volunteers: for TPO, p?=?0.01, IL-6, p?=?0.0005 and sP-selectin, p?=?0.00008, respectively. Marked differences were observed in the concentration of sP-selectin, expression of PDGF and MKs counts between patients with MM stage I and MM stage III. Statistically meaningful correspondences were also found between MKs versus TPO, NN versus TPO, as well as MKs versus MPV, p?=?0.009, p?=?0.004 and p?=?0.0005, respectively. Furthermore, the analysis exhibited some statistically meaningful divergences between initial concentrations of sP-selectin in subgroups with different response after chemotherapy. The initial concentration of sP-selectin in the group of MM patients with complete or partial remission stood at 31.86?±?6.13?ng/ml. In the remaining patients (stable disease), the concentration of sP-selectin amounted to 35.15?±?7.23?ng/ml (p?=?0.048). We found a correlation between sP-selectin and IL-6 (ρ?=?0.57, p?=?0.0004), TPO and IL-6 (ρ?=?0.46, p?=?0.001) as well as sP-selectin and TPO (ρ?=?0.36, p?=?0.043), and sP-selectin and PDGF (ρ?=?0.36, p?=?0.03). Our study has eventually demonstrated that sP-selectin, as a marker of platelet activation, could be a useful marker of maximum response to therapy. Its strong association with another marker like PDGF-AB could further lead to the development of new combinational therapeutic strategies of anti-angiogenic therapy in MM patients.     

The prognostic value of serum albumin in healthy older persons with low and high serum interleukin-6 (IL-6) levels

OBJECTIVE: We sought to determine the prognostic value of serum albumin for 4-year mortality among high-functioning persons who did or did not have evidence of inflammation as indicated by high interleukin-6 (IL-6) levels. DESIGN: We used a case-cohort design of healthy, nondisabled older persons who had serum albumin and plasma IL-6 measured at baseline. Crude and multiply adjusted (for sociodemographics and chronic diseases) proportional hazards models were used to identify the effect of baseline levels of serum albumin level on 4-year mortality among those with higher and lower levels of IL-6. RESULTS: Among subjects without evidence of IL-6-mediated inflammation (IL-6 < 3.20 pg/mL), having a lower (< or = 4.4 g/dL) albumin level was associated with a multiply adjusted relative risk of 2.1 for 4-year mortality compared with those with higher albumin. In the presence of inflammation (IL-6 > or = 3.20 pg/mL), higher and lower serum albumin levels had similar risks (adjusted relative risks 4.0 and 3.8, respectively) compared with the referent group (higher albumin and low IL-6). CONCLUSIONS: High serum albumin has a protective effect in healthy older persons who do not have evidence of cytokine-mediated inflammation. This protective effect is not conferred in presence of inflammation. The mechanisms by which inflammation eliminates the protective effect of high albumin remain to be determined.     

Serum levels of interleukin-10 in patients with diffuse large cell lymphoma: lack of correlation with prognosis [see comments]

Interleukin-10 (IL-10), also known as cytokine synthesis inhibitory factor, has multiple effects on lymphoid development. In addition, it has been previously reported that serum levels of IL-10 correlate with failure-free and overall survival in patients with non-Hodgkin's lymphoma. In this study, we used a sensitive enzyme-linked immunosorbent assay specific for human IL-10 (lower limit of sensitivity, 5 pg/mL) to measure serum levels in 52 newly diagnosed patients with diffuse large cell lymphoma and at least one adverse prognostic feature who were subsequently treated in a uniform way. Lymphoma patients had significantly higher serum levels of IL-10 (median, 7.98 pg/mL; range, < or = 5 to 27,143 pg/mL) than healthy volunteers (N = 50; median, < or = 5 pg/mL; range, < or = 5 to 19.21 pg/mL) (P = .0000012). Individuals with B symptoms had significantly higher serum levels of IL-10 than those without them (P = .03), but there was no correlation between IL-10 levels and any of the other prognostic variables analyzed, including age, lactic dehydrogenase, beta 2-microglobulin levels, performance status, bulky disease, Ann Arbor stage, or International Index score. More importantly, we found no correlation between IL-10 levels and the achievement of complete remission, nor with failure-free survival or overall survival. We conclude that in a uniform population of untreated patients with diffuse large cell lymphoma, serum levels of IL-10 do not appear to have any prognostic value.     

Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization

Interphase fluorescence in situ hybridization (FISH) studies of chromosomal region 13q14 were performed to investigate the incidence and clinical importance of deletions in multiple myeloma (MM). Monoallelic deletions of the retinoblastoma-1 (rb-1) gene and the D13S319 locus were observed in 48 of 104 patients (46.2%) and in 28 of 72 (38.9%) patients, respectively, with newly diagnosed MM. FISH studies found that 13q14 was deleted in all 17 patients with karyotypic evidence of monosomy 13 or deletion of 13q but also in 9 of 19 patients with apparently normal karyotypes. Patients with a 13q14 deletion were more likely to have stage III disease (P =.022), higher serum levels of beta(2)-microglobulin (P =.059), and a higher percentage of bone marrow plasma cells (P =.085) than patients with a normal 13q14 status on FISH analysis. In patients with a deletion of 13q14, myeloma cell proliferation (Ki-67) was markedly increased (22.0% +/- 6.9% compared with 15.6% +/- 8.2% in patients without the deletion; P =.0008). Evaluation of bromodeoxyuridine incorporation in 5 patients revealed that both rb-1-deleted and rb-1-normal MM subpopulations were proliferative. The presence of a 13q14 deletion on FISH analysis was associated with a significantly lower rate of response to conventional-dose chemotherapy (40.8% compared with 78. 6%; P =.009) and a shorter overall survival (24.2 months compared with > 60 months; P <.005) than in patients without the deletion. Multivariate analysis of prognostic factors confirmed the independent predictive value of 13q14 deletions for shortened survival. In conclusion, deletions of 13q14 are frequently detected by interphase FISH in patients with newly diagnosed MM, correlate with increased proliferative activity, and represent an independent adverse prognostic feature in MM. (Blood. 2000;95:1925-1930)     

血清乳酸脱氢酶水平与初诊老年多发性骨髓瘤病人预后的相关性分析

目的探讨血清乳酸脱氢酶(LDH)与初诊老年多发性骨髓瘤(MM)临床指标的相关性及其预后意义。方法回顾性分析我院2009年7月至2016年1月年龄≥65岁的78例初诊老年MM病人的临床资料,并绘制病人的Kaplan-Meier生存曲线,分析初诊时血清LDH水平与病人预后的关系。根据病人的LDH水平分为LDH正常组和LDH升高组,并根据荧光原位杂交技术检测结果对60例资料完整的MM病人进行修正的国际分期系统(R-ISS)分期,比较其与国际分期系统(ISS)分期对预后判断的准确性。结果所有病人中位随访时间为16.5个月,初诊时LDH水平升高者占11.5%(9/78)。LDH正常组中位生存期(OS)和中位无进展生存期(PFS)分别为44.0个月、23.0个月,LDH升高组分别为14.0个月、12.0个月,2组间比较,差异有统计学意义(P<0.01)。COX多因素回归分析显示,LDH水平升高是老年MM病人OS的独立不良预后因素(HR=5.998,95%CI2.454~14.664,P<0.001)。另外,ISS分期Ⅱ期和Ⅲ期病人的中位OS差异无统计学意义(44.0个月比39.0个月,P=0.713),中位PFS差异也无统计学意义(26.0个月比20.0个月,P=0.569);而R-ISS分期Ⅱ期和Ⅲ期病人的中位OS差异有统计学意义(44.0个月比15.5个月,P<0.001),中位PFS差异无统计学意义(21.0个月比14.0个月,P=0.097)。结论LDH水平是判断老年MM病人预后的重要指标,基于其基础上的R-ISS分期在预后判断中要优于ISS分期。     

High levels of interleukin-6 are associated with low tumor burden and low growth fraction in multiple myeloma

Interleukin-6 (IL-6) is a multifunctional cytokine postulated to play a central role as a growth factor for multiple myeloma (MM). We evaluated the spontaneous secretion of IL-6 in supernatants of Ficoll-Hypaque-- enriched bone marrow (BM) cultures from 35 patients with MM. The levels of IL-6 were correlated with biological and clinical characteristics of the disease. High levels of IL-6 production defined a subgroup of patients with low tumor burden as determined by lower serum beta 2- microglobulin (B2M) (P = .02) and lower percentage of myeloma cells infiltrating the bone marrow (P = .003), higher synthetic rates of monoclonal protein (P = .006), and low proliferative compartments as measured by the percentage of Ki-67--positive myeloma cells. Patients with high proliferative fractions (Ki-67--positive myeloma cells > 20%) had significantly lower levels of IL-6 when compared with patients with low proliferative fractions (P = .005). Our findings do not support IL- 6 as a major growth factor for MM, but demonstrate an association of high levels of IL-6 secretion with low tumor cell burden and low proliferative fraction.     

Serial measurement of free light chain detects poor response to therapy early in three patients with multiple myeloma who have measurable M-proteins

Free light chain (FLC) assays are important in the diagnosis and monitoring of patients with multiple myeloma (MM). Serum FLC concentrations also correlate with disease course in the majority of MM patients and have been incorporated into the new response criteria. Although baseline values of FLC are prognostic in newly diagnosed MM, serial measurement of serum FLC does not appear to be of greater value in patients who have measurable M-proteins by electrophoresis. We examined the kinetics of serum FLC in six patients with newly diagnosed MM during treatment with high-dose dexamethasone (HD-DEX) and bortezomib and dexamethasone. In some cases, the involved serum FLC increased in the latter part of each chemotherapy cycle before the start of the next cycle, especially in HD-DEX, suggesting that the response to these agents may be insufficient for induction therapy for MM. Earlier disease assessment by serum FLC assays may be of value in detecting poorly responding patients who require alternative forms of therapy.