[Bone changes in multiple myeloma--current etiopathogenic, diagnostic and therapeutic aspects]. / Kostné zmeny pri mnohopocetnom myelóme--súcasné etiopatogenetické, diagnostické a liecebné aspekty.

Myelomatous bone disease affects about 90% patients with multiple myeloma and solitary myeloma as well. In initial stage it is manifested as osteopenia with osteoporosis or osteolytic foci, pathologic fractures followed by neurologic complications. Ethiopathogenitically a role is played by cytokine interactions with local chemokines produced by myeloma cells and activated stromal and hemopoietic cells (osteoblasts, monocytes, macrophages) resp. From the TNF-alpha family glycoprotein complexes are liberated (RANK-L), which support activation and proliferation or are inhibitory (osteoprotegerins). Similarly in the family TGF-beta several izotypes of antiinflammatory cytokines are known (the most important is TGF-beta 1 and the morphogenetic protein-2), which have a fibrotizing effect in bones, because the produced osteoid is insufficiently mineralized. The effect is a pathologic remodelation of the skeleton. In the diagnosis of multiple myeloma the immunological knowledge is used in the initial diagnosis (immunophenotypization, follow up of TNF-alpha, TGF-beta 1, IL-1, IL-6 etc). Important are also biochemistry values of increased osteoresorption (changes of calcium, parathormone, excretion of collagen fission products, osteocalcin, the bone alkaline phosphatase). In the following part the authors inform about favourable results of long-term treatment with bisphosphonates (Bonefos, Ibandronate) in combination with anti-tumor chemotherapy in 364 patients. During a 15 years observation period median survival of 94 months with a 35% probability of 10 year survival was achieved with a significant decrease of bone complications in 58% compared to 14% in the placebo group.

Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.

PURPOSE: To evaluate the impact of an additive therapy with an oral enzyme (OE) preparation given for more than 6 months additionally to standard combination chemotherapy (vincristine/melphalan/cyclophosphamide/prednisone (VMCP)- or methylprednisolone/ vincristine/CCNU/cyclophosphamide/melphalan (MOCCA)-regimen) in the primary treatment of patients with multiple myeloma stages I-III. METHODS: A cohort of 265 patients with multiple myeloma stages I-III was consecutively treated at our institution in two parallel groups (control group (n = 99): chemotherapy +/-OE for less than 6 months; OE-group (n = 166): chemotherapy + OE for more than 6 months). The median follow-up time in the stages I, II, and III for the OE-group was 61, 37, and 46.5 months, respectively; for the control group the respective values were 33, 51.5, and 31.5 months. The primary endpoint of the study was disease-specific survival. Secondary endpoints were response to therapy, duration of first response and side effects. The chosen method for evaluation was the technique of a retrolective cohort analysis with a concurrent control group. Survival analysis was performed by the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model. RESULTS: Significantly higher overall response rates and longer duration of remissions were observed in the OE-group. Primary responders showed a longer mean survival time than non-responders. Additive therapy with OE given for more than 6 months decreased the hazard of death for patients at all stages of disease by approximately 60%. Observation time was not long enough to estimate the median survival for patients at stages I and II; for stage III patients it was 47 months in the control group versus 83 months for the patients treated with OE (P = 0.0014) which means a 3-year gain of survival time. Significant prognostic factors for survival, in the Cox regression analysis, were stage of disease and therapy with OE. The OE-therapy was generally well tolerated (3.6% of patients with mild to moderate gastrointestinal symptoms). CONCLUSION: OEs represent a promising new additive therapy in multiple myeloma which will be further evaluated in a randomized phase III trial in the USA.

[Osteoporosis in multiple myeloma]. / Problém osteoporózy pri mnohopocetnom myelóme.

The problem of osteoporosis is world-wide in people above 50 years of age. As this period is also a risk period for the development of multiple myeloma or other malignant processes, comprehensive differential diagnosis of malignant and benign osteoporosis is essential. By retrospective analysis of a 12-year group of 270 patients treated by chemotherapy on account of multiple myeloma the authors selected a group of 151 patients treated in addition to chemotherapy and immunomodulating drugs (mixture of proteolytic enzymes-Wobe Mugos) for 2-3 years, also with biphosphonates. At the time ofdiagnosis osteoporosis was in 24.5% patients the only finding on bones. When biphosphonates (Bonefos, Ibandronate) and chemotherapy were administered during a three-year observation period the bone process was stable in 61.59%, osseous changes disappeared in 11.26% and progression of osteolysis was recorded in 27.15%. The objective of the work was to emphasize the importance of a correct diagnosis of osseous changes which can progress even in clinically asymptomatic myelomas.

[Comparison of the effectiveness and tolerance of Aktiferrin, a ferrous sulfate capsule preparation and Tardyferon pills in patients with uncomplicated sideropenic anemia]. / Porovnanie úcinnosti a tolerancie ferosulfátových prípravkov Aktiferrin kapsle a Tardyferon drazé u pacientov s nekomplikovanou sideropenickou anémiou.

BACKGROUND: The most frequent complications of oral administration of medicinal iron are gastrointestinal complaints the incidence of which correlates with the iron content of the preparation. The objective of the present work was to compare the effectiveness and tolerance of two ferrous sulphate preparations, Aktiferrin capsules and Tardyferon dragées which differ as to the elemental iron content. METHODS AND RESULTS: To two groups of patients with sideropenic anaemia selected at random (39 women and 1 men, age 14-61 years, median 28 years) Aktiferrin or Tardyferon was administered. Administration of the preparations which have a more than double different elemental iron content had a comparable effect on the investigated haematological parameters. In the group treated with Akiferrin no GIT intolerance was observed, in the group with Tardyferon it was observed in four patients. CONCLUSIONS: Aktiferrin has a comparable therapeutic effect although it contains 2.5 times less elemental iron, as compared with Tardyferon.

[Long-term survival in multiple myeloma]. / Dlhodobé prezitie pri mnohopocetnom myelóme.

The authors present the results of 23-year protocol studies of survival with multiple myeloma, focused on problems of perspective long-term survival. Of 535 diagnosed patients between 1970 and 1990 the authors checked regularly and treated 475. In addition to 60 latent forms where treatment was administered only when clinical symptoms developed or after progression of laboratory signs, to all patients treatment was administered according to protocols (monotherapy-cyclophosphamide prednisone in 1970-1975 only to 30 patients, the remainder had combined treatment--COPP, VMCP, MOCCA); in the third stage of the disease MOCCA treatment is better. The median of survival of patients after VMCP treatment (in stage II) MOCCA (in stage III) is more than 90 months, 15% survive for more than 10 years. The authors emphasize the importance of combined intensive treatment of patients for the prognosis of survival. Long-term experience revealed that patients achieve an objective response in 85%, while the risk of leukaemic and cancerogenic complications is low (1.1%). The therapeutic effect and survival period are favourably affected by immunomodulation treatment (Interferon, proteolytic enzymes, thymus factor).

[The favorable effect of hydrolytic enzymes in the treatment of immunocytomas and plasmacytomas]. / Podporný úcinok hydrolytickych enzýmov pri liecbe imunocytómu a plazmocytómu.

At present attention is focused on research of biomodulating influences on tumorous processes, in particular inhibition of metastatic spread of tumors. In the aetiopathogenesis an important part is played by immune complexes, interaction of cytokines. The authors tested the supporting effect of hydrolytic enzymes in plasmocytoma and immunocytoma. The enzymes were administered along with cytostatic preparations according to the MOCCA pattern. They recorded a more rapid onset and longer persistence of remissions, a marked decline of total proteins, paraproteins, beta-2-microglobulin. Complications associated with paraprotein (hyperviscosity syndrome, nephrotic syndrome, peripheral angiopathy) improved. A combination of chemotherapy and enzymatic treatment proved effective and suitable, in particular for patients with interferon intolerance.

[Immunotyping of medullary and circulatory cells for prognostic evaluation of plasmacytoma]. / Imunotypizácia drenových a cirkulujúcich buniek pri prognostickom posúdení plazmocytómu.

The authors discuss the prognostic impact of immunophenotyping of circulating lymphoplasmatic cells in the peripheral blood stream in patients with generalized plasmocytoma. From a group of 250 patients followed up from 1981 to 1991 they selected a sub-group of 70 patients where they evaluated in 1986-1991 after six-month intervals the phenotype of medullary and circulating cells. They used the method of immunofluorescent detection of the presence of cytoplasmic Ig, the kappa-lambda index and phenotyping of antigens CD 9, CD 10, CD 20, CD 38, HLA-DR by monoclonal antibodies. In a longitudinal investigation of the survival period they revealed that the finding of circulating cells with signs of non-differentiation (presence of antigen CD 10 detected by antibody CALLA, presence of antigens B 1 (CD 20), CD 9 on circulating lymphocytes) has a prognostic meaning suggesting shorter survival. There was a direct correlation between the increase of CALLA positive cells and CD 9 positive cells. The authors found also that release of the clonus with signs of immaturity was present when the disease developed into the aggressive stage. While the group of 250 patients had according to statistical analyses, when treated according to protocol VMCP/MOCCA, a median survival of 90 months, the median survival of the aggressive stage (with the plasmoblast and lymphoplasmocytic type resp.) was only 12 months. The authors emphasize the prognostic importance of immunological typing of heterogeneous plasmocytoma populations.

Results and further perspectives of plasmocytoma chemotherapy.

Polychemotherapy has improved prognostic parameters of survival in patients with plasmocytoma. The mean survival in patients given long-time prednisone and melphalan treatment is 20 months, in those given polychemotherapy over 30 months. In patients with a slow disease progression the combinations COPP and VMCP give satisfactory results in about 40%, but in a majority of patients more effective treatment is necessary. The authors compare the 5-year survival of two polychemotherapy groups with the prednisone and melphalan group. The mean survival after prednisone and melphalan was 33 months, after polychemotherapy (groups COPP, VMCP) 46 months and 57 months (VMCP + M2), respectively. Survival time was influenced by the clinical stage.

Some immunological peculiarities in generalized plasmacytoma and their possible clinical interpretation.

According to the immunological classification, plasmacytoma is assigned to the group of secretory immunocytomas. The designation "immunoproliferative hemoblastosis" implies certain peculiarities of immunological reactivity in its malignant transformation. The study deals with some of the more recent concepts on the immunochemical properties and morphological differentiation of plasmatic or plasmacytoma cells. Mention is also made of the results of some tests for evaluation of the function of T and B lymphocytes in patients suffering from a generalized plasmacytoma, during the course of chemotherapy.

[Clinical trial with long-term therapy of generalized plasmacytoma]. / Klinische Erfahrungen mit der Langzeittherapie beim generalisierten Plasmozytom.

The authors report on findings in long-term therapy made by means of a combination of cyclophosphamide as attack dosis (partially also with polychemotherapy--COP, COPP-scheme) and double plasmapheresis. Since 1967 33 patients have been treated in this way. A group (6 patients) only received cyclophosphamide in a attack therapy of 15...25 mg/5g per body weight; a second group of 14 patients received the same dosis in combination with a double plasmapheresis. The third group of 13 patients in an advanced stage of the illness was treated polychemotherapeutically according to various schemes (COP-cyclophosphamide, vincristine, prednisone; COPP with Natulan) likewise in combination with double plasmapheresis. The observations made for 4 years in the two groups first mentioned showed favourable results in the second group with an average survival time of 35 months. In the third group only experiences of two years can be reported and thus a final answer cannot be given. However, it can already be stated that a clinical success requires the cytostatic therapy to be continued for a long time in combination with plasmapheresis.

Follow-up of certain immunologic indicators in the treatment of plasmacytoma with cyclophosphamide in combination with plasmapheresis.

Changes in the immunoglobulin and complement levels in untreated plasmacytoma were compared with those resulting from massive doses of Cyclophosphamide (15--25 mg per kg b. w. at intervals of 10--14 days) applied in combination with double plasmapheresis (involving removal of about 500 ml of plasma). A follow-up of the levels of normal immunoglobulins, paraprotein, total complement and the C3 component revealed a significant decline in the total complement following each single application of this treatment, but the decrease in C3 was nonsignificant. A decline of about 20% in immunoglobulins and of about 15% in paraprotein was observed in relation to the pretreatment values, but only that in the IgM class proved to be of statistical significance. The decrease in proteins was also established with the methods of total protein determination (refractometric or biuret methods) and was found to amount to 1000--3000 mg% after each dose of Cyclophosphamide with plasmapheresis. In the author's view, a combined Cyclophosphamide-plasmapheresis treatment is effective for achieving clinical remission. It should, however, be kept in mind that the effect of protein and paraprotein depression persists for only a few days, hence, to achieve long-term results, this treatment should be repeated in 2--3 week's cycles. The lowered values of humoral immunity indicators do not increase the danger of complications from a clinical aspect, when suitable preventive measures are taken.