Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies.

We have previously reported presentation serum selenium level to be predictive of outcome in diffuse large B-cell lymphoma. This has now been studied in a further 430 patients, 163 with acute myeloid leukaemia (AML), 156 with Hodgkin Lymphoma (HL), and 111 with Follicular Lymphoma (FL). Serum selenium was below the UK normal reference range in 45% of patients, and correlated with serum albumin (r=0·24-0·46, P<0·001-0·003) in all tumour types. Independent predictors of presentation selenium were; French-American-British subtype and albumin (P<0·001 for both) in AML, haemoglobin (P=0·002) and B-symptoms (P=0·01) in HL, and albumin (P<0·001) in FL. In AML and HL, response to first line therapy was lower in patients with low serum selenium, but selenium was no longer predictive of response when other variables were entered into a multivariate model. Low selenium was also associated with a worse overall survival in FL [Hazard Ratio (HR) 2·3, 95% confidence interval (CI) 1·4, 4·0] and a trend to a worse overall survival in AML (HR 1·43, 95% CI 0·96, 2·13) by univariate Cox regression analysis, but not by multivariate analysis. In conclusion, low serum selenium is associated with a worse outcome in patients with haematological malignancies, but is not independently predictive, suggesting that it reflects other factors.

Zinc and selenium status in pediatric malignant lymphomas.

Ninety-six untreated patients with malignant lymphoma (ML), 81 Hodgkin's disease, and 15 Burkitt's lymphoma were studied for zinc (Zn) status, and 21 patients also had selenium (Se) status analysis. Plasma and hair Zn and Se levels were measured by atomic absorption spectrophotometry. Chronic Zn and Se deficiencies (low plasma and low hair Zn and Se levels together) were found to be associated with ML in Turkish children. This was most likely due to the poor "nutritional environment" of the patients because majority of the ML patients were from families of low socioeconomic status. Supplementation of pediatric ML patients with Zn and Se, in addition to standard chemotherapy and radiotherapy regimen, is recommended.

Reduced bone mineral density in men following chemotherapy for Hodgkin's disease.

We have measured bone mineral density (BMD) in 29 men, mean age 35.0 (range 19.7-58.0) years, with testicular damage following MVPP or hybrid chemotherapy for Hodgkin's disease. Forearm cortical bone mineral content (BMC) and lumbar spine and femoral neck integral BMD were measured 3.4 (1.1-6.8) years after completion of chemotherapy, and results expressed as Z (standard deviation) scores. There was a significant reduction in forearm cortical BMC (median BMC 1.727 g cm-1, median Z-score -0.8, P < 0.0005), in lumbar spine integral BMD (median BMD 1.141 g cm-2, median Z-score -0.6, P < 0.0005) and in femoral neck integral BMD (median BMD 0.991 g cm-2, median Z-score -0.4, P < 0.05). There was no significant correlation between Z-score and time elapsed since completion of chemotherapy, and no significant difference in Z-score according to type of chemotherapeutic regimen or number of cycles of chemotherapy received. In conclusion, men who are in complete remission following treatment of Hodgkin's disease have reduced cortical and trabecular BMD. Possible causes include mild hypogonadism secondary to chemotherapy-induced impairment of Leydig cell function, a direct effect of chemotherapy on bone, an effect of high-dose glucocorticoid on bone or an effect of Hodgkin's disease per se.

Post-5-fluorouracil human marrow: stem cell characteristics and renewal properties after autologous marrow transplantation.

The effect of 5-fluorouracil (5-FU) pretreatment on human bone marrow (BM) progenitor/stem cells and recovery of hematopoiesis after autologous marrow transplant was studied. Twenty-one patients were treated with 5-FU (15 mg/kg to 45 mg/kg) intravenously (IV) for 1 to 3 days administered 6 to 22 days before BM harvest. Post-FU marrow was infused into 15 patients after high-dose cyclophosphamide, carmustine (BCNU), and VP-16 (CBV). Seventeen patients (historical controls) were treated with CBV and autologous BM transplantation but did not receive 5-FU before marrow harvest. The groups were comparable for diagnosis and prior therapy. In the 5-FU-treated group and control group, median recovery times for platelet count to 50,000/mm3 were 20 and 30 days, respectively (P = .007), and for platelet count to 100,000/mm3, 23 and 38 days, respectively (P = .007), while neutrophil recovery was not significantly altered. In vitro cultures with 1 to 7 growth factors (interleukin-1 [IL-1], IL-3, IL-4, IL-6, colony-stimulating factor-1 [CSF-1], granulocyte-macrophage colony-stimulating factor [GM-CSF], and G-CSF) were performed. In 8 of 10 patients whose marrow was studied before and after 5-FU treatment, the numbers of CFU-C responsive to the combination of GM-CSF and IL-3 was increased 6.15-fold by 5-FU pretreatment. In 4 of these patients, thymidine suicide of GM-CSF- and IL-3-stimulated CFU-C ranged from 17% to 42%. High proliferative potential colony-forming cell (HPP-CFC) was observed in low frequency in normal marrow and patient's marrow before 5-FU treatment. In 11 of 16 patients pretreated with 5-FU, increased numbers of HPP-CFC were noted. GM-CSF and IL-3 interacted synergistically to stimulate HPP-CFC. Multifactor combinations, especially GM-CSF + G-CSF + IL-3 + IL-6 + IL-1 + CSF-1 did not increase total colony count or classic HPP-CFC but did result in altered morphology, producing huge, loose colonies. The marrow from patients pretreated with 5-FU is enriched with multifactor-responsive HPP-CFC, renews in vivo granulopoiesis in a manner comparable with marrow harvests without 5-FU pretreatment, and provides accelerated in vivo platelet recovery. This marrow may be an appropriate target marrow for gene insertion in gene-therapy protocols.

[The role of stem cell mobilization in the scope of autologous blood stem cell transplantation]. / Die Rolle der Stammzell-Mobilisation im Rahmen der Autologen Blutstammzell-Transplantation (ABSZT).

It is widely believed that hemopoietic stem cells have to be mobilized from extravascular sites into the circulation to guarantee a sufficient and safe blood stem cell autograft. The question of using mobilized or non-mobilized stem cells for transplantation purposes addresses the quality of hemopoietic engraftment rather than its feasibility. Two aspects are of clinical relevance: 1. The increment of peripheral cell concentration per time, and 2. shortening the duration of total aplasia following myeloablation and stem cell transplantation. When comparing the various stem cell mobilization techniques the CFU-GM yield per apheresis was highest during rh GM-CSF application (250 micrograms/m2/day continuous i.v. infusion), whereas the MNC yield was not greatly affected. More severe side effects were seen during rh GM-CSF infusion: One patient experienced an axillary phlebothrombosis. In a series of 15 advanced stage Hodgkin's lymphoma patients the reconstitutive ability of the various stem cell autografts, whether chemotherapy-, cytokine-, or non-mobilized, did not vary. Particularly in acute leukemias, mobilization of hemopoietic precursor cells does not necessarily exclude a concomitant mobilization of clonogenic tumor cells, and, therefore, the probability of disease-free survival after ABSCT might be lower when using mobilized stem cells for transplant.

Concurrent comparison of the Cobe Spectra and Fenwal CS3000 for the collection of peripheral blood mononuclear cells for autologous peripheral stem cell transplantation.

Hematopoietic stem cells, collected by leukapheresis from peripheral blood, can be used as an alternative to autologous bone marrow transplantation following high-dose chemotherapy as treatment of several malignancies. We compared the ability of the Cobe Spectra and the Fenwal CS3000 to collect peripheral blood mononuclear cells (MNC) for autologous peripheral blood stem cell transplantation. Ten patients experienced repeated leukapheresis (10 L blood processed per procedure) using both instruments. Procedures were alternated between the two until a total of 7 x 10(8) MNC/kg was collected. Data from 61 Spectra and 50 CS3000 collections were analyzed. The yield (mean per procedure) of nucleated cells (NC) and MNC was higher (P less than .005) with the Spectra (0.77 x 10(10) NC and 0.54 x 10(10) MNC) than with the CS3000 (0.59 x 10(10) NC and 0.40 x 10(10) MNC). However, colony forming units (CFU-GM) were not different (P greater than .05) for Spectra (0.92 x 10(4)) and Fenwal (0.65 x 10(4) collections. Platelet contamination was lower (P less than .001) with the Spectra (2.2 x 10(11)) than the CS3000 (5.0 x 10(11)). This correlated with a higher patient blood platelet count immediately following Spectra collections (117 x 10(9)/L) versus the CS3000 (86 x 10(9)/L). Using the methods described, the Spectra product contained greater yields of NC and MNC with less platelet contamination than did the CS3000.

Peripheral blood mononuclear cell collection from patients undergoing adoptive immunotherapy or peripheral blood-derived stem cell transplantation and from healthy donors.

The demand for collection of mononuclear cells from the peripheral blood of patients for therapeutic purposes is rapidly increasing. Automated blood cell separators are usually designed for collection of blood components from healthy donors. We reviewed safety and efficiency of collection data of a new procedure for the Fenwal CS 3000 blood cell separator in 125 collections from normal donors and 101 collections from patients after IL-2 pretreatment or chemotherapy. The new procedure set red blood cell spillovers to occur at 3.5 minute intervals, using procedure 1 with the interface detector set at 1,000 and the standard granulocyte and collection chambers. Despite significant anemia and thrombocytopenia in a large number of patients no serious procedure-related side effects occurred. The lymphocyte yield was 4.74 +/- 1.6 x 10(9) per 5 liters of blood processed in normal donors and 24.2 +/- 12.0 x 10(9) per 10 liters of blood processed after IL-2 treatment. After chemotherapy the lymphocyte yield was 4.5 +/- 3.1 x 10(9) per 10 liters of blood processed; the collection efficiency was found to be significantly lower in this group. The main problem was the platelet loss of 35.6 +/- 12% of the initial count in normal donors, 40.3 +/- 14.1% after IL-2 treatment, and 42.1 +/- 18.0% after chemotherapy. The platelet loss is, however, closely related to the preapheresis platelet count; patients with thrombocytopenia lose fewer platelets than normal donors. Therefore the procedure was found to be safe for patients with a platelet count as low as 20/nl. This report provides a basis for safe, effective mononuclear cell collection from patients with very abnormal peripheral blood counts.

Serum selenium levels in untreated children with acute lymphoblastic leukemia. I.

Serum selenium in the control group of 79 children aging 1 to 16 years was measured. A slight increase in serum selenium values with age occurred. The 89 patients of the test group were suffering from malignant proliferative diseases. The largest number of patients was suffering from acute lymphatic leukemia (78 patients), then Hodgkin's and non-Hodgkin's lymphoma (5 patients) and other malignant proliferative diseases (6 patients). Samples were taken before any therapeutic treatment at the time of diagnosis. Patients were of the same ages as the control group. Statistical analysis of the data shows that a significant difference exists in the selenium level of most of the patients as compared with the control group. They have a lower serum selenium. Only patients with Hodgkin's and non-Hodgkin's lymphoma have same selenium content as the control group.

Leucocyte zinc in non-Hodgkin's lymphoma and Hodgkin's disease.

Zinc status and the effect of zinc supplementation were assessed in groups of patients with non-Hodgkin's lymphoma and Hodgkin's disease; patients were either untreated or in remission. In the patients in remission, plasma zinc was normal; and whereas 30% of untreated patients had low plasma zinc, the group as a whole did not differ from normal. For mononuclear cell zinc, the range of values in the disease group was far wider than in controls, but there was no significant difference between the means of the groups. Granulocyte zinc was significantly lower in both the groups of patients in remission from non-Hodgkin's lymphoma and Hodgkin's disease compared with the control group. Significant increases were found in the plasma copper, ceruloplasmin, and the copper-to-zinc ratio in several of the patient groups. Plasma zinc increased by 23% with zinc supplementation (50 mg elemental Zn/day), but there was no effect on mononuclear cell or granulocyte zinc. Apart from granulocyte zinc, there is little evidence of zinc deficiency in non-Hodgkin's lymphoma or Hodgkin's disease. However, the presence of depleted granulocyte zinc levels could modify the immune function of this cell population.

Serum selenium levels in malignant lymphoproliferative diseases.

Serum selenium levels were measured in 38 patients with malignant lymphoproliferative diseases (MLD) and in 34 non-hospitalized healthy individuals. Selenium was determined by proton induced x-ray emission. In Hodgkin's disease and non-Hodgkin malignant lymphoma the mean serum levels of selenium were not different from those of the control group. On the contrary lowered mean serum selenium concentrations were observed in the group with chronic lymphocytic leukaemia (5.2 +/- 0.7 microgram/100 ml) as compared to normal individuals (7.9 +/- 0.3 microgram/100 ml). The difference is highly significant (P less than 0.005). A second selenium test was made in 11 out of the 38 patients within 8 weeks from the beginning of radiotherapy or chemotherapy; unchanged levels were found.

Serum copper compared to erythrocyte sedimentation rate as indicator of disease activity in Hodgkin's disease.

Serum copper and erythrocyte sedimentation rate were recorded in 54 patients with active Hodgkin's disease and at 186 occasions in 78 patients during stable complete remission. Relatively high and age-dependent normal limits for erythrocyte sedimentation rate were used. Each of the tests was elevated in 70% of patients with active disease. During remission serum copper was elevated in 14% and erythrocyte sedimentation rate in 16.5% of the determinations. Thus the two tests are considered not far from equal in their ability to discriminate between presence and absence of specific disease activity in Hodgkin's disease. Simultaneous elevation during remission occurred in less than 5% of the recordings as compared to 61% during active disease. It is therefore concluded that serum copper level may be of some value as a supplement to erythrocyte sedimentation rate.

Serum selenium and reticuloendothelial tumors.

Serum selenium levels were determined by neutron activation analysis on 59 patients with a variety of reticuloendothelial neoplasms. Correlations were attempted between the widely variable range in the serum concentrations of the trace element with the parameters employed in this study. Therapy, particularly less than six weeks initiation, produced elevations in the serum selenium levels.

Cap formation on lymphocytes from patients with leukemic diseases induced by four different lectins.

When ficoll purified peripheral blood lymphocytes were treated with fluorescein conjugated lectins from lentils (LCH), castor beans (RCA) and phaseolus coccineus beans (L-and E-PHA) for 15 min and the percentages of the cap forming cells were examined, the values of leukemic lymphocytes were reduced compared to the values obtained with normal lymphocytes. The reduction was more than half in patients with acute and chronic myelogenous leukemia and immunoblastoma, it was only one quarter in patients with chronic lymphocytic leukemia, Hodgkin's disease and lymphosarcoma. The lowest number of cap forming cells was found in lymphoblasts of established lymphoblastoid cell lines. The four different lectins showed nearly the same capacity in the induction of caps. After successive binding, the different lectins showed cocapping on the lymphocyte surface.

Pituitary function in patients receiving intermittent cytotoxic and corticosteroid therapy for malignant lymphoma.

Diurnal variation in plasma-cortisol was studied immediately before and after intermittent steroid therapy in seven patients receiving monthly courses of quadruple chemotherapy for Hodgkin's or non-Hodgkins lymphoma over a period of 6 months. The serum-thyroid-stimulating-hormone (T.S.H.) response to intravenous T.S.H.-releasing factor was also measured before and during the first course and before the second and fourth courses. The morning plasma-cortisol concentration fell significantly over 6 months when measured immediately before the start of each course. The mean evening cortisol concentration also fell over this period. In most patients the T.S.H. response showed a downward trend during treatment, although in two patients the response returned to normal whilst they were still undergoing therapy.

Hypothalamic/pituitary/adrenal function in patients treated with intermittent high-dose prednisolone and cytotoxic chemotherapy.

Hypothalamic/pituitary/adrenal (H.P.A.) function was assessed in ten patients receiving intermittent high-dose prednisolone and cytotoxic chemotherapy for myeloma of lymphoma in order to predict their possible requirement for additional steroid therapy between and at the end of treatment courses. Standard insulin hypoglycaemia tests performed 36 hours after the last dose of prednisolone often demonstrated impairment of corticotrophin (adrenocorticotrophic hormone, A.C.T.H.) and growth-hormone responses, indicating hypothalamic/pituitary suppression; plasma-corticosteroid responses to endogenous A.C.T.H. and tetracosactrin were abnormal in two patients, indicating secondary adrenal suppression. Such hypothalamic/pituitary and adrenal suppression may make these patients susceptible to acute adrenal insufficiency in times of stress. H.P.A. function should be fully assessed on completion of chemotherapy.