[Contribution to the evaluation of the relationship between angiogenic cytokines, selected biological parameters and prognostic factors in multiple myeloma]. / Príspevek k hodnocení vztahu angiogenních cytokinu a vybraných biologických ukazatelu k prognostickým faktorum mnohc'etného myelomu.

BACKGROUND: Multiple myeloma is an unusually heterogeneous disease with individually different clinical course, sensitivity to therapy and prognosis. The undoubted limitation of contemporary diagnostic stratification systems is the insufficient credit of those parameters that express the intrinsic biological properties of myeloma cells and the microenvironment of the bone marrow. The aim of this study was to evaluate the relationship of 10 biological parameters to 6 fundamental prognostic factors of multiple myeloma. METHODS AND RESULTS: The analysed group consisted of 66 individuals examined at the time of diagnosis before the start of therapy. For the estimation of serum levels of investigated molecules there were used following methods: REA RIA, ELISA and the technique of quantitative sandwich enzyme immunoassay. For the analysis of proliferative and apoptotic properties of myeloma cells we used propidium iodide (PC-PI) and annexin-V (PC-AI) indices. The statistical estimation was carried out with the help of Pearson and Spearman test, eventually with the help of U-test according to Mann-Whitney. Increased incidence of abnormal serum levels of examined parameter was registered in the case of S-beta2-microglobulin (95.5%), S-thymidinekinase (57.5%), S-sVCAM-1 (78.5%), S-ICTP (87.0%), S-solubile osteoprotegerin (sOPG 76.5%), S-sSyndecan-1 (56.5%) and low index of plasma cell apoptosis (PC-AI, 78.0%). The statistical analysis (Pearson's test) revealed the mutual relationship of serum levels of: S-beta2-microglobulin to sVCAM-1, (r = 0.39, p = 0.002), sICAM-1 (r = 0.33, p = 0.011), sOPG (r = 0.53, p = 0.001), sHGF (r = 0.34, p = 0.006), sSyndecan-1 (r = 0.38, p = 0.003) and sFas (r = 0.42, p = 0.001); S-albumin to sVCAM-1 (r = -0.29, p = 0.036), ICTP (r = -0.33, p = 0.016), sOPG (r = -0.63, p = 0.000), sHGF (r = -0.39, p = 0.003), sSyndecan-1 (r = -0.29, p = 0.042); S-thymidinekinase to sSyndecan-1 (r = 0.46, p = 0.000) and sFas (r=0.29, p = 0.019). There was no relationship of PINP and VEGF to any of the evaluated prognostic factors. There was no relationship found between either of the analysed parameters to PC-PI and PC-AI. With the help of U-test there was found the relationship of sIL-6R to S-beta2-microglobulin (p = 0.001), albumin (p = 0.002) and PC-PI (p = 0.046). CONCLUSIONS: The presented study implies that the traditional algorithm of parameters used in clinical practice for individual characteristics of MM should be enriched with sOPG, sHGF, sSyndecan-1 and sFas.

[Therapeutic results and changes in prognosis in patients with multiple myeloma in central and northern Moravia over the past 40 years]. / Výsledky lécby a zmena prognózy nemocných s mnohocetným myelomem v období predchozích 40 let v oblasti strední a severní Moravy--rozbor souboru 562 nemocných.

OBJECTIVE: The objective of the investigation is evaluation of therapeutic results and the development of the prognosis of patients with multiple myeloma (MM) as a result of consecutive changes of therapeutic procedures in patients of central and northern Moravia in the course of the last 40 years. METHODS AND RESULTS: The analyzed group of 562 patients with MM was concentrated at the Ist and IIIrd Medical Clinic of the Faculty Hospital Olomouc in 1959 - 2000, median age 63 (28-91) male/female ratio 1.1: 1.0. From analysis of Kaplan-Meier survival curves and the results of statistical analysis (log rank test p = 0.0000) ensued that during the evaulated period a very substantial change of prognosis occurred with improvement of theraupeutic results and a significant prolongation of survival in general. The first " turning point" was the introduction of chemotheraphy with alkylating substances with Prednisone (1963-1975), leading as compared with the period of symptomatic treatment alone (1959-1063) to a significant prolongation of the media value of general survival (M) from 8 to 19 months (p = 0.0031) and 3-year survival from 4 to 23 % patients, whereby 10-year survival was only 0 % and 1 %. The second "turning point" was the period from 1976 - 1980 with introduction of systematic chemotherapy using conventional doses of polychemotherapeutic (CP) regimes with better opportunities of supporting treatment (M = 40 months, p = 0.0000; 3-year and 10-year survival 55% and 5.5% patients). The therapeutic results acheived during the subsequent 15 years were however an unsatisfactory advance. During the interval between 1976-1995 in a group of 295 patients divided into 5-year sub-periods remission was acheived (R = < 25 % of the baseline value of M-protein) in 10-24 % patients, an inadequate response (NR) = persistence in > 50 % M-protein) in 55-28 %, prolongation of the median of total survival in 232 of the accessble patients for 44 months and long-term survival of 5 - 10 years after establisment of the diagnosis increased from 25 to 36 % and from 5.5 to 16.5 % patients. The third "turning point" was 1996 characterized by the introduction of high-dosage chemotheraphy with transplantation of autologuos peripheral haematopoietic cells ("HD" therapy with ASCT) leading ina group of so far only 33, assessable patients under 65 years to acheived remission in 71 %, to decline of NR in 10 % only and 5 -year suvival so far in 91 % patients ( p = 0.0037). Improvement of therapeutic results and prognosis of the disease as compared with 1976 - 1995 occurred in the whole group of patients also in 1996 - 2000 (CP and "HD"-therapy with ASCT) characterized by remission in 36 %, NR IN 33 % and 5 -year survival in 57 % (p = 0.030). It was reveled that the application of "HD" theraphy with ASCT led in 1995-2000 to the acheivement of more favorable therapeutic results (R - 71 % NR - 10 %. 5-year survival after the interval which elapsed so far 91 %), as compared with 2 similar groups of subjects under 65 years meeting the criteria of "HD" theraphy with ASCT, but treated only by conventional polychemotheraphy (1991 - 1995 and 1996 - 2000: R - 24 and 32 %, NR - 42 and 23 %, 5-year survival 46 and 68 % of the patients). In the group of 148 patients from the period of 1991-2000 the patients had as regards remission (R) more favourable results as compared with patients with NR concerning the prognosis [M 63 vs.22 months, 5-year and 10-year survival 53 vs. 17 % and 17 vs. 0 % of patients (p = 0.0000)]. CONCLUSION: From the submitted analysis ensured that during the period form 1959 - 2000 in patients with mutiple myeloma in central and northern Moravia as a result of the application of modern methods of chemotheraphy and supporting treatment a significant improvements of results of conventional treatment occurred with a more than 5 fold prolongation of so far assessable median values of survival (8 - 44 months) and long-term 10-year survival of almost one sixth of the patients. The real asset of "HD" theraphy with transplantation of ASCT will be revealed by analyses made after a longer time interval.

[Importance of determining the propidium-iodide index of plasmacytes in multiple myeloma. II. Relation to disease extent and activity]. / Význam vysetrení propidium-jodidového indexu plazmocytu u mnohocetného myelomu. II. Vztah k rozsahu a aktivite nemoci.

The authors evaluated in a group of 50 patients with multiple myeloma (MM), examined when the diagnosis was established before onset of treatment, and in a group of 85 patients examined in different stages of MM the relationship of proliferative characteristics of myeloma plasmocytes assessed by means of the propidium-iodide index PI/CD38, PI/"UHKT" and PI/B-B4(CD138) with the progression, "performance status" and the activity of the disease. With the exception of a different value of the PI/CD38 index between stages 1 and 3 evaluated according to Durie-Salmon, in the whole group of patients no relationship was found with the progress of the disease. When evaluating the whole group the authors observed a difference between sub-stages A and B (i.e. between patients without and with a serious impairment of renal function) when using indexes PI/CD38 and PI/B-B4(CD138). Only in the whole group of 85 patients the authors found a significant relationship of all proliferation indexes (PI/CD38PI/"UHKT" and PI/B-B4) with the "performance status" according to ECOG score to or > or = 3 vs. < 3. In both groups there was a very close statistically significant relationship without the activity of the disease whichever of the three proliferation indexes was used. It was revealed that patients with the active but stable form of the disease have different PI/CD38 and PI/B-B4(CD138) indexes within the framework of the same stage of MM (stages 1 + 2 vs. 3). From the investigation ensues that examination of the PI proliferation index, in particular PI/B-B4(CD138) or possibly PI/CD38 using multiparametric flow cytometry is a valuable method extending hitherto used examination procedures in MM, and that it replaces adequately former autoradiographic and microscopic immunofluorescent techniques.

[Serum interleukin-6 in multiple myeloma. II. Relation to activity and stage of disease]. / Interleukin-6 v séru u mnohocetného myelomu. II. Vztah k aktivite a k pokrocilosti nemoci.

In a group of 111 subjects with multiple myeloma (MM) comprising a group of 34 patients examined when the diagnosis was established and a group of 77 patients examined in different stages of development of MM the authors evaluated the relationship between interleukin-6 (IL-6) serum levels and the clinical activity and the stage of the disease. In both groups a significant relationship was found between IL-6 and the clinical activity of MM; "stable" and "active" stages of the disease differed by the frequency of elevated values and the level of IL-6. In both groups the authors recorded rising levels and a rising rate of subjects with elevated IL-6 levels with advancing stages of the disease. When staging systems were used according to Durie-Salmon, the British Medical Research Council and according to Bataille the highest IL-6 values were recorded in the third stage of the disease, these values being significantly higher than in stages 1 and 2. In the group assembled at the time of assessment of the diagnosis of MM the described differences did not reach (with the exception of the evaluation according to Bataille) statistical significance. The classification of patients in stages 1-3 into sub-groups with regard to the activity of the disease ("stable" and "active") was associated with significantly different IL-6 levels. The investigation revealed that examination of IL-6 levels contributes at present rather to the understanding of the pathogenesis and biology of MM than to practical evaluation of the severity, activity and stage of the disease.

[Serum thymidine kinase in multiple myeloma: I. Relation to selected laboratory indicators in the disease]. / Tymidinkináza séra u mnohotného myelomu: I. Vztah k vybraným laboratorním ukazatelum nemoci.

In a group of 74 patients with multiple myeloma the authors revealed elevated values of serum thymidine kinase (REA kit ADICO Praha, range of normal values 0-5 U/l) in 40% of the patients-incl. a group of 22 subjects examined at the time of diagnosis of the disease in 50%, and a group of 52 subjects examined in different stages of the disease in 36% of the patients. If the upper range of S-TK 10 U/l was used, the ratio of patients with a raised value declined to 15%, in selected groups to 18 and 14% resp. The authors found a satisfactory correlation of serum thymidine values and values of S-beta-microglobulin, S-albumin, with the percentage ratio of plasmocytes in bone marrow and a less significant correlation was found with the red cell sedimentation rate (in IgG and IgA type) to the index of paraprotein and the serum interleukin-6 level. The authors did not reveal significant differences of serum thymidine kinase levels with regard to age, sex and immunochemical type of M-protein and type of light chains. The authors did not reveal any correlation of thymidine kinase serum levels and haemoglobin values, S-ferritin levels, the beta 2-microglobulin index and the synthetic score of plasma cells. It was found that examination of S-thymidine kinase extends in a useful way the existing spectrum of laboratory tests which help to elucidate the individual character of multiple myeloma.