Higher serum free thyroxine levels are associated with increased risk of hip fractures in older men.

Overt and subclinical hyperthyroidism are associated with an increased fracture risk, but whether thyroid hormones are associated with fracture risk in individuals with normal thyroid-stimulating hormone (TSH) has mostly been investigated in women. Therefore, we investigated if serum levels of free thyroxine (FT4) or TSH are associated with fracture risk in Swedish men. We followed (median 12.2 yr) elderly men (n = 1825; mean age 75, range 69-81 yr) participating in the Gothenburg and Malmö subcohorts of the prospective, population-based MrOS-Sweden study. The statistical analyses included Cox proportional hazards regression. Men receiving levothyroxine treatment were excluded. In our total cohort, serum FT4 (per SD increase) was associated with increased risk of major osteoporotic fractures (MOFs; n = 479; fully adjusted hazard ratio [HR] 1.14, 95% CI, 1.05-1.24) and hip fractures (n = 207; HR 1.18, 95% CI, 1.04-1.33). Also, in men with normal TSH (n = 1658), FT4 (per SD increase) was significantly associated with increased risk of MOF and hip fractures. Furthermore, men in the highest FT4 quartile had a 1.5-fold increase in hip fracture risk compared with men in the three lower FT4 quartiles, both in the total population and in men with normal TSH (fully adjusted: HR 1.45, 95% CI, 1.04-2.02 and HR 1.51, 95% CI, 1.07-2.12, respectively). In contrast, the risk of MOF was not statistically different in the highest FT4 quartile compared with the three lower FT4 quartiles. Finally, serum TSH was not associated with fracture risk after full adjustment for covariates. In conclusion, serum FT4, but not serum TSH, is a predictor of hip fracture risk in elderly Swedish men. Additionally, there was an association between FT4 (per SD increase) and the risk of MOF.

Intermittent high-dose glucocorticoid treatment does not cause adrenal insufficiency in patients with diffuse large B-cell lymphoma - a prospective study.

Glucocorticoid (GC) treatment suppresses the hypothalamic-pituitary-adrenal axis and can cause GC-induced adrenal insufficiency. In this study we investigated the incidence of GC-induced adrenal insufficiency in patients receiving intermittent short-term high-dose oral GC treatment for newly diagnosed diffuse large B-cell lymphoma. Cosyntropin stimulation test was used to assess adrenal function at study entry (baseline), at 2 months (before the 5th cycle), and 6 months from baseline (3 months after the last cycle). Ten patients were included (40% women). Mean age was 61 years. The mean (range) plasma morning cortisol was 407 (320-530) nmol/L at baseline, 373 (260-610) nmol/L at 2 months, and 372 (230-520) nmol/L 6 months from baseline. All patients had normal response to cosyntropin stimulation at baseline as well as 2 and 6 months from baseline. Thus, none of the patients developed biochemically verified adrenal insufficiency. Therefore, short-term high-dose GC therapy, a commonly used adjuvant treatment in patients with malignant hematological diseases, does not seem to down-regulate the hypothalamic-pituitary-adrenal axis.

Nationwide Assessment of Patient Trajectories in Mantle Cell Lymphoma: The Swedish MCLcomplete Project.

Mantle cell lymphoma (MCL) is a B-cell malignancy currently considered incurable. Although some patients obtain prolonged remission after first-line chemoimmunotherapy, many will need several treatment lines. Here, we present a nationwide assessment of treatment strategies, time to progression and survival in MCL. All patients diagnosed with MCL 2006-2018 were identified in the Swedish Lymphoma Register. Information on all lines of therapy was extracted from the medical records. Overall and progression-free survival (OS and PFS) were assessed through August 2021. In total, 1367 patients were included (median age, 71 years) and median follow-up was 6.8 years. Two hundred and one (15%) were managed initially with watch-and-wait, but 1235 (90%) eventually received treatment. The most frequently used first-line regimens were rituximab-bendamustine (BR) (n = 368; 30%) and Nordic MCL2 (n = 342; 28%). During follow-up, 630 patients (46%) experienced relapse/progression and 546 (40%) received second-line treatment. The most frequently used second-line regimen was BR (n = 185; 34%) but otherwise a wide variety of second-line treatments were used. Further, 382 and 228 patients experienced a second or third relapse/progression, respectively. Median PFS after first (PFS-1), second (PFS-2), third (PFS-3), and fourth (PFS-4) treatment lines was 29.4, 8.9, 4.3, and 2.7 months. Patients with early progression, defined as a PFS-1 <24 months, had an inferior median OS of 13 versus 37 months in patients with later relapse. For patients treated with frontline BR, however, time to relapse had no impact on later outcome. By use of nationwide population-based data, we provide important benchmarks for future studies of all treatment lines in MCL.

Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia: A Swedish nation-wide real-world report on consecutively identified patients.

OBJECTIVES: We examined the efficacy and toxicity of the PI3Kδ inhibitor idelalisib in combination with rituximab salvage therapy in consecutively identified Swedish patients with chronic lymphocytic leukemia (CLL). METHODS AND RESULTS: Thirty-seven patients with relapsed/refractory disease were included. The median number of prior lines of therapy was 3 (range 1-11); the median age was 69 years (range 50-89); 22% had Cumulative Illness Rating Scale (CIRS) >6 and 51% had del(17p)/TP53 mutation. The overall response rate was 65% (all but one was partial response [PR]). The median duration of therapy was 9.8 months (range 0.9-44.8). The median progression-free survival was 16.4 months (95% CI: 10.4-26.3) and median overall survival had not been reached (75% remained alive at 24 months of follow-up). The most common reason for cessation of therapy was colitis (n = 8, of which seven patients experienced grade ≥3 colitis). The most common serious adverse event was grade ≥3 infection, which occurred in 24 patients (65%). CONCLUSIONS: Our real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2.

Infection with Neoehrlichia mikurensis promotes the development of malignant B-cell lymphomas.

The tick-borne pathogen Neoehrlichia (N.) mikurensis is implicated in persistent infection of the vascular endothelium. B cells are crucial for the host defence to this infection. Chronic stimulation of B cells may result in B-cell transformation and lymphoma. Five patients with malignant B-cell lymphoma and concomitant N. mikurensis infection were investigated regarding clinical picture, lymphoma subtype, B-cell lymphoma immunophenotype and IGHV (variable region of the immunoglobulin heavy) gene repertoire. Three of the five patients improved markedly and ceased lymphoma treatment after doxycycline treatment to eliminate N. mikurensis. Sequencing the B-cell lymphoma IGHV genes revealed preferred usage of the IGHV1 (IGHV1-2, and -69) and IGHV3 (IGHV3-15, -21, -23) families. In conclusion, N. mikurensis infection may drive the development of malignant B-cell lymphomas. Eradication of the pathogen appears to induce remission with apparent curing of the lymphoma in some cases.

Diagnostic Outcomes and Treatment Modalities in Patients with Mycosis Fungoides in West Sweden-A Retrospective Register-Based Study.

(1) Background: Mycosis fungoides (MF) is a variant of primary cutaneous T-cell lymphoma. The aim of this study was to describe the clinical features and epidemiological and diagnostic findings in addition to the treatment modalities and responses in patients with MF. Furthermore, comparisons between patients in the early stage and the advanced stage were evaluated. (2) Methods: A retrospective register-based study based on data collected from the primary cutaneous lymphoma register and medical records was performed at the Department of Dermatology and Venerology at Sahlgrenska University Hospital, Gothenburg, Sweden. (3) Results: Eighty-four patients with a median age of 55 years with MF were included. Most of the patients (n = 73) were diagnosed at the early stage of the disease (IA-IIA). Overall disease progression was seen in 12.5% (n = 9) of the patients. Nine (10.7%) patients were deceased, out of which four (4.8%) deaths were associated with MF-related causes. (4) Conclusions: This study contributes to the knowledge of the epidemiological and clinical features in addition to the diagnostic findings and treatment responses in patients with MF in Sweden.

Anemia is associated with increased risk of non-vertebral osteoporotic fractures in elderly men: the MrOS Sweden cohort.

This study includes 1005 men from the Gothenburg part of the Osteoporotic Fracture in Men Study (MrOS). Included are 66 men with anemia (hemoglobin < 130 g/L). The follow-up time was up to 16 years, and the main results are that anemia is associated with all fractures and non-vertebral osteoporotic fractures. INTRODUCTION: Anemia and osteoporotic fractures are conditions that are associated with increased morbidity and mortality. Clinical studies have suggested that anemia can be used as a predictor of future osteoporotic fractures. METHOD: Men from the Osteoporotic Fractures in Men Study (MrOS) Sweden, Gothenburg, with available hemoglobin (Hb) values (n = 1005, median age 75.3 years (SD 3.2)), were included in the current analyses. Of these, 66 suffered from anemia, defined as Hb < 130 g/L. Median follow-up time for fracture was 10.1 years and the longest follow-up time was 16.1 years. RESULTS: Men with anemia had, at baseline, experienced more falls and had a higher prevalence of diabetes, cancer, prostate cancer, hypertension, and stroke. Anemia was not statistically significantly associated with bone mineral density (BMD). Men with anemia had higher serum levels of fibroblast growth factor 23 (iFGF23) (p < 0.001) and phosphate (p = 0.001) and lower serum levels of testosterone (p < 0.001) and estradiol (p < 0.001). Moreover, men with anemia had an increased risk of any fracture (hazard ratio (HR) 1.97, 95% CI 1.28-3.02) and non-vertebral osteoporotic fracture (HR 2.15, 95% CI 1.18-3.93), after adjustment for age and total hip BMD, in 10 years. The risk for any fracture was increased in 10 and 16 years independently of falls, comorbidities, inflammation, and sex hormones. The age-adjusted risk of hip fracture was increased in men with anemia (HR 2.32, 95% CI 1.06-5.12), in 10 years, although this was no longer statistically significant after further adjustment for total hip BMD. CONCLUSIONS: Anemia is associated with an increased risk for any fracture and non-vertebral osteoporotic fracture in elderly men with a long follow-up time. The cause is probably multifactorial and our results support that anemia can be used as a predictor for future fracture.

Childhood body mass index is associated with the risk of adult hematologic malignancies in men-The best Gothenburg cohort.

Hematologic malignancies are common and the incidence is increasing. Adult obesity has been associated with hematologic malignancies (HM), but the importance of body mass index (BMI) in childhood and during puberty has not been evaluated. The aim of the present study was to evaluate the relative contribution of BMI and height in childhood and during puberty for the risk of adult HM. 37 669 men born in 1946 to 1961 who had weight and height measured at 8 (childhood) and 20 (young adult age) years of age available from the BMI Epidemiology Study were included in the study. Pubertal BMI change was calculated as BMI at 20 years of age minus BMI at 8 years of age. Information on HM was retrieved from Swedish registers (459 cases of HM). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions. Childhood BMI (HR 1.11 per SD increase [95% CI 1.02-1.23]), but not pubertal BMI change, was associated with hematologic malignancies in a linear manner. Childhood BMI was, independent of childhood height, associated with the diagnostic entities Non-Hodgkin lymphoma (HR 1.14 [95% CI 1.00-1.30]) and its largest subgroup diffuse large B-cell lymphoma (HR 1.31 [95% CI 1.03-1.67]). Childhood height was associated with multiple myeloma (HR 1.30 [95% CI 1.04-1.64]) independent of childhood BMI. We conclude that childhood but not puberty is the critical developmental period regarding future risk of HM and we suggest that elevated childhood BMI is a determinant of Non-Hodgkin lymphoma and diffuse large B-cell lymphoma.

Increased Risk of Hip Fracture in Patients with Lymphoma, a Swedish Population Study of 37,236 Lymphoma Patients.

Increased bone loss has been noted in lymphoma patients; however, the incidence of hip fracture is not known. The aim of our study was to explore the risk for hip fracture in patients with lymphoma compared with the entire Swedish population. The risk of hip fracture was determined in a retrospective population cohort study of adult Swedish lymphoma patients (n = 37,236), diagnosed 1995-2015 and compared with the entire Swedish population during the same period. The incidence of hip fracture in lymphoma patients was higher in women than in men, increased by age, and decreased by calendar year as also demonstrated in the total population. 2.2% of the men and 4.7% of women with lymphoma sustained a hip fracture. For the total group of females, the hazard ratio (HR) was 1.19 (95% CI 1.11-1.28) and for men, the hazard ratio was 1.06 (95% CI 0.97-1.17) compared with the Swedish population. The HR for hip fracture (2016) was 2.80 (95% CI 1.20-6.53), 2.04 (95% CI 1.30-3.20), 1.56 (95% CI 1.21-2.01), 1.08 (95% CI 0.89-1.30), and 1.07 (95% CI 0.92-1.25) in females aged 40, 50, 60, 70, and 80 years, respectively. Corresponding figures for men were not significant in 2016. Unmarried men with lymphoma had a two times higher risk for hip fracture (HR 2.02 95% CI 1.63-2.50) compared with married men. Patients with lymphoma had an increased risk of hip fracture, especially younger women and unmarried men. The incidence of hip fracture is decreased by calendar year in the lymphoma patients and the entire Swedish population.

Trends in the prevalence, incidence and survival of non-Hodgkin lymphoma subtypes during the 21st century - a Swedish lymphoma register study.

Non-Hodgkin lymphoma (NHL) prognosis has improved in recent years, yet the number of patients living with the diagnosis, i.e. the prevalence, has seldom been reported. The prevalence provides a measure of the burden of disease, useful for healthcare planning and to optimise resource allocation. We provide a systematic presentation of temporal trends in absolute numbers of prevalent patients by NHL subtypes, linking them to trends in incidence, survival and mortality. Patients diagnosed 2000-2016 were identified in the national Swedish lymphoma register. Incidence and mortality rates, relative survival and prevalence were estimated for NHL overall and for major clinical and morphological subtypes. Poisson regression was used to test for temporal trends. Increasing incidence and improved survival have led to a 47% increase in the five-year prevalence of NHL overall in 2016 compared to 2004. An increasing prevalence was observed for all investigated subtypes during the study period, but most notably for diffuse large B cell lymphomas among aggressive subtypes (66%), and marginal zone lymphomas among indolent subtypes (135%). This dramatic increase in NHL prevalence underscores the need to develop and evaluate alternative follow-up schemes to use resources efficiently and still ensure optimal care of lymphoma survivors.

Five-year survival follow-up of a phase III randomised trial comparing ofatumumab versus physicians' choice for bulky fludarabine-refractory chronic lymphocytic leukaemia: a short report.

In 2014, an interim analysis of a phase 3 study was performed to evaluate the effectiveness of ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukaemia (BFR CLL) as compared to physician's choice. The five-year follow-up of this phase 3 trial showed that ofatumumab therapy resulted in a numerically but not significantly longer overall survival. As only few patients had the chance to receive a kinase inhibitor later, the study displays the survival of BFR CLL patients in the period prior to receiving small-molecule inhibitors. Ofatumumab is a well-tolerable treatment option in multiresistant advanced CLL.

High Plasma Erythropoietin Predicts Incident Fractures in Elderly Men with Normal Renal Function: The MrOS Sweden Cohort.

Preclinical studies on the role of erythropoietin (EPO) in bone metabolism are contradictory. Regeneration models indicate an anabolic effect on bone healing, whereas models on physiologic bone remodeling indicate a catabolic effect on bone mass. No human studies on EPO and fracture risk are available. It is known that fibroblast growth factor 23 (FGF23) affects bone mineralization and that serum concentration of FGF23 is higher in men with decreased estimated glomerular filtration rate (eGFR). Recently, a direct association between EPO and FGF23 has been shown. We have explored the potential association between EPO and bone mineral density (BMD), fracture risk, and FGF23 in humans. Plasma levels of EPO were analyzed in 999 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) study, MrOS Sweden. The mean ± SD EPO was 11.5 ± 9.0 IU/L. Results were stratified by eGFR 60 mL/min. For men with eGFR ≥60 mL/min (n = 728), EPO was associated with age (r = 0.13, p < 0.001), total hip BMD (r = 0.14, p < 0.001), intact (i)FGF23 (r = 0.11, p = 0.004), and osteocalcin (r = -0.09, p = 0.022). The association between total hip BMD and EPO was independent of age, body mass index (BMI), iFGF23, and hemoglobin (beta = 0.019, p < 0.001). During the 10-year follow-up, 164 men had an X-ray-verified fracture, including 117 major osteoporotic fractures (MOF), 39 hip fractures, and 64 vertebral fractures. High EPO was associated with higher risk for incident fractures (hazard ratio [HR] = 1.43 per tertile EPO, 95% confidence interval [CI] 1.35-1.63), MOF (HR = 1.40 per tertile EPO, 95% CI 1.08-1.82), and vertebral fractures (HR = 1.42 per tertile EPO, 95% CI 1.00-2.01) in a fully adjusted Cox regression model. In men with eGFR<60 mL/min, no association was found between EPO and BMD or fracture risk. We here demonstrate that high levels of EPO are associated with increased fracture risk and increased BMD in elderly men with normal renal function. © 2019 American Society for Bone and Mineral Research.

High Serum Serotonin Predicts Increased Risk for Hip Fracture and Nonvertebral Osteoporotic Fractures: The MrOS Sweden Study.

Because several studies have implicated serotonin as a regulator of bone mass, we here explore its potential association on fracture risk and falls, as on bone mineral density (BMD) and muscle strength, in humans. Serum levels of serotonin were analyzed in 950 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based study MrOS Sweden. Men taking selective serotonin reuptake inhibitors (SSRIs) had a mean value of 31.2 µg/L compared with 159.4 µg/L in those not taking SSRIs. SSRI users were excluded from further analysis. During 10-year follow-up, 224 men exhibited fractures, including 97 nonvertebral osteoporotic fractures (57 hip fractures), and 86 vertebral fractures. Serotonin was associated with hip fracture in linear analysis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] 1.03-1.58) and to all fractures in a nonlinear manner, when quintiles of serotonin was included in quadratic terms (HR = 1.12, 95% CI 1.04-1.21). Men in serotonin quintile 5 had, in multivariable analysis, a HR of 2.30 (95% CI 1.31-4.02) for hip fracture and 1.82 (95% CI 1.17-2.85) for nonvertebral fractures compared with men in quintiles 1 to 4. Men in quintile 1 had, in multivariable analysis, a HR of 1.76 (95% CI 1.03-2.99) for nonvertebral fractures compared with men in quintiles 2 to 4. No association was found with vertebral fractures. Individuals in serotonin quintile 1 had higher prevalence of falls compared with quintiles 2 to 5 (odds ratio = 1.90, 95% CI 1.26-2.87). Serotonin was positively associated with hand-grip strength (r = 0.08, p = 0.02) and inversely with hip BMD (r = -0.10, p = 0.003). To assess the association between SSRIs and falls and fractures, the total MrOS Sweden cohort was examined (n = 3014). SSRI users (n = 90) had increased prevalence of falls (16% versus 33%, p = 0.0001) and increased rate of incident fractures (28.0 versus 44.7 per 1000 person-years, p = 0.018). We present novel data showing that high levels of serotonin predict an increased risk for hip fracture and nonvertebral osteoporotic fractures. © 2018 American Society for Bone and Mineral Research.

Low serum iron is associated with high serum intact FGF23 in elderly men: The Swedish MrOS study.

BACKGROUND: Fibroblast growth factor (FGF23) is a protein that is produced by osteoblasts and osteocytes. Increased serum levels of FGF23 have been associated with increased risks of osteoporotic fractures and cardiovascular disease, particularly in participants with poor renal function. Serum iron (Fe) has been suggested as a regulator of FGF23 homeostasis. OBJECTIVE: To determine whether Fe and iron status are determinants of the levels of intact FGF23 (iFGF23) in elderly men. METHODS: The MrOS study is a population-based study of elderly men (N=1010; mean age, 75.3years; range, 69-81years). The levels of Fe, transferrin saturation (TS), and ferritin were evaluated in relation to the serum concentrations of iFGF23 before and after adjustments for confounders. RESULTS: TS <15% was found in 3.5% (34/977) of the participants, who had a higher median level iFGF23 compared with the remaining subjects (47.4µmol/L vs. 41.9µmol/L, p=0.008). The levels of iFGF23 correlated negatively (un-adjusted) with the levels of Fe (r=-0.17, p<0.001), TS (r=-0.16, p<0.001) and serum ferritin (r=-0.07, p=0.022). In addition, in participants with estimated glomerular filtration rate eGFRCystatin C>60mL/min, the levels of iFGF23 correlated (age-adjusted) negatively with the levels of Fe (r=-0.15, p<0.001) and TS (r=-0.17, p<0.001). The level of iFGF23 correlated positively (un-adjusted) with lumbar spine bone mineral density (BMD) (r=0.14, p<0.001), total body BMD (r=0.11, p=0.001), and total hip BMD (r=0.09, p=0.004). The corresponding correlations, when adjusted for age, weight, and height were: r=0.08, p=0.018; r=0.05, p=0.120; and r=0.02, p=0.624, respectively. No associations were found between BMD and the levels of Fe or TS. Multiple step-wise linear regression analyses [adjusting for age, body mass index (BMI), comorbidity index, cystatin C, C-reactive protein (hs-CRP), serum vitamin D 25-OH (25OHD), phosphate, calcium, parathyroid hormone (PTH), erythropoietin, hemoglobin, lumbar spine BMD, apolipoprotein B/A1 ratio] were performed in three separate models with Fe, TS or ferritin as potential explanatory variables. Fe and TS, but not ferritin, were independent predictors of iFGF23 level (standardized ß-values: -0.10, p<0.001; -0.10, p<0.001; and -0.05, p=0.062, respectively). CONCLUSION: Low levels of Fe in elderly men are associated with high levels of iFGF23, independently of markers of inflammation and renal function, suggesting an iron-related pathway for FGF23 regulation.

Multilocus Sequence Analysis of Clinical "Candidatus Neoehrlichia mikurensis" Strains from Europe.

"Candidatus Neoehrlichia mikurensis" is the tick-borne agent of neoehrlichiosis, an infectious disease that primarily affects immunocompromised patients. So far, the genetic variability of "Ca. Neoehrlichia" has been studied only by comparing 16S rRNA genes and groEL operon sequences. We describe the development and use of a multilocus sequence analysis (MLSA) protocol to characterize the genetic diversity of clinical "Ca. Neoehrlichia" strains in Europe and their relatedness to other species within the Anaplasmataceae family. Six genes were selected: ftsZ, clpB, gatB, lipA, groEL, and 16S rRNA. Each MLSA locus was amplified by real-time PCR, and the PCR products were sequenced. Phylogenetic trees of MLSA locus relatedness were constructed from aligned sequences. Blood samples from 12 patients with confirmed "Ca. Neoehrlichia" infection from Sweden (n = 9), the Czech Republic (n = 2), and Germany (n = 1) were analyzed with the MLSA protocol. Three of the Swedish strains exhibited identical lipA sequences, while the lipA sequences of the strains from the other nine patients were identical to each other. One of the Czech strains had one differing nucleotide in the clpB sequence from the sequences of the other 11 strains. All 12 strains had identical sequences for the genes 16S rRNA, ftsZ, gatB, and groEL. According to the MLSA, among the Anaplasmataceae, "Ca. Neoehrlichia" is most closely related to Ehrlichia ruminantium, less so to Anaplasma phagocytophilum, and least to Wolbachia endosymbionts. To conclude, three sequence types of infectious "Ca. Neoehrlichia" were identified: one in the west of Sweden, one in the Czech Republic, and one spread throughout Europe.

Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals.

BACKGROUND: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain. OBJECTIVE: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging. DESIGN: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)-type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals). RESULTS: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: -0.054 ± 0.004 and -0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: -0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: -0.01; 95% CI: -0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: -0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment. CONCLUSION: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.

Serum estradiol associates with blood hemoglobin in elderly men: the MrOS Sweden study.

CONTEXT: Blood hemoglobin (Hb) declines with age in healthy elderly men, in whom decreasing T has been regarded as part of normal aging. However, the association between Hb and serum estradiol is incompletely known. OBJECTIVE: To determine whether estradiol is associated with anemia/Hb and established determinants of Hb in elderly men without prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: The MrOS (Osteoporotic Fractures in Men) is a population-based study (n = 918; median age, 75.3 y; range, 70-81 y). MAIN OUTCOME MEASURES: We evaluated total estradiol in relation to Hb and adjusted for potential confounders (ie, age, body mass index [BMI], erythropoietin [EPO], total T, cystatin C, and iron and B-vitamin status). RESULTS: Estradiol correlated negatively with age (r = -0.14; P < .001). Hb correlated (age adjusted) positively with estradiol (r = 0.21; P < .001) and T (r = 0.10; P < .01). Independent predictors for Hb in multivariate analyses were estradiol, EPO, BMI, transferrin saturation, cystatin C, and free T4, but not T. After exclusion of subjects with Hb <130 g/L and/or T < 8 nmol/L (n = 99), the correlation between Hb and T was no longer significant, whereas the associations between Hb and estradiol remained. After adjusting for age, BMI, and EPO, men with lower estradiol levels were more likely to have Hb in the lowest quartile of values (odds ratio per SD decrease in estradiol = 1.61 [95% confidence interval, 1.34-1.93]). Anemic subjects (Hb < 130 g/L) had lower mean estradiol than nonanemic subjects (67.4 vs 79.4 pmol/L; P < .001). CONCLUSIONS: Estradiol correlated positively and independently with Hb. Decreased estradiol might partly explain the age-related Hb decline observed in healthy elderly men.

Holotranscobalamin is not influenced by decreased renal function in elderly men: the MrOS Sweden study.

BACKGROUND: Subclinical cobalamin deficiency is common in the elderly, but the sensitivity and specificity of serum total cobalamin for this diagnosis is poor. Serum holotranscobalamin (holoTC), a measure of biologically available cobalamin, is considered a better marker for early cobalamin depletion than total cobalamin. However, in elderly populations, health-related reference intervals for holoTC and correlations to renal function are not entirely clear. METHODS: HoloTC was determined with an automated microparticle enzyme immunoassay (AxSYM®) in 790 elderly non-vitamin-supplemented Swedish men, median age 75.3 years. Renal function was assessed with creatinine, cystatin C and estimated glomerular filtration rate (eGFR calculated from creatinine). RESULTS: Median holoTC was 51.8 pmol/L, the health-related reference interval 19.6-132.3 pmol/L. There was no significant difference in mean holoTC in probands with normal compared to high creatinine (P = 0.80) and cystatin C (P = 0.82). No significant differences between the quartiles of creatinine or cystatin C in mean of log holoTC were seen. HoloTC correlated strongly with total cobalamin (r = 0.69, P < 0.001), weaker with eGFRcreatinine (r = -0.09, P < 0.05) and creatinine (r = 0.09, P < 0.05), the latter correlation was only seen in subjects with creatinine <100 µmol/L. HoloTC correlated negatively with plasma total homocysteine (r = -0.24, P < 0.001), but not with cystatin C and age. CONCLUSIONS: Serum holoTC in healthy elderly men shows the same distribution as earlier described for a younger reference population. In this group of elderly subjects, holoTC did not correlate to reduced renal function. Thus, holoTC appears to be a promising tool for evaluating cobalamin status also in elderly populations.

Improved outcome for very elderly patients with diffuse large B-cell lymphoma in the immunochemotherapy era.

The prognosis of diffuse large B-cell lymphoma (DLBCL) has improved significantly since the introduction of immunochemotherapy (rituximab [R] with cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP]). However, few outcome data are available for very elderly patients (≥ 80 years). Therefore, we compared all patients with DLBCL aged ≥ 80 years diagnosed in the Gothenburg area during two time periods (2006-2009, "post-R" and 1997-2000, "pre-R"). Forty and 30 patients were identified, corresponding to 23.5% and 20.5%, respectively, of the entire population with DLBCL. Estimated 3-year progression-free (PFS) and overall (OS) survival was better post-R than pre-R: 41% vs. 17% (p = 0.015) and 41% vs. 17% (p = 0.01), respectively. Fifty-three percent of post-R patients were treated with curative intent with a moderately reduced R-CHOP regimen (median relative dose intensity: 0.86). At a median follow-up of 29 months, the 3-year PFS and OS were 70% (p = 0.018) and 76% (p = 0.0089), respectively. In conclusion, moderately reduced R-CHOP is tolerable and effective for a considerable number of very elderly patients with DLBCL and high age by itself should not be a reason for excluding a patient with DLBCL from such treatment.

Serum biomarkers for atrophic gastritis and antibodies against Helicobacter pylori in the elderly: Implications for vitamin B12, folic acid and iron status and response to oral vitamin therapy.

OBJECTIVES: To investigate the prevalence of serological markers for chronic atrophic gastritis (AG) and Helicobacter pylori antibodies (HPAb) in an elderly population, and to examine the interrelationship and significance for cobalamin, folic acid and iron status and response to oral vitamin therapy. MATERIAL AND METHODS: The study included community-dwelling subjects (n=209), mean age 76 years, randomized to 4 month of oral daily treatment with 0.5 mg cyanocobalamin, 0.8 mg folic acid and 3 mg vitamin B(6) or placebo (double-blind). Biochemical tests were carried out before and after treatment. RESULTS: AG, as indicated by a pepsinogen I/II ratio <2.9, occurred in 14% (26/190) and HPAb in 54% (102/190) of the subjects. AG subjects had higher levels of serum methylmalonic acid (MMA) (p<0.001), plasma homocysteine (tHcy) (p<0.05), lower haemoglobin (Hb) (p<0.01) and a higher prevalence of vitamin B(12) deficiency (p<0.01). HPAb was associated with AG, whereas AG subjects without HPAb had higher tHcy and MMA levels. There was no correlation between AG and iron status. Oral vitamin treatment led to greater (albeit non-significant) improvements in MMA, tHcy and total cobalamins in AG subjects compared to non-AG subjects. CONCLUSIONS: AG is a common condition and is a significant determinant of vitamin B(12) status. AG is correlated to HPAB and lower Hb. Elderly AG subjects respond at least as well as non-AG subjects to oral treatment with B-vitamins in the doses employed.