PTPN22 gene regulates natural killer cell proliferation during in vitro expansion.

The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is expressed in hematopoietic tissue and peripheral blood mononuclear cells including natural killer (NK) cells. The rs2476601 single nucleotide polymorphism (SNP) in the PTPN22 gene is an important susceptibility marker for autoimmunity but its role in NK cell biology is not yet clear. The aim of the current study was to evaluate in a cohort of healthy individuals, whether allelic variants of the rs2476601 SNP are associated with NK cell expansion in vitro. The CT genotype of the rs2476601 SNP was significantly (P = 0.0013) associated with reduced NK cell CD3(-) CD56(+) fraction in culture. The current study shows that the T variant of the rs2476601 SNP could alter NK vs T-cell balance in vitro and suggests that the PTPN22 gene might have an important immune regulatory role in NK cell function which needs further investigation.

Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries.

This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.

Hormones and immune responsiveness in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a B cell disorder with multiple abnormalities in T-cell function. The status of the immune system will depend to some extent upon the net effect of the changes in the equilibrium of various hormones. In order to investigate the association of the defects in the cellular immunity and hormonal dysregulation in CLL, studies were performed in 130 CLL patients with that disorder. Decreased lymphocyte proliferation in response to mitogen stimulation appears to be an early event in CLL pathogenesis and is not always influenced by the clinical stage of the disease or the specific treatment. The dysfunction of T-lymphocytes was accompanied by increased serum cortisol (C) concentrations. Elevated levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-estradiol (E) and testosterone (T) ratio were found in male CLL patients, but not in female patients. In view of our findings, it is conceivable that there are a number of disturbances in the lymphocyte-microenvironmental regulation, which may be responsible for immuno-hormonal imbalance in some patients with CLL.

Possible imbalance of the immuno-hormonal axis in multiple myeloma.

A comparative study of some immunologic aspects and hormonal balance was performed on 49 multiple myeloma (MM) patients and 29 healthy persons. Functional immunoregulatory imbalances were evident in the majority of patients with MM, as demonstrated by a significant reduction in the mitogenic response of peripheral blood lymphocytes (PBL) to phytohemagglutinin, increased mean stimulation indices of PBL to pisum sativatum agglutinin, wheat germ agglutinin (WGA) and dextran sulphate. Our results appear to provide important evidence in support of the existence of hormonal imbalance in MM: increased cortisol levels, augmented concentrations of follicle stimulating hormone, luteinizing hormone and 17 beta-estradiol and an increased estrogen to androgen ratio in male patients; decreased estrogen values and estrogen to androgen ratios were evident in female patients. Triiodothyronine and thyroxine mean concentrations were also found to be markedly diminished in MM patients. Our studies suggest some potentially important interactions between the immune and endocrine systems in multiple myeloma.

Organizational changes in Estonia.

The situation of the blood transfusion service in Estonia is analyzed since 1991. Considerable changes towards the establishment of a cost-effective on a cost-efficient system providing self-sufficiency of good quality blood products in future have been made. National blood transfusion service based on voluntary nonremunerated donations is under development.

Sex hormones and immune dysregulation in multiple myeloma.

A group of 49 multiple myeloma patients, 20 men and 29 women, were evaluated. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-oestradiol (E) and testosterone (T) serum concentrations have been detected by radioimmunoassay. Peripheral blood lymphocyte proliferation in response to phytohaemagglutinin (PHA), concanavalin A (ConA), recombinant interleukin-2 (rIL-2) and dextran sulphate (DxS) was investigated. Our findings provide evidence for two different patterns of sex hormone changes and immune dysfunctions presented differently by male and female multiple myeloma patients. In men increased FSH, LH and E concentrations and an augmented E to T ratio were associated with decreased lymphocyte blastogenic response to PHA, ConA and increased proliferation to rIL-2 and DxS. Female patients with multiple myeloma demonstrated normal values of FSH, LH and T, but a diminished E level and decreased E to T ratio correlated with a lymphocyte normal response to PHA and ConA and augmented blastogenesis to IL-2 and DxS. Our data, while admittedly preliminary, suffice to provide an indication of sex hormone changes in multiple myeloma patients, which could be responsible, at least in part, for the immune dysfunction observed in multiple myeloma.

Some aspects of morphological and dysplastic changes of the bone marrow in malignant lymphoma.

Cytological and histological study of the bone marrow of 33 patients with malignant lymphoma was performed to evaluate (1) the occurrence of secondary myelodysplastic changes, (2) the cell lines involved and (3) whether secondary myelodysplastic changes were similar or different for non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). Different changes in erythro-, granulo- and megakaryopoiesis were revealed. Granulo- and erythropoiesis were disturbed more frequently. Morphological changes of the erythroid series, megaloblastoid maturation of the nucleus and multinuclearity, were seen more often in NHL patients. Cells of the granulocytic series demonstrated different changes: hypogranulation and hypersegmentation in NHL, hypergranulation and Döhle's bodies in HD. No remarkable dysplastic changes of megakaryopoiesis were demonstrated.

Active and indolent chronic lymphocytic leukaemia--immune and hormonal peculiarities.

A group of 138 B cell chronic lymphocytic leukaemia (B-CLL) patients, 83 with active disease and 53 having the indolent form of the disease, were evaluated. The aim of the study was to clarify whether indolent and active B-CLL differ in their immune and hormonal characteristics. Peripheral blood lymphocyte proliferation in response to phytohaemagglutinin, concanavalin A, recombinant interleukin-2, dextran sulphate, Pisum sativatum agglutinin and wheat germ agglutinin was investigated. Serum immunoglobulin and beta 2 microglobulin levels were determined. Adrenocorticotropic hormone (ACTH), cortisol, follicle-stimulating hormone luteinizing hormone, 17 beta-oestradiol, testosterone, triiodothyronine, thyroxine, thyroglobulin and thyrotropic hormone levels were determined by radioimmunoassay. Active and indolent CLL presented differences in immunological characteristics, as demonstrated by the more severe suppression of T lymphocyte function, reduced IgA level and considerably higher serum beta 2-microglobulin values in active disease. Immune disturbances were accompanied by hormonal imbalance, depending on disease status: lower ACTH, cortisol and triiodothyronine levels were established to occur in active CLL compared to indolent disease. Male patients demonstrated striking changes in sex hormones, which were more evident in active disease. The findings point to the complexity of immuno-hormonal disturbances in CLL with differences in the active and indolent state of the disease.

Immune and hormonal changes in early-stage chronic lymphocytic leukemia patients.

Fifty-six previously untreated stage-I (according to Rai) chronic lymphocytic leukemia (CLL) patients were examined for their clinical data, immunological characteristics, and hormonal values. Dysfunction of T and B lymphocytes was demonstrated by changed lymphocyte blastogenic response to stimulation with phytohemagglutinin (PHA), concanavalin A (ConA), pisum sativatum agglutinin (PSA), wheat germ agglutinin (WGA), recombinant interleukin 2 (IL 2), and dextran sulfate (DxS); also by decreased immunoglobulin levels (IgG, IgA, IgE) and increased beta 2-microglobulin (beta 2-M) values. Simultaneously, dysregulation of the hypothalamic-pituitary-adrenal axis, immune system integration, imbalance of sex hormones, and changes in thyroid hormones were observed in the same group of patients. Disturbed immunohormonal interactions in early-stage CLL may be responsible for the pathogenetic mechanisms in this lymphoproliferative malignancy.

The incidence and survival of acute de novo leukaemias in Estonia and in a well-defined region of western Sweden during 1982-1996: a survey of patients aged > or =65 years.

OBJECTIVES: To compare the incidence and survival of acute de novo leukaemias with particular reference to political/socio-economic and environmental factors in two neighbouring countries over the three 5-year periods (1982-1996). PATIENTS: The present report covers only patients diagnosed when aged > or =65 years. SETTING: A well-defined area of Sweden, the so-called Western Swedish Health Care Region and Estonia. Population-wise, the western Swedish Region and Estonia are very similar; area-wise they are also well comparable. RESULTS: The number of acute de novo leukaemias was quite dissimilar in the two countries (Estonia, n = 137, Sweden, n = 354). The age standardized incidence rates regarding the total number of acute de novo leukaemias was 5.31 per 100,000 inhabitants/year for Estonia and 7.99 for Sweden, this difference being statistically significant. However, the difference was merely attributable to incidence rates as regards acute myeloblastic leukaemias (AML); on the contrary, differences as regards acute lymphoblastic leukaemias (ALL) and non-classifiable, undifferentiated or biphenotypic acute leukaemias (uAL) were negligible. The relative survival for the total material of patients was significantly higher for Swedish when compared with Estonian patients (P < 0.001). Thus, the relative survival for the total material of patients aged > or =65 years in Estonia at 1 year was 8.5% and at 3 years 3.5% respectively. The corresponding figures for the Swedish patients were considerably higher, 22.7 and 7.7% respectively. This difference, however, applied only for patients with AML (P < 0.001), whereas the results for patients with ALL and uAL were equally dismal. CONCLUSION: The results clearly reflect how political and socio-economic factors may influence the survival of acute leukemia patients in two neighbouring countries.