Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) are elevated in advanced stages of non-Hodgkin's lymphomas

Abstract: The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in 116 patients with non-Hodgkin's lymphomas (NHL) tested previously for soluble intercellular adhesion molecule-1 (sICAM-1). In contrast to Hodgkin's disease and chronic lymphocytic leukaemia, the sVCAM-1 levels in NHL patients were not significantly different from the levels of healthy controls (n = 31). However, sVCAM-1 was elevated in advanced stage disease, i.e. stages III + IV. Elevated serum levels of sVCAM-1 were associated with significantly poorer disease-free (p = 0.024) and overall (p = 0.02) survival. sVCAM-1 correlated poorly with other known prognostic variables (LDH, sTK and β₂m) and with sICAM-1. None of the tested markers added prognostic information for disease-free survival independently of Ann Arbor stage and B-symptoms. The expression of VCAM-1 and ICAM-1 in tumour biopsies from 15 patients representing 7 different histologies were examined and compared with the serum levels of the soluble adhesion molecules. No correlation was found between the adhesion molecule expression by vascular endothelium and the corresponding serum levels.     

Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) are elevated in advanced stages of non-Hodgkin's lymphomas

The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in 116 patients with non-Hodgkin's lymphomas (NHL) tested previously for soluble intercellular adhesion molecule-1 (sICAM-1). In contrast to Hodgkin's disease and chronic lymphocytic leukaemia, the sVCAM-1 levels in NHL patients were not significantly different from the levels of healthy controls (n = 31). However, sVCAM-1 was elevated in advanced stage disease, i.e. stages III + IV. Elevated serum levels of sVCAM-1 were associated with significantly poorer disease-free (p = 0.024) and overall (p = 0.02) survival. sVCAM-1 correlated poorly with other known prognostic variables (LDH, sTK and beta 2m) and with sICAM-1. None of the tested markers added prognostic information for disease-free survival independently of Ann Arbor stage and B-symptoms. The expression of VCAM-1 and ICAM-1 in tumour biopsies from 15 patients representing 7 different histologies were examined and compared with the serum levels of the soluble adhesion molecules. No correlation was found between the adhesion molecule expression by vascular endothelium and the corresponding serum levels.     

Elevated serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) closely reflect tumour burden in chronic B-lymphocytic leukaemia

The present study is the first to report elevated serum levels of soluble (s)VCAM-1 in B-cell chronic lymphocytic leukaemia (B-CLL). A large cohort of 106 untreated patients was studied. sVCAM-1 was compared to known prognostic serum markers (soluble (s)ICAM-1; lactate dehydrogenase, LDH; sCD23; thymidine kinase, TK; β2microglobulin, β2m). The serum levels of sVCAM-1 reflected tumour burden as expressed by Binet/Rai stages more closely than any other marker. sVCAM-1 also reflected the kinetics of the disease as revealed by lymphocyte doubling time. sVCAM-1 was the only one of the studied markers which showed elevated levels in smouldering disease compared to controls. sVCAM-1, sICAM-1 and sCD23 (but not LDH, TK, β2m) separated smouldering from non-smouldering B-CLL. Only sICAM-1, sCD23 and TK added independent prognostic information for survival to that of stage and lymphocyte doubling time.
The expression of both adhesion molecules was examined in lymph node and splenic specimens. VCAM-1 and ICAM-1 were overexpressed by vascular endothelium and stroma, but the intensity of expression correlated poorly with serum levels of the soluble molecules.
In conclusion, serum levels of sVCAM-1 correlated with tumour burden and other prognostic markers in B-CLL. VCAM-1 was overexpressed in tumour tissue as was ICAM-1. sVCAM-1 could prove a valuable marker in younger early-stage patients eligible for therapeutic trials.     

Soluble intercellular adhesion molecule-1 (sICAM-1) in patients with systemic lupus erythematosus

Summary Circulating sICAM-1 is known to be elevated in various inflammatory disorders. It is further suggested that elevated levels correlate well with disease activity in several autoimmune disorders. The objectives of this study are to determine the serum sICAM-1 levels in patients with systemic lupus erythematosus (SLE) and correlate sICAM-1 levels with clinical and laboratory (ESR, CRP, anti-dsDNA) measures of disease activity. Forty-one patients (34 female, 7 male) all fulfilling 1982 ARA classification criteria for SLE and 16 healthy controls (8 female, 8 male) were included in the study. Disease activity was measured according to SLEDAI. sICAM-1 was determined by ELISA. Mean sICAM-1 in SLE patients (339±161 ng/ml) were significantly higher than in the controls (216±85 ng/ml) (p<0.005). Although slightly elevated in active patients, there was no statistically significant difference between mean sICAM-1 levels of active and inactive SLE patients (349±183 ng/ml and 316±103 ng/ml respectively) (p>0.05). We could not find a correlation between sICAM-1 levels and any organ involvements. Similarly, no significant correlation was found between ESR, CRP, anti-ds-DNA and sICAM-1. These results suggest that although higher than normal, sICAM-1 levels in SLE do not provide additional information over conventional activity markers.     

Hodgkin's disease and age

506 unselected, previously untreated patients with Hodgkin's disease were treated at the Finsen Institute between 1969 and 1983. The prognostic significance of age, sex, stage, systemic symptoms, histologic subtype, number of involved nodal regions, total tumour burden (peripheral + intrathoracic nodal tumour burden, intraabdominal nodal tumour burden, and number of involved extranodal sites), pretreatment ESR, lymphocytopenia, and treatment modality were examined in multivariate analyses. The only factors of independent prognostic significance for disease-free survival proved to be treatment modality, stage, and total tumour burden, whereas age had no prognostic significance. With regard to death from Hodgkin's disease only age and total tumour burden had independent significance. The significance of age would seem to stem from the fact that some older patients could not be given adequate treatment for relapse. The present study indicates that Hodgkin's disease in older patients is not prognostically very different from Hodgkin's disease in younger patients.     

Soluble adhesion molecules ICAM-1, VCAM-1, P-selectin in children with Helicobacter pylori infection

AIM: To assess the sICAM-1, sVCAM-1, and sP-selectin levels in children with Helicobacter pylori (H pylori) infection and to evaluate their significance for the morphological changes found in gastric mucosa. METHODS: The study included 106 children: 59 children (55.7%) with chronic gastritis and positive IgG against H pylori, 29 children (27.3%) after previous H pylori infection without the bacterium colonization but with positive IgG against H pylori, and 18 children (17%) with functional disorders of the gastrointestinal system but with normal IgG against H pylori. Endoscopic and histopathological evaluation of gastric mucosa was performed based on the Sydney System classification. The evaluation of sP-selectin, sICAM-1, sVCAM-1 levels in the sera of children was carried out using ELISA test. RESULTS: The assessment of gastritis activity degrees indicated statistically significant values in the antrum and corpus (P＜0.001) of children examined. Serum sVCAM-1 levels were higher in group with gastritis due to H pylori infection than in group without infection and differed statistically (P＜0.05). Serum sVCAM-1 levels proved to be the highest among other adhesive molecules in infected children and decreased after eradication of H pylori. Serum sICAM-1 levels were similar in all examined groups. Serum sP-selectin levels were similar in children with and without H pylori infection. CONCLUSION: Assessment of adhesive molecules (sP-selectin, sICAM-1, sVCAM-1) in the sera of children with active H pylori infection can show the participation of sVCAM-1 in the pathogenesis of gastric mucosal inflammation. sP-selectin and sICAM-1 concentrations in the sera of children with H pylori infection after eradication cannot reveal any significant differences as compared to healthy children.     

Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement

Systemic sclerosis (SSc) is a chronic, multisystemic, autoimmune disease characterised by vascular changes and varying degrees of fibrosis of the skin and visceral organs. Organ systemic involvement in SSc is associated with an altered function of endothelial cells, perivascular infiltrating mononuclear cells and interstitial fibrosis. To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were determined by an enzyme-linked immunosorbent assay in 31 SSc patients and in 30 healthy controls. In comparison with the control group, higher serum concentrations of sVCAM-1, sE-selectin, VEGF and ET-1 were detected in SSc patients (in all cases p<0.001). Elevated concentrations of sVCAM-1 (p<0.05), sE-selectin (p<0.05), VEGF (p<0.05) and ET-1 (p<0.01) dominated in the serum of SSc patients with organ systemic involvement compared to those without systemic manifestation of the disease. These results suggest that the serum levels of sVCAM-1, sE-selectin, VEGF and ET-1 may reflect the extent of internal organ involvement in SSc patients and point to a pathogenic role of these molecules in systemic manifestation of the disease.     

冠心病可溶性细胞间黏附分子-1的检测 及其临床意义

目的　检测冠心病患者可溶性细胞间黏附分子-1(sICAM-1)的变化,探讨其在冠心病发病机理、病情监测中的意义。方法　用酶联免疫吸附法检测50例急性心肌梗死(AMI)、50例不稳定性心绞痛(UA)、30例稳定性心绞痛(SA)、30例健康者血浆sICAM-1水平。结果　AMI、UA、SA患者sICAM-1水平均较正常对照组高,且三组间差异有显著性。AMI患者按心功能分组,各组间差异亦有显著性(P均<0.05)。结论　sICAM-1可能参与了冠心病的发病过程,它可作为病情监测的指标。     

Depressed NK cell activity of peripheral blood mononuclear cells in untreated Hodgkin's disease: Enhancing effect of interferon in vitro

Natural killer (NK) cell activity of unseparated peripheral blood mononuclear cells from 30 untreated patients with Hodgkin's disease and 22 age- and sex-matched normal controls was evaluated using the classical K 562 cells as targets. A significant defect was demonstrated in the patients with stage I-II and seemed to be more profound in patients with advanced disease (stage III-IV) and in those with B symptoms. The differences between subgroups of patients, however, were not statistically significant, mostly because of the wide dispersion of individual data. Pre-incubation of effector cells with alpha A leucocyte recombinant interferon led to a clear increase in NK cell activity in 4 of 6 patients tested, showing that depressed NK activity in Hodgkin's disease is still susceptible to the enhancing effect of interferon, at least in some patients.—     

Prognostic factors in Hodgkin's disease stage III with special reference to tumour burden

143 patients with Hodgkin's disease stage III (65 PS III, 78 CS III) were treated with radiotherapy alone (33 patients), combination chemotherapy alone (56 patients), or radiotherapy plus combination chemotherapy (54 patients). They were followed till death or from 7 to 191 months. Prognostic factors including treatment, peripheral + intrathoracic tumour burden (assessed by combining tumour size in each involved region with number of involved regions), intraabdominal tumour burden (assessed by combining size of lymphographically involved lymph nodes in each region with number of lymphographically involved regions), histologic subtype, B-symptoms, number of involved regions, mediastinal involvement, pretreatment ESR, sex, age, laparotomy, and substage were examined in multivariate analysis. With regard to disease-free survival, total tumour burden (intraabdominal and peripheral + intrathoracic) emerged as the only pre-treatment factor of independent prognostic significance. With regard to overall survival the only factor of independent significance apart from age turned out to be intraabdominal tumour burden. The results of the present study thus support recently published findings regarding early stage disease to the effect that tumour burden is the single most important prognostic factor in Hodgkin's disease.     

Instability of dinucleotide repeats in Hodgkin's disease

Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor suppressor genes. However, the investigation of genomic instability of microsatellites has disclosed a new mechanism for human carcinogenesis, which is involved not only in hereditary nonpolyposis colon cancer (HNPCC) but in a number of other malignancies as well. To determine whether microsatellite instability is involved in Hodgkin's disease, we screened 16 such tumors using 7 microsatellite marker loci on 6 chromosome arms 4, 5, 9p, 9q, 11, 14, and 17. Using the polymerase chain reaction method, DNA samples from the tumors and from normal peripheral blood leukocytes from each patient were compared for the allelic pattern produced at each locus. Five cases of genomic instability were identified, suggesting that this mechanism is relevant to the pathogenesis of HD. Am. J. Hematol. 57:148–152, 1998. © 1998 Wiley-Liss, Inc.     

Prognostic factors in Hodgkin's disease stage IV

104 patients with previously untreated Hodgkin's disease stage IV were examined and treated at the Finsen Institute between 1969 and 1983. 99 patients were treated with combination chemotherapy (MOPP or equivalent regiments) with or without additional irradiation of some involved areas. Prognostic factors including age, sex, peripheral plus intrathoracic nodal tumour burden, intraabdominal nodal tumour burden, B-symptoms, histologic subtype, number of involved nodal regions, mediastinal involvement, number of involved extranodal sites, type of extranodal involvement, ESR, and haematologic and other blood values, together with exploratory laparotomy and treatment were examined in multivariate analyses. With regard to disease-free survival, the only factors of independent prognostic significance were sex and lymphocytopenia. With regard to overall survival the factors of independent significance were age, sex, bone marrow involvement, and an elevated serum creatinine. If only deaths of Hodgkin's disease were considered in overall survival, both lymphocytopenia and bone marrow involvement had independent prognostic significance. These two factors thus emerged as the most important prognostic factors in disseminated Hodgkin's disease, and both would appear to be related to the patient's total tumour burden.     

Secondary T-cell lymphoma in the setting of nodular lymphocyte predominance Hodgkin's disease.

Lymphocyte predominance Hodgkin's disease (LPHD) can be histologically subdivided into a nodular and diffuse variety. The two subtypes differ in immunophenotypic characteristics but have a similar long-term clinical outcome. Nodular LPHD has immunophenotypic and histological characteristics suggestive of a B-cell derived neoplastic process. Nodular LPHD is associated with an increased risk of secondary large cell lymphoma (LCL). Gene rearrangement studies in some of these cases have revealed a B-cell clonal process, further supporting the association between nodular LPHD and the B-cell system. In addition, it has been suggested that the apparent secondary LCL, at least in some cases, may represent a histologic progression of nodular LPHD. We report a unique case of T-cell lymphoma, confirmed by T-cell receptor gene rearrangement studies, which developed in the setting of nodular LPHD. Our observation demonstrates that the association of nodular LPHD and LCL is complex and that LCL developing in the context of nodular LPHD may be an independent secondary process sometimes involving T-cell lymphomas.     

胃肿瘤患者循环可溶性细胞间粘附分子-1和血管细胞粘附分子-1

AIM To elucidate the biological and clinical significance of sICAM-1 and sVCAM-1 in patients with gastric cancer.METHODS The serum levels of soluble ICAM-1 and VCAM-1 were measured with sandwith enzyme immunoassay.RESULTS In gastric cancer patients, soluble ICAM-1 and VCAM-1 concentrations were significantly elevated in comparision with those of healthy subjects (289.23μg/L±32.69μg/L vs 190.44μ/L±35.92μg/L,1430.88μg/L±421.71μg/L vs 727.24μg/L±157.68μg/L, respectively, P＜0.01). The increment in serum sICAM-1 and sVCAM-1 concentrations correlated well with the staging of gastric cancer. The serum levels of sICAM-1 and sVCAM-1 in patients of Ⅲ-Ⅳ stages were higher than those of Ⅰ-Ⅱ stages (346.60μg/L±92.10μg/L vs 257.54μg/L±32.77μg/L, 1800.60μg/L±510.76μg/L vs 1262.81μg/L±236.73μg/L). The levels of sICAM-1 and sVCAM-1 were correlated significantly (r=0.49,P＜0.01). The sICAM-1 and sVCAM-1 levels correlated positively with alkaline phophatase (r=0.63,0.71,P＜0.001) and white cell count (r=0.52,0.43, P＜0.01); but correlated negatively with serum albumin (r=-0.41, -0.49, P＜0.01).CONCLUSION The measurement of circulating ICAM-1 and VCAM-1 may bring additional prognostic information for patients with gastric cancer in varying stages.INTRODUCTIONTumor growth and metastasis involves a variety of cell-cell and cell-extracellular matrix interactions mediated by cell adhesion molecules. Currently, a number of cell adhesion molecules, such as intercellular adhesion molecules-1 (ICAM-1), vascular cell adhesion molecules-1 (VCAM-1), etc. have been found.ICAM-1 and VCAM-1 are members of the immunoglobulin supergene family which are cytokine-induced glycoproteins (IL-1, TNFα and IFNγ). Both of them have five or seven extracellular immunoglobulin-like domains, a single transmembranous domain and a short cytoplasmic tail[1,2]. The natural ligand of ICAM-1 or VCAM-1 is LFA-1 (CD11a) and Mac-1 (CD11b) or VLA-4, respectively[3]. ICAM-1 is a widely distributed protein on a variety of tissues, and can be detected in many cells such as macrophage, T- and B-cells, or fibroblasts, endothelial and epithelial cells. VCAM-1 is also a widely distributed protein and is constitutively expressed on tissue macrophage, dentritic cells in lymphoid tissue and skin, as well as on bone marrow fibroblasts and epithelial cells. Expression of VCAM-1 is inducible on vascular endothelial cells under pathological conditions[4].Recently, soluble forms of several adhesion molecules including ICAM-1 and VCAM-1 were found in serum of normal donors[5]. Abnormally high levels of them have been described in some solid malignant tumors, leukemia, autoimmune disease, infectious disease, etc.The present study was carried out to measure the circulating levels of sICAM-1 and sVCAM-1 in gastric cancer before treatment was given and to study their correlation with clinical, histological and routine laboratory parameters.     

Natural killer cell activity in Hodgkin's disease patients undergoing radiation therapy or chemotherapy and radiation therapy

Natural killer (NK) cell activity in peripheral blood mononuclear cells (PBMCs) from patients with Hodgkin's disease was studied using 4 h ⁵¹Cr release assay and K562 cells as sensitive targets. PBMCs were obtained from 15 previously untreated patients at different stages of their disease. PBMCs were also obtained from 46 patients treated by radiation therapy or combined chemotherapy and radiation therapy. Twenty healthy age-matched volunteer donors were used as controls to the treated patients. For these normal donors the mean cytotoxicity was 24.8 ± 5.67% at a 100:1 effector-target cell ratio; and 43.7 ± 12.1% for the treated cancer patients. Fifteen healthy age-matched volunteer donors were used as controls to the untreated patients. The mean cytotoxicity for these normal donors was 20.8 ± 3.61% at a 100:1 effector-target cell ratio; and 37.6 ± 6.65% for the previously untreated cancer patients. The mean cytotoxicity for all 35 normal donors was 23.1 ± 5.22% at a 100:1 effector-target cell ratio. Most treated patients (93.5%) had a complete response to therapy and a significant difference was found between the mean cytotoxicity of the whole group (46 treated patients), compared with controls (P < 0.001). A significant difference (P < 0.05) was also observed when the same 11 patients were studied before and after treatment.     

Hodgkin's disease stages I and II with infradiaphragmatic presentation: A rare and prognostically unfavourable combination*

Out of 323 patients with Hodgkin's disease CS I or II treated during the period 1969 to 1983 at Denmark's Finsen Institute, 35 presented with infradiaphragmatic disease. Patients with infradiaphragmatic presentation were older than patients with supradiaphragmatic presentation and were more often in stage II as opposed to stage I. NS histology was less prevalent among infradiaphragmatic than among supradiaphragmatic patients. Disease-free survival and overall survival was poorer in infradiaphragmatic patients. When other factors of prognostic importance were taken into account in a multivariate analysis, infradiaphragmatic presentation turned out to be an adverse prognostic factor with regard to disease-free survival, whereas it was not of significant independent prognostic value with regard to overall survival. Staging laparotomy in 11/35 infradiaphragmatic patients revealed 1 stage-IV case. The 34 remaining early stage patients were treated by irradiation plus combination chemotherapy (21 patients), irradiation only (9 patients), or combination chemotherapy only (4 patients). They were followed until death or from 4 to 171 months after initiation of therapy. With regard to disease-free survival, combined modality treatment (as opposed to radiotherapy only) was found to be of prognostic significance.     

Gallium scanning in the management of mediastinal Hodgkin's disease

Gallium-67 scanning was performed pre- and post-therapy in 25 patients with Hodgkin's disease and a mediastinal mass. At restaging after therapy, radiographs (or CT scans) did not predict the presence of active disease whereas gallium scans did with a high degree of accuracy. Gallium-67 determined disease activity in those patients who had a residual mediastinal mass predicting outcome in 11 out of 12 patients; one had a late relapse at 7 years. In patients without a residual mass gallium scanning was again accurate, predicting outcome in 11 of 13 patients. Two patients with negative gallium scans but subsequent active disease were scanned too soon after chemotherapy. The results suggest that gallium scanning has an important role in the management of mediastinal Hodgkin's disease and is superior to all current methods of assessing disease activity irrespective of the presence of a residual mediastinal mass.     

糖尿病患者血清可溶性细胞间粘附分子-1和可溶性血管细胞粘附分子-1变化的研究

目的　研究糖尿病患者血清可溶性细胞间粘附分子 - 1(s ICAM- 1)和可溶性血管细胞粘附分子 - 1(s VCAM- 1)水平的变化。方法　应用酶联免疫吸附法 (EL ISA)检测了 18例 1型糖尿病和 47例 2型糖尿病患者及 2 0例健康对照者的血清 s ICAM- 1、s VCAM- 1以及甘油三酯 (TG)水平。结果　 1血清 s ICAM- 1和 s VCAM- 1水平 ,1型、2型糖尿病患者组均显著高于健康对照组 (P<0 .0 5～ 0 .0 1) ,2型糖尿病有微血管病变组又高于无微血管病变组 (P<0 .0 5～ 0 .0 1) ,1型糖尿病与 2型糖尿病组之间无显著性差异 ;2血清 s VCAM- 1水平 ,2型糖尿病的高甘油三酯血症组 (A组 )、高甘油三酯血症合并高血压组 (B组 )高于单纯高血压组 (C组 )和甘油三酯、血压正常组 (D组 ) (P均 <0 .0 5 ) ;3 1型糖尿病和 2型糖尿病患者血清 s ICAM- 1和 s VCAM- 1之间均呈正相关关系 (r=0 .83、0 .5 3,P均 <0 .0 1)。结论　 12型糖尿病患者血清 s VCAM- 1升高与高甘油三酯血症有关 ;2血清 s ICAM- 1和 s VCAM- 1参与了糖尿病微血管病变的发病过程 ,并可作为糖尿病病情变化的监测指标     

Study of HLA antigens in patients with Hodgkin's disease

This paper studies relations of 21 HLA antigens of the A and B loci to selected characteristics in a group of patients with Hodgkin's disease. The investigated characteristics are age, sex, histological patterns, clinical stage and symptomatology. The considered group consists of 68 patients, 37 males and 31 females aged from 19 to 66 years and from 26 to 63 yr, respectively. A comparison between antigen frequencies for patients and controls (301 unrelated blood donors) is carried out. The results confirm that there is no relation between HLA antigens and Hodgkin's disease. A significant increase of A11 is found for females under 40 yr. Certain HLA antigens show significant correlation neither with the patient age nor with clinical or histological stages. A significant increase of B5 is observed for 16 relapsed patients. For them, significant test characteristics are found in the presence of cross-reacting HLA-B5, B35.     

sICAM-1、sVCAM-1在急性动脉硬化性脑梗死中的临床意义

目的:探讨可溶性细胞间黏附分子-1(sICAM-1)及可溶性血管细胞间黏附分子-1(sVCAM-1)在急性动脉硬化性脑梗死中的临床意义。方法:研究对象分为急性脑梗死组(n=60例)及对照组(n=28例),检测所有受试者血清sICAM-1、sVCAM-1水平,分析二者与脑梗死面积及临床转归之间的关系。结果:急性脑梗死患者血清sICAM-1、sVCAM-1水平显著高于对照组(P<0.01),二者与梗死面积大小呈正相关;而不同转归组之间二者含量无显著差别。结论:sICAM-1、sVCAM-1参与脑梗死炎症过程,可预示脑梗死严重程度。