Serological evidence of Mycoplasma pneumoniae infection in patients with acute exacerbation of COPD: analysis of 100 hospitalizations.

PURPOSE: A prospective study was conducted in order to investigate the serologic evidence of Mycoplasma pneumoniae infection in Greek hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Furthermore, we have assessed the frequency of a number of variables in the group of patients with a serological diagnosis of an acute M. pneumoniae infection compared to patients in whom M. pneumoniae infection was not documented. MATERIALS/METHODS: One hundred patients with AECOPD were enrolled in a 29- month study period. Serum IgG, IgA and IgM M. pneumoniae antibody titers were determined during the first day of their hospitalization and 30 days after enrolment, using a commercial ELISA. RESULTS: Nine patients (9%) had serological evidence of an acute M. pneumoniae infection. Acute infection was mainly documented by IgA antibody titer changes. It was mainly attributed to a reinfection rather than a primary infection. Patients with serological evidence of an acute M. pneumoniae infection had a higher heart rate (99±12 versus 88±14 beats/minute, p=0.02) and a higher hematocrit value (47±4.5% versus 40.4±6.2%, p=0.004) at admission than patients without a serological diagnosis for this pathogen. CONCLUSIONS: Serologic evidence of M. pneumoniae infection is rather common in Greek hospitalized patients with AECOPD. The determination of all three antibody classes was necessary in order to obtain an optimal level of serodiagnosis. No differences were found in the majority of characteristics of patients with and without serological evidence for this pathogen. The clinical utility of these results should be further clarified in future studies.

Angiogenesis-related growth factors and cytokines in the serum of patients with B non-Hodgkin lymphoma; relation to clinical features and response to treatment.

Increased angiogenesis has been shown to be a feature of non-Hodgkin lymphomas (NHL). In the current study, the pretreatment levels of circulating molecules related to angiogenesis were determined in 49 B-cell NHL patients and correlated with histological grade, disease stage and prognostic score. In 25 patients, the same molecules were defined after standard treatment. Vascular endothelial growth factor (VEGF), angiogenin, interleukin-2 (IL-2), IL-6, IL-8 and IL-16 were measured. Increased levels of VEGF, IL-6 and IL-8 were found in the whole group of untreated patients in comparison with normal controls (P < 0.05), whereas, IL-2 was higher in the subgroup of indolent NHL. Overall, there was no significant decrease in the levels of these molecules after treatment. However, by stratification into group of responders vs. non-responders pretreatment IL-8 was significantly increased whereas IL-16 was decreased in the subgroup of complete responders. According to the REAL classification IL-2 was higher in the low risk compared with intermediate plus high-risk group. There was no association with disease stage or the International Prognostic Score. Both indolent and aggressive B cell lymphomas have increased production of angiogenic mediators and cytokines with IL-8 and IL-16 potentially reflecting the response to treatment.

Angiogenic molecules in Hodgkin's disease: results from sequential serum analysis.

Increased angiogenic activity has been demonstrated in lymphoproliferative diseases including Hodgkin's disease. In the current study, the levels of circulating angiogenic molecules in 60 Hodgkin's patients were determined prior to and after treatment and correlated to disease stage and prognostic score. Hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were increased in Hodgkin's patients in comparison to healthy controls (p<0.001). Angiogenin and angiopoietin-2 levels did not differ from controls. HGF, VEGF, TNF-alpha and angiogenin decreased significantly in Hodgkin's patients after standard treatment (p<0.001 for HGF, p<0.05 for VEGF, TNF-alpha and angiogenin). Furthermore, HGF and TNF-alpha increased with advancing stage of disease (p<0.05). HGF and VEGF correlated significantly with IL-6 (r=0.56, p<0.0005 and r=0.57, p<0.001 respectively). In conclusion, Hodgkin's disease displays an angiogenic activity as depicted by the increased serum levels of a number of angiogenic cytokines. HGF seems to be the prominent molecule in Hodgkin's disease, which may be used to monitor the disease status and the response to treatment.

Circulating soluble E-cadherin levels are of prognostic significance in patients with multiple myeloma.

BACKGROUND: The epithelial transmembrane molecule E-cadherin (E-Cad) is the prime mediator of epithelial cell-cell adhesion, through homotypic interactions. It also participates in the maintenance of cytoskeletal structure and cell-cell signalling, while there are no published reports of expression of E-Cad in non-epithelial tissues. We examined whether the circulating levels of soluble E-Cad in newly diagnosed patients with multiple myeloma (MM) are of prognostic significance. PATIENTS AND METHODS: We used an ELISA method to determine the levels of circulating soluble E-cadherin (sE-Cad) in 21 newly diagnosed patients with MM and in 29 healthy volunteers, as a control group. RESULTS: MM patients demonstrated increased circulating levels of sE-Cad, compared with controls (p<0.0001). Increased circulating sE-Cad levels correlated with LDH levels at diagnosis (p<0.001) and poor prognosis. Multivariate analysis demonstrated that sE-Cad levels are an independent prognostic factor of survival (p<0.0207). CONCLUSION: Our data suggest that adhesion molecules play a role in the pathogenesis of MM, establish sE-Cad as an independent marker of survival and, finally, provide evidence of non-epithelial production of E-Cad in MM patients.

Prognostic significance of soluble adhesion molecules in Hodgkin's disease.

BACKGROUND: Cell adhesion may play a pivotal role in the development, progression and metastasis of solid malignancies. We evaluated the serum concentration of four adhesion molecules and their prognostic significance in patients with Hodgkin's Disease (HD). PATIENTS AND METHODS: Serum samples from 20 HD patients were collected at diagnosis, after 3 cycles of chemotherapy and at completion of treatment and compared with a control group of 29 apparently healthy subjects. Soluble forms of E-Selectin (sE-Selectin), ICAM-1 (sICAM-1), VCAM-1 (sVCAM-1) and E-Cadherin (sE-Cad) were measured by standard ELISA assays. RESULTS: Significantly increased serum levels of sICAM-1 and sE-Selectin were determined in HD patients at diagnosis compared to controls (p<0.0001), while sVCAM-1 at diagnosis correlated significantly with both sICAM-1 and sE-Selectin levels (r=0.5, p=0.03). Chemotherapy resulted in a significant decrease of sICAM-1 and sE-Selectin levels (p=0.02 and p=0.002, respectively). CONCLUSION: Serum levels of ICAM-1 and E-Selectin in newly diagnosed HD patients were found significantly increased, suggesting a possible involvement of these two molecules in the pathogenesis of the disease. Their rapid decrease following chemotherapy was found to be an independent predictor of response to treatment.

Interleukin-18 in multiple myeloma patients: serum levels in relation to response to treatment and survival.

Interleukin-18 (IL-18) plays a role in the host's response to tumours and angiogenesis. We determined serum levels of IL-18, vascular endothelial growth factor (VEGF), angiogenin (ANG), tumor necrosis factor (TNF-alpha) and CRP in 65 newly diagnosed myeloma patients. IL-18, VEGF, angiogenin, TNF-alpha and CRP were significantly higher at stage III in comparison to stages II and I. These cytokines (measured in 27 patients) significantly decreased after treatment. In survival analysis, higher levels of IL-18 were associated with a poorer prognosis. We conclude that increased serum IL-18 in myeloma patients correlates with advanced disease, increased levels of angiogenic cytokines and worse survival.

Survival and prognostic factors after initiation of treatment in Waldenstrom's macroglobulinemia.

BACKGROUND: Waldenstrom's macroglobulinemia (WM) is an unusual lymphoplasmacytoid lymphoma characterized by the presence of a serum monoclonal immunoglobulin M. Although several studies have evaluated possible prognostic factors of this disease, few have focused on the survival and prognosis of symptomatic patients after the initiation of treatment. PATIENTS AND METHODS: Our study included 122 previously untreated patients with a median age of 67 years who required systemic treatment. Multiple variables were analyzed for their prognostic value on survival after initiation of treatment using univariate and Cox regression multivariate analysis. RESULTS: The median overall survival was 106 months. Pretreatment factors associated with shorter survival were age >/=65 years, splenomegaly, B-symptoms (weight loss, fever or night sweats), hemoglobin <10 g/dl, platelets <100 x 10(6)/dl, albumin <3.5 g/dl and bone marrow lymphoplasmacytic infiltrate >/=50%. In the multivariate analysis, the two variables with independent prognostic value were age >/=65 years and hemoglobin <10 g/dl. Furthermore, we were able to divide our patients into three risk groups based on the presence of two, one or none of these two adverse prognostic factors. The median survival times in the high-, intermediate- and low-risk groups were 46 months, 107 months and 172 months, respectively (P <0.0001). DISCUSSION: Our findings suggest that advanced age and anemia appear to be the two dominant prognostic factors for survival after initiation of treatment in patients with WM. These two readily available parameters can stratify the patients into three distinct subgroups and may help the selection of appropriate treatment.

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.

Relationship between circulating serum soluble interleukin-6 receptor and the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in multiple myeloma.

Angiogenesis plays an important role in multiple myeloma (MM) progression. Various mitogens such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) have been implicated in the angiogenic process of various malignancies. Interleukin-6 (IL-6) is a growth factor of myeloma cells and its signaling is mediated via a cell surface receptor complex (IL-6r). IL-6 and tumor necrosis factor-alpha (TNF-alpha) are involved in the secretion of VEGF by IL-6r expressing myeloma cells. In this study, serum FGF-2, VEGF, IL-6r, and TNF-alpha were measured in 46 untreated MM patients and were studied in relation to disease stage (by Salmon-Durie criteria) and severity [assessed by serum beta(2)-microglobulin (beta(2)M), C-reactive protein (CRP), alpha(1)-antitrypsin (alpha(1)AT), and lactic dehydrogenase (LDH) levels]. The results showed that FGF-2, VEGF, IL-6r, and TNF-alpha were significantly elevated in MM patients in comparison to controls ( p<0.008) and were significantly higher in stage III disease in comparison to stages I and II ( p<0.03). The mean concentrations of IL-6r were 877+/-374, 1220+/-308, 1431+/-878, and 453+/-180 pg/ml for stages I, II, and III and controls, respectively. Levels of beta(2)M, alpha(1)AT, CRP, and LDH were all significantly higher in MM patients than controls and increased with advancing stage of disease. There were positive correlations of both VEGF and FGF-2 with IL-6r, TNF-alpha, beta(2)M, alpha(1)AT, CRP, and LDH. We conclude that IL-6r and TNF-alpha increase in parallel to VEGF and FGF-2 with increasing stage of MM disease. These molecules correlate with biochemical markers of disease activity and may play a role in the progression of multiple myeloma.

The prognostic role of CD5 negativity in B-cell chronic lymphocytic leukaemia: a case-control study.

B cells in chronic lymphocytic leukaemia (CLL) usually express the CD5 antigen, which appears to participate in the pathogenesis of autoimmune phenomena. However, 7-20% of B-CLL patients are CD5-. The aim of this study was to assess whether CD5 expression could be used as a discriminating factor for two subgroups of B-CLL. Twenty-nine CD5- B-CLL patients were compared in terms of clinico-biological characteristics and survival with a control group of 29 sex- and age-matched, consecutive CD5+ B-CLL subjects. B-CLL was considered to be CD5- when less than 5% of mononuclear cells expressed CD5 after subtraction of the number of T cells. Splenomegaly, lymph node involvement, and haemolytic anemia were found in CD5+ patients in a significantly higher proportion than in their CD5- counterparts, who presented with an earlier stage of disease. CD5- patients had a median survival of 97.2 (22-130) months, exceeding CD5+ subjects significantly [84.0 (19-120) months, p = 0.0025]. CD5- patients seemingly present with milder disease and have a favourable prognosis compared with the vast majority of B-CLL patients who express CD5.

Soluble interleukin 2 receptors' levels versus thyroid hormones levels in nonthyroidal disease.

Serum soluble interleukin-2 receptor levels, basal thyrotropin, total thyroxine, total triiodothyronine and free triodothyronine were assayed in 29--otherwise healthy--patients with pulmonary tuberculosis before initiation of anti-tuberculosis treatment and after two weeks of therapy. Twenty seven out of 29 patients presented low-normal total triiodothyronine levels, showing a statistical elevation after anti-tuberculosis therapy. Total triiodothyronine levels before anti-tuberculosis therapy were inversely correlated with levels of serum soluble interleukin-2 receptors. Further investigation on the relationship between soluble interleukin-2 receptor's levels and thyroid hormones in non-thyroidal disease can be envisaged.

Mediastinal B-cell high grade non-Hodgkin's lymphoma with sclerosis: report of three cases.

Mediastinal large B-cell lymphomas are uncommon haematologic malignancies seen mostly in women. We report our recent experience with three patients, only one of whom survived after an autologous bone marrow transplantation.

Ulcerative colitis and Sjogren's syndrome in the same patient: report of two cases and a review of the literature.

Two cases of coexisting ulcerative colitis and Sjogren's syndrome are presented. Both patients were women and in both ulcerative colitis preceded the diagnosis of Sjogren's syndrome by several years. The course of ulcerative colitis before the onset of Sjogren's syndrome was quite severe. On the basis of clinical signs and serological and immunogenetic patterns, both patients were classified as suffering from secondary Sjogren's syndrome. Although the combination of the two diseases in the same patient seems to be the result of chance, we think that this combination offers an opportunity for future studies related to the pathogenesis of ulcerative colitis.

Inverse relationship between proliferation and differentiation in a human TNP-specific B cell line. Cell cycle dependence of antibody secretion.

Studies of an EBV-transformed and TNP-specific human B cell line revealed that, unlike myeloma or hybridoma cell lines that consist mainly of fully differentiated cells, most of the cloned EBV-transformed cells were not fully differentiated, as judged by inability to bind TNP-SRBC and to secrete anti-TNP antibody. The minority of more differentiated cells were selected by TNP-SRBC rosetting. They were found to proliferate to a lesser extent than nonrosetting cells and to contain increased numbers of antibody-secreting cells. This inverse relationship between proliferation and differentiation was also shown to be cell cycle related in that the TNP-SRBC rosetting cells resided, to a greater extent than the nonrosetting cells, in the G1 phase of the cell cycle. The finding that the G1 phase of the cell cycle was associated with differentiation into anti-TNP secreting cells was confirmed by demonstrating that treatment with hydroxyurea, which arrests the cells in G1, resulted in decreased proliferation and an increased proportion of antibody-secreting cells. Similarly, addition of phorbol ester resulted in increased antibody secretion and decreased proliferation, suggesting a role for protein kinase C in this differentiation pathway. The strategy of increasing the number of antibody-producing cells in this human EBV line, by promoting differentiation of the cells in G1, may be relevant to the large scale production of specific human mAb for the treatment and diagnosis of human diseases.

B-chronic lymphocytic leukemia. Prognostic implication of bone marrow histology in 120 patients experience from a single hematology unit.

The available staging systems for B-chronic lymphocytic leukemia (B-CLL) do not always predict the clinical course and the prognosis of the disease. In these systems, the pattern of bone marrow histology is not incorporated. In the current report we investigate the prognostic value of the diffuse or nondiffuse pattern of bone marrow involvement in 120 B-CLL patients in relation to their actuarial survival, and we compare these results with the actuarial survival based on the International Workshop system. In addition, we analyze the influence of the diffuse or nondiffuse pattern on the actuarial survival, in relation to the individual clinical stages (A, B, C). All patients were diagnosed and followed-up in the same Unit. Our patients were divided into Stage A (64), Stage B (22), and Stage C (34). They were also subdivided into those with a diffuse (46) and those with a nondiffuse (74) pattern of bone marrow histology. The difference in the actuarial survival in relation to their clinical stage (A, B, C) was statistically significant (P less than 0.025). A greater statistical difference (P less than 0.005) was found when the actuarial survival was analyzed in relation to the diffuse or nondiffuse pattern of bone marrow histology. No statistically significant differences could be found (P greater than 0.1), when the actuarial survival was calculated in every stage (A, B, C), on the basis of the diffuse or nondiffuse pattern of bone marrow histology. When our Stage A and B patients were analyzed for disease progression, in relation to the diffuse or nondiffuse bone marrow histology, it was found that 66.6% of the diffuse Stage A patients and 88% of the diffuse Stage B patients had disease progression as compared to only 8.6% for the nondiffuse Stage A patients and 33% for the nondiffuse Stage B patients. Our findings indicate that: the pattern of bone marrow histology in B-CLL patients is the single most important prognostic parameter in this disease; a clinicopathologic staging system for B-CLL may be justified; and the diffuse pattern of bone marrow histology could be considered as the best criterion for initiation of therapy in these patients.

Poly(A)-polymerase activity in chronic lymphocytic leukemia of the B cell type.

Poly(A)-polymerase enzymic activity was biochemically determined in lymphocytic extracts from 40 patients with chronic lymphocytic leukemia of the B cell type. The enzymic activities of patients with stage A, B and C disease were (U/mg of protein): 4.9 +/- 5.5, 12.5 +/- 7.5 and 20.9 +/- 18.9, respectively. The difference in the enzyme level between stage A and C patients was statistically significant (p less than 0.05). Comparison of the enzyme activity level in relation to the pattern of bone marrow involvement revealed that patients with a diffuse pattern of infiltration had a significantly higher enzyme level (17.9 +/- 15.5 U/mg of protein) than patients with interstitial or mixed infiltration patterns (5.9 +/- 6.6 and 7.9 +/- 7.0 U/mg of protein; p less than 0.025). Finally, patients who required treatment for their disease also had a significantly higher poly(A)-polymerase activity level (14.5 +/- 13.9 U/mg of protein) than patients with stable disease (4.9 +/- 5.5 U/mg of protein; p less than 0.05). Our results indicate that the enzyme poly(A)-polymerase may be used as a biological marker in patients with chronic lymphocytic leukemia.

Patterns of bone marrow involvement in chronic lymphocytic leukemia and small lymphocytic (well differentiated) non-Hodgkin's lymphoma. Its clinical significance in relation to their differential diagnosis and prognosis.

Forty-eight patients with chronic lymphocytic leukemia (CLL), and 12 patients with small (well differentiated) lymphocytic lymphoma (WDL) were histologically evaluated for their pattern of bone marrow (BM) involvement. Four different types of BM infiltration were recognized: nodular (N), interstitial (I), nodular and interstitial (mixed) and diffuse (D). The pattern of BM involvement was compared with the clinical, laboratory, and survival status in all patients. The extent of the disease in CLL patients, was determined by the Rai and the International Workshop on CLL Staging Systems, while in WDL patients the Ann Arbor staging system was used. In the CLL group the N pattern was found in 8%, the I in 33%, the mixed in 31%, and the D in 27% of the patients. Based on the International Workshop on CLL Staging System, the I pattern of BM involvement was more frequently found in Stage A (56%), the mixed in Stage B (68%), and the D in Stage C disease (90%). All CLL patients with D pattern required treatment from the beginning, contrary to CLL patients with the other patterns, in whom therapy was required in less than 50%. Similarly, deaths were more common in the D pattern in whom therapy pattern than in the other patterns. In the WDL patients BM involvement was found in 4 of 12, (33%) and its pattern of positivity was always nodular, although most patients (10 of 12) had advanced disease. It is concluded that the frequency of BM involvement may contribute in the differential diagnosis of WDL from CLL. In addition, the pattern of BM infiltration correlates very well with the International Staging System for CLL, and the pattern of BM positivity in CLL patients also has prognostic significance.