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BACKGROUND: Body mass index (BMI) and smoking have been positively associated with hemoglobin concentration, and both are risk factors for cardiovascular disease. OBJECTIVE: The aim of this study was to assess whether there were sex differences in how changes in BMI and smoking habits influenced hemoglobin concentration. METHODS: In 1994-95 and 2001-02, a longitudinal, population-based study was conducted in the municipality of Tromsø, in northern Norway. Inhabitants aged > or =25 years were invited to participate. Participants replied to a questionnaire regarding health, physical activity, coffee and alcohol consumption, and smoking habits. Blood samples were drawn to analyze hemoglobin concentration. All analyses were performed separately for each sex. Differences between 1994-95 and 2001-02 were examined with t or chi(2) (McNemar) tests for paired data. Cross-sectional comparisons were made using 2-sample t tests. Different models of univariate and multiple linear regression analyses were used to investigate the impact of the various variables on hemoglobin change. RESULTS: Data from a total of 2105 men and 2945 women were examined. At baseline, mean age was 58.9 years for men (range, 25-78 years) and 57.8 years for women (range, 25-82 years); mean BMI was 26.1 kg/m(2) for men and 25.8 kg/m(2) for women. In men, hemoglobin decreased with age, on average from 147.5 to 145.1 g/L. In women, hemoglobin decreased from 135.6 to 134.7 g/L, but increased with increasing age up to 54 years, and thereafter decreased gradually. Mean BMI increased 0.8 kg/m(2) in men and 1.2 kg/m(2) in women. In total, 394 of 2057 men (19%) and 499 of 2889 women (17%) stopped smoking or smoked fewer cigarettes per day. In a univariate regression model, an increase of 1 kg/m(2) in BMI was associated with an increase in hemoglobin of 1.1 g/L (95% CI, 0.84 to 1.27) in men and 0.4 g/L (95% CI, 0.30 to 0.56) in women. In another univariate model, smoking cessation was associated with a decrease in hemoglobin of 1.9 g/L (95% CI, -3.32 to -0.56) in men and 1.7 g/L (95% CI, -2.93 to -0.56) in women. In men who smoked less and had a BMI increase of >2.5 kg/m(2), hemoglobin decreased 0.3 g/L. In contrast, hemoglobin decreased 3.4 g/L in men who smoked less and lost weight (P for trend, < 0.001 by changing BMI). Women who smoked less had a decrease in hemoglobin independent of BMI changes. CONCLUSIONS: The positive association between an increase in BMI and hemoglobin was stronger in men than in women. The effect of smoking reduction on hemoglobin was attenuated with increasing BMI in men, but not in women. [ABSTRACT FROM AUTHOR]

Aim: To examine whether N-terminal proCNP concentrations in serum is associated with bone destruction in patients with multiple myeloma., Materials & Methods: N-terminal proCNP and biochemical bone markers were measured in 153 patients. Radiographic bone disease and skeletal-related events were evaluated at specific time-points., Results: N-terminal proCNP concentrations increased with age. High N-terminal proCNP concentrations were associated with high-risk disease and renal impairment. Renal function explained 22% of the variation. N-terminal proCNP concentrations correlated with serum bone ALP and serum PINP, but lacked association with bone resorption markers, radiographic bone disease and skeletal-related events., Conclusion: Serum N-terminal proCNP are associated with bone formation activity in patients with multiple myeloma, but should be interpreted with caution in patients with renal impairment.

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the ≥ VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

Objective: Hereditary hemochromatosis has an autosomal recessive inheritance. The C282Y homozygosity is the most common genetic mutation in persons of Northern European descent. A screen of two multiethnic populations in Northern Norway was performed to investigate whether the prevalence of hereditary hemochromatosis was consistent with previous results in Northern Europe., Material and Methods: Participants in two population-based studies in Northern Norway were analyzed for serum ferritin (s-ferritin) and transferrin saturation. Participants with s-ferritin or transferrin saturation above the reference limits in two separate blood samples were tested for three different HFE mutations, namely C282Y, H63D and S65., Results: The estimated prevalence of the C282Y/C282Y mutation in the two municipalities studied was lower than in comparable studies in Norway. The prevalence was the lowest in the Sør-Varanger population (men 0.19% and women 0.22%), which also had the highest proportion of individuals with Sami and Kven affiliation. In Tromsø, the prevalence was consistent with previous results in Norway., Conclusions: The prevalence of hereditary hemochromatosis is lower in multiethnic populations in Northern Norway than in previous studies from other parts of Norway.

Background: Several laboratories have shown that cells with a memory B-cell phenotype can have the same clonotype as multiple myeloma tumor cells., Design and Methods: The aim of this study was to determine whether some memory B cells have the same genetic alterations as their corresponding multiple myeloma malignant plasma cells. The methodology included sorting multiple myeloma or memory B cells into RNA stabilizing medium for generation of subset-specific polymerase chain reaction complementary DNA libraries from one or 100 cells., Results: Cells with the phenotype of tumor plasma cells (CD38(++)CD19(-)CD45(-/+)CD56(-/+/++)) or memory B cells (CD38(-)/CD19(+)/CD27(+)) were isolated by flow activated cell sorting. In samples from all four patients with multiple myeloma and from two of the three with monoclonal gammopathy of undetermined significance, we identified memory B cells expressing multiple myeloma-specific oncogenes (FGFR3; IGH-MMSET; CCND1 high) dysregulated by an IGH translocation in the respective tumor plasma cells. By contrast, in seven patients with multiple myeloma, each of whom had tumor plasma cells with a K-RAS61 mutation, a total of 32,400 memory B cells were analyzed using a sensitive allele-specific, competitive blocker polymerase chain reaction assay, but no K-RAS mutations were identified., Conclusions: The increased expression of a specific "early" oncogene of multiple myeloma (monoclonal gammopathy of undetermined significance) in some memory B cells suggests that dysregulation of the oncogene occurs in a precursor B-cell that can generate memory B cells and transformed plasma cells. However, if memory B cells lack "late" oncogene (K-RAS) mutations but express the "early" oncogene, they cannot be involved in maintaining the multiple myeloma tumor, but presumably represent a clonotypic remnant that is only partially transformed.

Background: Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma., Methods: This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883., Findings: From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group., Interpretation: Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma., Funding: Nordic Cancer Union and Novartis Healthcare., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

Background and Aim: The clinical impact of multiparametric flow cytometry (MFC) in multiple myeloma (MM) is still unclear and under evaluation. Further progress relies on multiparametric profiling of the neoplastic plasma cell (PC) compartment to provide an accurate image of the stage of differentiation. The primary aim of this study was to perform global analysis of CD expression on the PC compartment and subsequently to evaluate the prognostic impact. Secondary aims were to study the diagnostic and predictive impact., Design and Methods: The design included a retrospective analysis of MFC data generated from diagnostic bone marrow (BM) samples of 109 Nordic patients included in clinical trials within NMSG. Whole marrow were analyzed by MFC for identification of end-stage CD45(-) /CD38(++) neoplastic PC and registered the relative numbers of events and mean fluorescence intensity (MFI) staining for CD19, CD20, CD27, CD28, CD38, CD44, CD45, CD56, and isotypes for cluster analysis., Results: The median MFC-PC number was 15%, and the median light microscopy (LM)-PC number was 35%. However, the numbers were significant correlated and the prognostic value with an increased relative risk (95% CI) of 3.1 (1.7-5.5) and 2.9 (1.4-6.2), P < 0.0003 and P < 0.004 of MFC-PC and LM-PC counts, respectively. Unsupervised clustering based on global MFI assessment on PC revealed two clusters based on CD expression profiling. Cluster I with high intensity for CD56, CD38, CD45, right-angle light-scatter signal (SSC), forward-angle light-scatter signal (FSC), and low for CD28, CD19, and a Cluster II, with low intensity of CD56, CD38, CD45, SSC, FSC, and high for CD28, CD19 with a median survival of 39 months and 19 months, respectively (P = 0.02)., Conclusions: The MFC analysis of MM BM samples produces diagnostic, prognostic, and predictive information useful in clinical practice, which will be prospectively validated within the European Myeloma Network (EMN). © 2010 International Clinical Cytometry Society., (Copyright © 2010 International Clinical Cytometry Society.)

Myelofibrosis is commonly seen in patients with chronic myeloproliferative diseases and sometimes in myelodysplastic syndrome, acute leukaemia and lymphoproliferative diseases. The fibrotic process is evaluated by grading the amount of collagen deposited in the bone marrow interstitium. The established method to evaluate bone marrow fibrosis is staining for reticulin to visualise the collagen fibres. However, the extra cellular matrix does not only contain collagens but also other components, e.g. glycosaminoglycans of which hyaluronan is the most abundant. Hyaluronan is important for structural and cellular functions. Earlier studies have shown that there is a positive correlation between hyaluronan and reticulin staining in healthy volunteers and in patients with de novo acute myeloid leukaemia. In this study bone marrow biopsies from 43 patients with a malignant disease involving the bone marrow were compared with 18 patients with a malignant disease not involving the bone marrow. The intensity of hyaluronan grading was significantly higher in the patients with disease involving the bone marrow compared to the healthy controls but not compared to the patients without disease involving the bone marrow. The staining intensity of reticulin in the bone marrow was significantly higher in the patients with disease involving the bone marrow, compared to those without disease involving the bone marrow and to the controls. In all patients and the controls there was a correlation between hyaluronan and reticulin.

We have used infrared emission spectroscopy (IRES) in order to perform in situ studies under flowing gas-phase conditions. When the small-volume cell developed herein is used, we can (1) observe emission spectra from a hot gas-phase sample having an effective volume much less than one milliliter, (2) observe spectra of typical molecular species present, and (3) observe spectra of the more important molecular species down to below 10% and in some cases even as low as 1%. In addition, an analytical method has been derived in order to conduct quantitative studies under typical reaction conditions. We show that simplifications can be made in the data acquisition and handling for a direct linear correlation between band intensity and concentration with only simple background correction. The practical lower limit for methane in the present setup is approximately 0.5-1% v/v depending on the selected temperature. Our data were collected at 500, 600, and 700 degrees C, respectively. The major features of the present cell design are fairly simple and basically formed by a quartz tube (outer diameter=6 mm, inner diameter=4 mm) inside a metal pipe and two tubular ceramic heaters. This simple setup has advantages and attractive features that have extended the application of IRES to new fields and, in particular, for in situ studies of hydrocarbon reactions at different residence times at high temperature.

Multiple myeloma (MM) is an incurable B-cell malignancy characterised by uncontrolled growth and accumulation of malignant plasma cells in the bone marrow. Aberrant expression of CD56 in patients with MM is thought to contribute to a worsened disease course and metastasis. We therefore investigated the regulation of the CD56 promoter in relation to typical clinical factors. We used qPCR and FACS to measure the expression levels of CD56, and potential regulatory factors in patients with MM and related these with MM progression/prognosis. The transcription factors BTBD3, Pax5, RUNX1 and MMSET were positively associated with CD56 expression, as was CYCLIN D1, which is involved in disease progression, anti-apoptosis and proliferation. RUNX1 was negatively associated with the survival of stem-cell transplanted patients. Our findings propose four potential activators of the CD56 promoter and for CD56 to be involved in proliferation and anti-apoptosis, leading to disease progression in MM.

Osteolytic bone disease (OBD) in multiple myeloma (MM) is caused by interactions between MM cells and the bone marrow microenvironment and is characterized by increased osteoclastic bone resorption and decreased osteoblastic bone formation. Recently, the role of osteoblast inhibition has come into focus, especially the possible role of overexpression of DKK1, an inhibitor of the Wnt signalling pathway. Further, CKS2, PSME2 and DHFR have also been reported as candidate genes for OBD. We studied the gene expression by quantitative reverse transcription polymerase chain reaction of TNFSF11 (RANKL), TNFSF11A (RANK), TNFRSF11B (OPG), CCL3 (MIP1A), CCL4 (MIP1B), PTHR1 (PTHrp), DKK1, CKS2, PSME2 and DHFR in purified, immunophenotypic FACS-sorted plasma cells from 171 newly diagnosed MM patients, 20 patients with monoclonal gammopathy of undetermined significance and 12 controls. The gene expressions of the analysed genes were correlated with radiographically assessed OBD. Only overexpression of DKK1 was correlated to the degree of OBD. Myeloma cells did not express TNFSF11A, TNFSF11, or TNFRSF11B, and very rarely expressed CCL3 and PTHR11. CCL4, CKS2, PSME2 and DHFR were variably expressed, but the expression of these genes showed no correlation with OBD. In contrast, loss of PSME2 expression in MM plasma cells was significantly correlated with OBD.

CD47 and thrombospondin 1 and 2 (TSP1 and TSP2) expression were analysed by real-time reverse transcription polymerase chain reaction in fluorescence-activated cell sorted plasma cells (PCs) from patients at consecutive stages of multiple myeloma (MM) development. 80% of MM patients, but only 39% of patients with monoclonal gammopathy of undetermined significance (MGUS) expressed CD47; median expression level increased 10-fold with progression from MGUS to MM. Elevated TSP1/TSP2 levels occurred in bone marrow cultures from MM patients compared with healthy donors. CD47 and TSP1/TSP2 may have a potential role in the pathophysiology of MM, probably in the interaction between MM PCs and the microenvironment.

Objectives: The purpose of this study was to investigate iron status in a population with a high proportion of miners in the northernmost part of Norway., Study Design: Cross-sectional, population-based study performed in order to investigate possible health effects of pollution in the population living on both sides of the Norwegian-Russian border., Methods: All individuals living in the community of Sør-Varanger were invited for screening in 1994. In 2000, blood samples from 2949 participants (response rate 66.8 %), age range 30-69 years, were defrosted. S-ferritin and transferrin saturation were analysed in samples from 1548 women and 1401 men. About 30 % (n = 893) were employed in the iron mining industry, 476 of whom were miners and 417 had other tasks in the company. Type and duration of employment and time since last day of work at the company were used as indicators of exposure., Results: Both s-ferritin levels and transferrin saturation were higher in men than in women. S-ferritin increased with increasing age in women, while the opposite was true for men. Iron deficiency occurred with higher frequencies in women (16 %) than in men (4 %). Iron overload was uncommon in both sexes. Adjustment for smoking and self-reported pulmonary diseases did not show any effect on iron levels. Miners had non-significant higher mean s-ferritin and transferrin saturation than non-miners. Neither duration, nor time since employment in the mine, had any impact on iron status., Conclusions: Our analyses did not show any associations between being a miner in the iron mining industry and serum iron levels compared to the general population.

Background: Normally the body is unable to regulate its own iron content effectively by excretion. Urinary excretion of iron is about 10% of total daily loss., Case Presentation: A 40-year-old woman was admitted to hospital because of anaemia that turned out to be caused by iron deficiency. In spite of extensive investigations no cause of her iron deficiency was identified. The urine was then tested for iron and showed excessive urinary loss as the cause of her anaemia. To our knowledge, extensive urinary iron loss as the cause of iron deficiency has not been reported before.

Objectives: A potential role in cancer biology is suggested for YKL-40 (CHI3L1, HC gp-39). The purpose of this study was to evaluate the clinical value of serum YKL-40 (sYKL-40) in multiple myeloma (MM) and to examine YKL-40 expression in malignant plasma cells (MM PCs)., Methods: sYKL-40 was measured by enzyme-linked immunosorbent assay (ELISA) in 82 patients with newly diagnosed MM. YKL-40 expression in immunophenotypically defined plasma cells was investigated by double-labelled immunohistochemistry in 21 MM patients and by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in cDNA archives generated by global RT-PCR in seven controls, 14 patients with monoclonal gammopathy of undetermined significance (MGUS), 45 MM patients, nine patients with extramedullary myeloma (exMM), and seven human myeloma cell lines (HMCLs)., Results: sYKL-40 was elevated above a constructed reference range for healthy controls in 29% of the patients investigated. Patients with elevated sYKL-40 had reduced overall survival and event-free survival when compared to patients with normal sYKL-40, but sYKL-40 level was defeated by beta(2)-microglobulin in the multivariate analyses. Intramedullary MM PCs lacked significant expression of YKL-40, but high levels of YKL-40 expression were seen in extramedullary MM PCs from one exMM patient and in six HMCLs. Further investigations of other bone marrow (BM) cells showed YKL-40 expression in megakaryocytes, neutrophils and adherent cells from long-term BM cultures., Conclusions: In newly diagnosed MM-patients, a sYKL-40 elevated above the reference range predicts a poor clinical outcome, and YKL-40 is expressed by other BM cells than MM PCs. At this point, routine measurements of sYKL-40 are not warranted, but YKL-40 should be considered as a potential player in the pathophysiology of MM.

Background and Objectives: From 1994 to 1997 we conducted a population-based, prospective study on intensive therapy in newly diagnosed symptomatic myeloma patients younger than 60 years, comparing their survival to that of a conventionally treated historic population. Long-term results are presented, including the impact of the degree of response on survival and relapse pattern after transplantation., Design and Methods: The prospective population was formed of 397 patients and the historic population of 313 patients. Both populations were calculated to comprise more than 75% of the expected number of new cases., Results: After a median follow-up of 7 years survival was longer in the prospective population than in the historic one (median 60 versus 39 months; p=0.0002). When comparing only patients eligible for intensive therapy the median survival was 63 versus 44 months (p<0.0001). Attaining a complete response was associated with prolonged event-free survival but not overall survival. The pattern of relapse after transplantation was heterogeneous but could be divided into four major groups; insidious, classical, plasmacytoma form and transformed disease. The median survival after relapse was 29 months. The relapse pattern and time to relapse predicted outcome. Patients relapsing with an insidious or classical form of disease with skeletal events only, or after a long lasting first response were likely to respond well to conventional salvage therapy. In contrast, relapse with multiple symptoms, transformed disease or a short duration of first response implied bad prognosis., Interpretation and Conclusions: The relapse pattern after autologous transplantation is heterogeneous and response to salvage therapy is variable. The degree of response and event-free survival after transplantation are not reliable surrogate markers for survival.

An experimental and theoretical study of the absolute value of the one-bond spin-spin coupling constant |(1)J(Si,H)| in SiH(n)Cl(4-n) (n = 0-4) dissolved in THF-d(8) is presented. We found |(1)J(Si,H)| to increase with an increasing number of chlorine substituents, and the quantitative changes were found to differ from the values previously reported for the same compounds dissolved in cyclohexane-d(12). We also report on the variations in |(1)J(Si,H)| as a function of temperature, which we found to be linearly temperature dependent for the chlorine-substituted silanes and temperature independent for SiH(4). Furthermore, the temperature dependence of |(1)J(Si,H)| varied between the different chlorosilanes. Solvent-solute interactions were studied by quantum chemical DFT calculations. The variations in chloro-silane bond lengths upon adduct formation and the different adduct interaction energies may explain the temperature dependences of the coupling constants.

The present study evaluated the combination of antithymocyte globulin (ATG) and cyclosporine A (CsA) in patients with low-risk myelodysplastic syndromes. Twenty patients (17 with refractory anemia and 3 with refractory anemia with excess blasts) received treatment with rabbit-ATG plus CsA. The overall response rate was 30% (6/20); three of the six responders had a complete response. The responses lasted 2-58 months, with two patients still being in complete remission at 42 and 58 months. Short-lasting cytogenetic remissions were achieved in two patients. ATG was poorly tolerated in patients over 70 years of age. Four out of 20 patients progressed to acute myeloid leukemia within a year. We conclude that immunosuppressive treatment may be a therapeutic option for selected patients with myelodysplastic syndrome.

The value of intensive therapy, including autologous stem cell transplantation, in newly diagnosed myeloma patients >60 years is not clear. We evaluated the impact of age (<60 years vs. 60-64 years) on survival in a prospective, population-based setting and compared survival with conventionally treated historic controls. The prospective population comprised 452 patients registered between 1998 and 2000. Of these, 414 received intensive therapy. The historic population, derived from our most recent population-based study on conventional therapy, comprised 281 patients. Of these, 243 fulfilled our eligibility criteria for intensive therapy. For patients undergoing intensive therapy it was found that two factors, beta-2-microglobulin and age <60 years vs. 60-64 years, had independent prognostic impact on survival. However, compared with the historic controls a survival advantage was found both for patients <60 (median 66 months vs. 43 months, P < 0.001) and 60-64 years (median 50 months vs. 27 months; P = 0.001). We conclude that in a population-based setting higher age adversely influences outcome after intensive therapy. Our results indicate that intensive therapy prolongs survival also at age 60-64 years but with less superiority than in younger patients.

Haemoglobin level declines with increasing age in cross sectional studies. Little is known about the longitudinal changes of haemoglobin. Because both high or low haemoglobin levels increase mortality and morbidity we examined how changes in lifestyle factors like body mass index (BMI) and smoking habits influence cohort changes in haemoglobin level. In all, 4159 men aged 20-49 years at baseline were examined in 1974 and 1994-1995 in a longitudinal, population-based study from the municipality of Tromsø, Northern Norway. Mean haemoglobin was 148 g/l. There was no difference in mean haemoglobin after 20 years in any strata of age. Mean BMI increased 2.1 kg/m(2). The prevalence of smokers decreased 20.1 percentage points. In a multiple regression analysis increase in BMI was associated with increased haemoglobin change. Smoking cessation lowered mean haemoglobin 1.6 g/l compared to never smokers. Haemoglobin increased 0.8 g/l in smoking quitters whose BMI increased >2.5 kg/m(2) compared to a decrease of 6.7 g/l in weight reducers. There was a positive dose-response relationship between changes in cigarettes smoked per day and change in haemoglobin among consistent smokers. In conclusion, in contrast to cross sectional studies, mean haemoglobin did not change during 20 years ageing of relatively young men. This could be explained by higher BMI and less smoking. The increase in BMI affected haemoglobin change to such an extent that the reduction in haemoglobin due to smoking cessation was counteracted. Prospective studies are needed to address the health implications.

Objectives: To examine the gender-specific distribution of haemoglobin (Hb) and the World Health Organization (WHO) criteria for anaemia compared with the 2.5 percentile for Hb., Methods: A population-based study from Tromsø, Northern Norway. All inhabitants above 24 yr were invited. In total, 26 530 (75%) had their Hb analysed., Results: The 2.5-97.5 percentile of Hb was 129-166 and 114-152 g/L for all men and women, respectively. In men, mean Hb decreased from 148 to 137 g/L between 55-64 and 85+ yr. In women, mean Hb increased from 132 to 137 g/L between 35-44 and 65-74 yr and then decreased to 131 g/L among the oldest. Using the WHO criteria for anaemia (Hb: <130 and <120 g/L, men and women respectively), the prevalence of anaemia in men increased with age from 0.6% aged 25-34 to 29.6% aged 85+. For women, the prevalence of anaemia varied from 9.1%, 2.2% and 16.5% in the age groups of 35-44, 55-64 and 85+ yr, respectively. The WHO criteria gave a two to three times higher prevalence of anaemia compared with the 2.5 percentile of Hb in women, but the difference was small in men. Poor self-rated health was not associated with low values of Hb in women. In men, there was an association in some age groups., Conclusion: The WHO criteria for anaemia and the 2.5 percentile for Hb corresponded well for men, but not for women. The WHO criteria of anaemia may result in medicalization of healthy women.

To assess a possible role in tumor progression, the occurrence and type of K- and N-RAS mutations were determined in purified tumor cells, including samples from patients with premalignant monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and extramedullary plasma cell (PC) tumors (ExPCTs). Immunophenotypic aberrant PCs were flow sorted from 20 MGUS, 58 MM, and 13 ExPCT patients. One RAS mutation was identified in 20 MGUS tumors (5%), in contrast to a much higher prevalence of RAS mutations in all stages of MM (about 31%). Further, oncogene analyses showed that RAS mutations are not evenly distributed among different molecular subclasses of MM, with the prevalence being increased in MM-expressing cyclin D1 (P = .015) and decreased in MM with t(4;14) (P = .055). We conclude that RAS mutations often provide a genetic marker if not a causal event in the evolution of MGUS to MM. Surprisingly, RAS mutations were absent in bone marrow tumor cells from all patients with ExPCT, a result significantly different from intramedullary MM (P = .001). From 3 of 6 patients with paired intramedullary and extramedullary PCs and identical immunoglobulin heavy chain gene (IgH) sequences, RAS mutations were identified only in extramedullary PCs, suggesting a role for RAS mutations in the transition from intramedullary to extramedullary tumor.

Acute myeloid leukemia (AML) is a clonal disorder characterized by abnormal proliferation of myeloid cell precursors. Research has mainly focused on the cellular events, but the bone marrow matrix has attracted minor interest. In this study bone marrow biopsies were obtained from 35 newly diagnosed AML patients. The bone marrows were analyzed regarding the occurrence and distribution of hyaluronan (HYA) and reticulin fibers (type III collagen). The bone marrow sections were analyzed histochemically and compared with bone marrows from 30 healthy controls. The HYA staining was significantly stronger in the AML patients compared with the controls. Only one patient demonstrated abnormal reticulin staining score, but in the group of patients with antecedent myelodysplastic syndrome (MDS), the reticulin staining score was significantly higher compared with the patients with de novo AML. There was a significant correlation between the HYA staining and reticulin staining scores in the AML patients as was seen in the control group.

Background and Objectives: Osteopontin (OPN) is a non-collagenous matrix protein produced by various cells including osteoblasts, osteoclasts and several types of tumor cells. It is involved in a number of physiologic and pathologic events including adhesion, angiogenesis, apoptosis, inflammation, wound healing and tumor metastasis. We wanted to investigate the potential role of OPN in multiple myeloma., Design and Methods: Myeloma cells and stromal cells from myeloma patients were investigated as potential OPN-producers. Furthermore, OPN was tested in proliferation, migration and adhesion assays with myeloma cells. Serum and plasma OPN in myeloma patients were measured by enzyme-linked immunosorbent assay (ELISA). OPN levels were correlated to disease variables at diagnosis and to disease outcome., Results: Myeloma cells produce OPN, and stromal cells from myeloma patients express higher levels of OPN than stromal cells from healthy controls. The myeloma cell lines ANBL-6 and INA-6 adhered to OPN. NOD/SCID mice inoculated with OPN-producing ANBL-6 cells had elevated levels of murine OPN in serum, whereas human OPN was not detectable. Plasma and serum levels of OPN were significantly higher in myeloma patients than in healthy individuals. Interpretation and Conclusions. Myeloma cell lines adhere to OPN, indicating that elevated stromal expression of OPN may be one of the factors responsible for the retention of myeloma cells in the bone marrow. The elevated plasma OPN levels in myeloma patients could be due to both production of OPN by the tumor cells and tumor-induced production of OPN by non-tumor cells.

This study investigated the expression pattern in primary plasma cells (PCs) of putative oncogenes suggested to be involved in multiple myeloma (MM) development. cDNA archives were generated by global reverse transcription polymerase chain reaction from CD38++/CD19-/CD56-/++ aberrant PCs of a prospective cohort of 96 subjects, including healthy individuals, patients with monoclonal gammopathies of undetermined significance (MGUS), MM and MM with extramedullary manifestations (ExMM). The cDNA archives were analysed quantitatively for expression of the cyclin D1, fibroblast growth factor receptor 3 (FGFR3), C-MYC, C-MAF and cyclin D3 oncogenes. In addition, all patients were screened for IGH-MMSET hybrid transcripts. None of the analysed oncogenes was randomly distributed. C-MYC and cyclin D3 expression increased at the extramedullary transformation stage. Furthermore, C-MYC and cyclin D3 expression in CD56+ MM was similar to MGUS, whereas CD56- MM was similar to ExMM. FGFR3/IGH-MMSET was only observed among CD56+ MM patients, whereas an increased frequency of C-MAF dysregulation was seen among CD56- MM. High cyclin D1 expression levels were identified at similar frequencies at all stages, whereas the frequency of patients with low cyclin D1 levels increased during MM development. These data support the stepwise transformation model accumulating genetic alterations and proliferative capacity during MM initiation and development resulting in different clinical entities.

To investigate the frequency and possible biological consequences of c-maf dysregulation, we designed c-maf and IL-4 real-time RT-PCR assays for determination of c-maf and IL-4 mRNA levels. Using the c-maf real-time RT-PCR assay, we tested a panel of 14 B-cell lines, 135 diagnostic bone marrow (BM) samples from patients with multiple myeloma and 10 BM samples from normal donors. In B cell lines and flowsorted CD38++/CD19-/CD56++ myeloma plasma cells (N = 14) the c-maf/GAPDH and IL-4/GAPDH ratios were determined simultaneously using real time RT-PCR. All B cell lines used in the study were characterized by flow cytometry and tested for the presence of Ebstein-Barr virus (EBV). B-cell lines, that were PCR negative for EBV and had a phenotype typical for primary myeloma cells, expressed medium to high levels of c-maf mRNA. However, all EBV PCR positive cell lines, showed a more immature phenotype, lacked expression of aberrant surface markers and contained very low levels of c-maf mRNA. In 4.4% (6/135) of MM patients tested, a c-maf mRNA level comparable to the cell line RPMI 8226 containing at (16:22), translocation was found. In addition, all c-maf positive myeloma cell lines and CD38++/CD19-/CD56++ myeloma plasma cells tested were IL-4 negative. In conclusion, high levels of c-maf mRNA were observed in "true MM cell lines" and 4.4% of MM patients. Further, c-maf dysregulation in myeloma plasma cells did not cause induction of IL-4 transcription.

In this prospective randomized multicenter trial 93 patients, median age 72 years, with RAEB-t (n=25) and myelodysplastic syndrome (MDS)-AML (n=68) were allocated to a standard induction chemotherapy regimen (TAD 2+7) with or without addition of granulocyte-macrophage-CSF (GM-CSF). The overall complete remission (CR) rate was 43% with no difference between the arms. Median survival times for all patients, CR patients, and non-CR patients were 280, 550, and 100 days, respectively, with no difference between the arms. Response rates were significantly better in patients with serum lactate dehydrogenase (S-LDH) levels

We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

Objectives: To investigate the prevalence and incidence of haematological malignancies, and to compare the rates found with those reported from the Cancer Registry of Norway., Methods: Three sources of information were used: (1) automated blood cell counts from 27 145 persons older than 24 yr (72% of those invited), participating in a population study (the Tromsø Study 1994-95); (2) patient medical records at the University Hospital of Tromsø during 1991-96; (3) the Cancer Registry of Norway., Results: (1) In the population study, 13 new cases of haematological malignancies were diagnosed. For five of these the early detection was probably beneficial. (2) From the hospital records another 59 participants and 36 non-participants to the population study were found to have haematological malignancies. (3) Additionally, six cases were identified from the Cancer Registry. Totally, we thus identified 114 period prevalent cases, of which 86% had been reported to the Cancer Registry. Age-adjusted period prevalence of haematological malignancies was 4.7 per thousand in men and 2.9 per thousand in women. The prevalence increased with age. There were 84 cases with leukaemia, lymphoma, or multiple myeloma diagnosed at any time and still alive at 31 December 1996 (point prevalence 2.2 per thousand). Our estimated incidence of haematological malignancies did not differ significantly from that reported from the Cancer Registry., Conclusion: We found approximately the same rates of haematological malignancies as the Cancer Registry, although an underreporting of 14% to the Cancer Registry was detected. The point prevalence of leukaemia, lymphoma, and multiple myeloma was 2.2%.

We report on the different expression of CD56 and CD44 in plasma cells (PCs) simultaneously collected from bone marrow, extramedullary locations and peripheral blood in seven patients with multiple myeloma. Extramedullary PCs showed absence of CD56. In the bone marrow, however, subsets with varying CD56 expression were found in five out of seven patients, with one subset corresponding to that of extramedullar PCs. This differs from the de novo downregulation of CD56 in PC leukaemia, and suggests different mechanisms of spread of myeloma cells. CD44 expression was generally upregulated on extramedullary PCs. In three of the patients we investigated the clonal origin of extramedullary myeloma cells by sequencing the variable portion of the heavy chain immunoglobulin gene in phenotypically defined PCs isolated from different locations. In each patient we found malignant PCs with different homing behaviour originating from a common precursor cell.

Background: Since the introduction of the simple cyclic oral treatment with melphalan and prednisone in the late 1960s, there has been no substantial improvement in the therapy of multiple myeloma. In 1994, the Nordic Myeloma Study Group initiated a population-based, prospective study to evaluate the impact on survival of high dose chemotherapy in newly diagnosed, symptomatic patients under 60 years of age, compared to a conventionally treated control group., Material and Methods: 274 patients were treated according to a specified high dose protocol and compared to 274 patients from previous population-based trials fulfilling the same eligibility criteria., Results: Median survival was 44 months in the control group and 62 months in the intensive treatment group (risk ratio 1.65; 95% CI = 1.28-2.14, P = 0.0001). A study of health-related quality of life (HRQoL) which was integrated in the trial showed a moderately reduced HRQoL associated with the intensive treatment phase, but no statistically significant difference beyond the first year of follow-up. In a cost-utility analysis of the trial, the cost per (quality-adjusted life years) was estimated at USD 26,000., Interpretation: The incremental cost of the treatment is within what is usually thought to be acceptable limits. Further improvement of the results and reduction of stay in hospital would give an even more favourable cost-utility ratio.

In a population-based study, the Nordic Myeloma Study Group found a survival advantage for high-dose melphalan with autologous blood stem-cell support compared to conventional chemotherapy in myeloma patients under 60 yr of age (risk ratio: 1.62; confidence interval [CI] 1.22-2.15; p = 0.001). A study of health-related quality of life (HRQoL) was integrated in the trial, using the EORTC QLQ-C30 questionnaire. Of the 274 patients receiving intensive therapy 221 (81%) were compared to 113 (94%) of 120 patients receiving conventional melphalan-prednisone treatment. Prior to treatment, there were no statistically significant differences in any HRQoL score between the two groups. One month after the start of induction chemotherapy, the patients on intensive treatment had more sleep disturbance than the control patients. At 6 mo, corresponding to a mean of 52 d after high-dose melphalan, the patients on intensive treatment had moderately lower scores for global QoL and role and social functioning and there was also a significantly higher score for appetite loss. At 12 and 24 mo, the HRQoL was similar to that of the control patients. At 36 mo, there was a trend toward less fatigue, pain, nausea, and appetite loss in the intensive-treatment group. Thus, the 18 mo of prolonged survival seem to be associated with a good health-related quality of life. Despite the moderate HRQoL reduction associated with the early intensive chemotherapy phase, this treatment modality must be regarded as an important step forward in the care of multiple myeloma.

Recently, a subset of dendritic cells with the phenotype CD68+/CD83+/CD1a-, present in patients with multiple myeloma (MM), was reported to be infected with human herpesvirus 8 (HHV-8). Therefore we wished to clarify whether HHV-8 infection might be related to the pathogenesis of MM. In an attempt to identify HHV-8 infected cells in patients with MM, long-term bone marrow cultures from 8 MM patients and dendritic cell cultures from 11 MM patients were established. In addition, fresh bone marrow aspirates from 10 MM and 10 patients with monoclonal gammopathy of undetermined significance (MGUS) were included in the study. All samples were analysed by a sensitive semi-nested PCR assay and were found to be consistently PCR negative. Phenotyping of day 7 dendritic cell cultures demonstrated the presence of a sufficient number of CD68+/CD1a- and CD83+/CD1a- cells. However, to exclude the presence of infrequent HHV-8 infected cells, the CD68+/CD1a- subset from 3 dendritic cell cultures was sorted in numbers of 105 for each PCR test, and again a negative PCR result was observed. This study documents that the CD68+/CD83+/CD1a- dendritic cells in patients with MM are not generally infected with HHV-8 and, as a consequence, it is unlikely that HHV-8 plays a role in the pathogenesis of MM.

Serum samples drawn at diagnosis from 174 myeloma patients were analyzed for the presence of the heparan [corrected] sulfate proteoglycan, syndecan-1. Syndecan-1 was elevated in 79% of patients (median, 643 units/mL) compared with 40 healthy controls (median, 128 units/mL), P <.0001. Serum syndecan-1 correlated with the following: serum creatinine, secretion of urine M-component over the course of 24 hours, soluble interleukin-6 (IL-6) receptor, C-terminal telopeptide of type I collagen, beta(2)-microglobulin, percentage of plasma cells in the bone marrow, disease stage, and serum M-component concentration. In order to evaluate syndecan-1 as a prognostic marker in multiple myeloma, it was entered into a multivariate Cox regression model. Data from 138 patients were available for this analysis. As a continuous variable, syndecan-1 was an independent prognostic parameter in addition to serum beta(2)-microglobulin and World Health Organization performance status. When syndecan-1 was dichotomized by the best cutoff (66th percentile, 1170 units/mL), the survival difference between the groups was highly significant: "high" syndecan-1 group had a median survival of 20 months, and the "low" syndecan-1 group had a median of 44 months (P <.0001). We conclude that syndecan-1 is a new independent prognostic parameter in multiple myeloma, and its role in prognostic classification systems should be further investigated. (Blood. 2000;95:388-392)

High-dose therapy has become a common treatment for myeloma. The objectives of this study were to estimate in a prospective, population-based setting the impact on survival of high-dose therapy in newly diagnosed, symptomatic patients less than 60 years old and to compare the results with those of conventionally treated historic controls. The prospective population comprised 348 patients. Of these, 274 were treated according to a specified intensive-therapy protocol (Nordic Myeloma Study Group [NMSG] #5/94) and constituted the intensive-therapy group. The historic population consisted of 313 patients identified from 5 previous population-based Nordic studies. Of these, 274 fulfilled the eligibility criteria for high-dose therapy stated in NMSG #5/94 and constituted the control group. The expected numbers of patients in the prospective population and the historic population were 450 and 410, respectively, estimated from previously established data on the incidence in this population and the population base for each study. Survival was prolonged in the intensive-therapy group compared with the control group (risk ratio for the control group 1.62; 95% confidence interval 1.22-2.15; P =.001). These groups represented more than 60% of the expected number of patients. When survival for all the registered patients in the 2 populations was compared, representing more than 75% of the expected number of patients, the advantage for the prospective population persisted (risk ratio for the historic population 1.46; 95% confidence interval 1.14-1.86; P =. 002). These results indicate that the introduction of high-dose therapy for newly diagnosed myeloma has resulted in prolonged survival for the total patient population aged less than 60 years. (Blood. 2000; 95:7-11)

Serum from 386 myeloma patients were analyzed for serum hyaluronan (HYA) at diagnosis. Median age was 68 years (range, 32 to 87 years). The distribution of Ig classes was typical (58% IgG, 21% IgA, 1% IgD, and 20% light chain disease). The patients comprised 58% in stage III, 33% in stage II, and 9% in stage I. The majority (82%) had HYA values within an intermediate range (10 to 120 micrograms/L), 13% had high values (>120 micrograms/L), and 5% had abnormally low values (0 to 9 micrograms/L). For the first time, a patient group with abnormally low HYA serum values is reported. An inverse correlation between survival and HYA serum level was found (P =.015). When tested separately, patients with abnormally low or high HYA values had significantly shorter median survival (21.1 and 19.7 months, respectively) than those with an intermediate HYA concentration (32. 6 months; P =.005). Patients with abnormally low or high HYA levels had more advanced disease as judged by staging and biochemical markers. Interestingly, there was an inverse correlation between the HYA value and the M-component concentration in serum. Fifty percent of patients with abnormally low HYA values had IgA myelomas. In conclusion, the serum concentration of HYA may be of prognostic value in selected cases of multiple myeloma. Further studies will be performed to elucidate possible explanations for our findings, especially those related to the HYA cell surface binding proteins.

The aim of the present investigation was to obtain information about treatment, clinical course and outcome for all patients with chronic myeloid leukaemia through a six-year period in a defined part of Norway. A total number of 141 patients fulfilled the diagnostic criteria. This is equivalent to 0.9 patients per 100,000 per year. The median age was 62 years. More than 70% of the patients were primarily treated with hydroxyurea, either alone or combined with interferon. 40 out of 57 patients younger than 55 years underwent allogeneic stem cell transplantation. Median survival for all patients was 36 months with an estimated five-year survival rate of 33%. Patients older than 55 years had a median survival of 30 months with 16% alive after five years. The five-year survival rate for patients younger than 55 years was 56%, for transplanted patients 72%. 60 of 84 patients older than 55 years have died after 4 1/2 years median observation time. Two thirds of those died of leukaemia; one third of other causes. 23 of 57 patients younger than 55 years have died. 11 of them had had transplantations and most of them died from transplantation-related causes, while leukaemia was the dominating cause of death in the others.

All febrile episodes (a total of 276) which occurred in 85 patients with acute myelogenous leukaemia treated in four Norwegian centres during the period 1990-1994 were studied retrospectively in order to assess the efficacy of antibiotic treatment. 72% of these episodes were initially treated with benzyl penicillin and aminoglycoside (standard treatment), while alternative empirical treatment was given in the remaining cases. The treatment was successful in 94% of the febrile episodes initially treated with standard treatment and in 96% of the episodes which received alternative antibiotics. For both types of treatment, a change to second line antibiotic regimen was made for various reasons in a majority of cases. The combination benzyl penicillin and aminoglycoside seems to be a safe empirical treatment for febrile neutropenia in patients with acute myelogenous leukaemia in our treatment centres, provided that the treatment is modified in patients with unsatisfactory clinical response.

In the past high-dose chemotherapy with autologous stem cell support in the treatment of certain types of cancer, was centralized to two hospitals in Norway. Almost three years ago it was decided that the treatment should be offered by all five university hospitals. In the northernmost university hospital of Norway, Tromsø, peripheral stem cells were harvested from 29 patients after successful mobilization with chemotherapy and granulocyte colony-stimulating factor (G-CSF). After high-dose chemotherapy, more than 2 x 10(6) CD34-positive stem cells/kg were transplanted in 24 patients and a sign of reconstitution of bone marrow function was achieved with mean time for neutrophils > 0.5x10(9)/l, 9.8 days and for platelets > 20x10(9)/l, 10.8 days. No treatment-related deaths have occurred. Transplantation of selected CD34-positive stem cells has been performed in one patient. Recovery was comparable to the recovery of patients who had undergone transplantation with unselected products. This indicates that even small centres performing as few as ten procedures per year may offer high-dose chemotherapy with autologous stem cell support safely and successfully.