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The development of some lymphomas has been associated with infections caused by bacterial species discovered in the 1980s, for example, I Helicobacter pylori i and I Borrelia burgdorferi s.l. i The first cases of human infection with a bacterial species that was first described in 2004, the tick-borne bacterium I Neoehrlichia mikurensis i were published in 2010. Patients with malignant B cell lymphomas emerged as a risk group for severe cases of infection, presenting with fever of unknown cause and venous thromboembolism. It was whilst conducting a study of patients with malignant B cell lymphomas scheduled to receive treatment with rituximab that we discovered several patients who had the infection already before the start of treatment. [Extracted from the article]

A few patients with MCL present with limited stage disease and for these, involved node radiotherapy may be a well tolerable alternative to immunochemotherapy regimens. How to choose between curative radiotherapy or chemotherapy in low stage MCL? Here, we aim to evaluate progression free survival (PFS) and overall survival (OS) in relation to given treatment and prognostic factors in patients with stage I-II MCL. [Extracted from the article]

Objectives Blood haemoglobin (Hb) concentration declines in elderly men, whilst the level of the adipocyte-derived protein adiponectin increases with age. The association between erythropoiesis and adiponectin in elderly men is unclear. The aim of this study was to determine whether adipokines such as adiponectin and leptin are associated with anaemia and Hb concentration in elderly community-dwelling men. Design and setting The Gothenburg part of the population-based Swedish Osteoporotic Fractures in Men (Mr OS) cohort ( n = 1010; median age 75.3 years, range 69-81). Main outcome measures We investigated the associations between levels of adiponectin and Hb before and after adjusting for potential confounders [i.e. age, body composition, erythropoietin ( EPO), total oestradiol, leptin, cystatin C and iron and B vitamin status]. Results In these elderly men, age was negatively associated with Hb ( r = −0.12, P < 0.001) and positively associated with adiponectin level ( r = 0.13, P < 0.001). In age-adjusted partial correlations, Hb and adiponectin levels were negatively correlated ( r = −0.20, P < 0.001); this association remained significant after multivariable adjustment for age, body composition, EPO, fasting insulin, sex hormones, leptin and ferritin. Age-adjusted mean adiponectin concentrations were significantly higher in anaemic men (66/1005; Hb <130 g L−1) compared to nonanaemic men (14.0 vs. 11.7 μg mL−1, P < 0.05). In multivariate analysis, adiponectin together with EPO, total oestradiol, insulin, albumin, transferrin saturation, HDL cholesterol, cystatin C, total body fat mass and free thyroxine, but not leptin, explained 35% of the variation in Hb level. These results remained essentially unchanged after exclusion of men with diabetes. Conclusions Serum adiponectin, but not leptin, was negatively and independently associated with Hb. This finding suggests a possible role of adiponectin in the age-related decline in Hb level observed in apparently healthy elderly men. [ABSTRACT FROM AUTHOR]

OBJECTIVES:: To investigate, in an elderly population: (1) the effects of oral B-vitamin therapy on P-tHcys, S-MMA and Hb/MCV, (2) the appropriate decision limit for ‘high’ metabolite concentrations and (3) the estimated prevalence of vitamin B12/folate deficiency on the basis of different decision limits. DESIGN:: Double-blind placebo-controlled intervention study. SETTING:: Outpatient clinic. SUBJECTS:: A total of 209 community-dwelling subjects, median age 76?y (range 70-93)?y. INTERVENTION:: Four months of oral daily supplementation with 0.5?mg cyanocobalamin, 0.8?mg folic acid and 3?mg vitamin B6. RESULTS:: High P- tHcys was found in 64% of men and 45% of women, high S-MMA in 11% of both. Vitamin B12 deficiency was observed in 7.2% and folate deficiency in 11% of all subjects. Health-related upper reference limits for the metabolites at the start were higher than the laboratory's upper reference limits. The latter were, however, similar to those of the vitamin replete group. There was a significant decrease in P-tHcys (P<0.001) and S-MMA (P=0.009) after 4 months of vitamin treatment. In a multivariate analysis, the P-Hcys change correlated positively with baseline P-tHcys and inversely with baseline P-folate and transferrin saturation (Fe/TIBC ratio). The S-MMA change correlated with baseline S-MMA and inversely with baseline vitamin B12 and age. CONCLUSIONS:: Suboptimal vitamin status is an important cause of elevated P-tHcys and S-MMA in apparently healthy elderly subjects. Oral B-vitamin therapy is an effective and convenient way to normalise P-tHcys and S-MMA. SPONSORSHIP:: Support-Recip AB.European Journal of Clinical Nutrition (2003) 57, 1426-1436. doi:10.1038/sj.ejcn.1601707 [ABSTRACT FROM AUTHOR]

In this retrospective cohort study of adult stem cell transplanted patients (n = 8463), a significant increased risk of both MOF and hip fractures was seen compared with the Swedish population and occurred in mean more than 2 years after stem cell transplantation., Purpose: To explore the risk for osteoporotic fracture in patients who have undergone hematopoietic stem cell transplantation (HSCT) compared with the Swedish population., Methods: The risk of osteoporotic fractures was determined in a retrospective population cohort study of adult (≥ 18 years) Swedish patients (n = 8463), who were transplanted with HSCT 1997-2016 and compared with all adults living in Sweden during the same period., Results: In the total study group (n = 8463), 90 hip fractures (1.1% both in males and females) and 361 major osteoporotic fractures (MOF) (3.2% in men and 6.0% in women) were identified. In the total study population, the ratio of observed and expected number of hip fracture for women was 1.99 (95% CI 1.39-2.75) and for men 2.54 (95% CI 1.91-3.31). The corresponding ratio for MOF in women was 1.36 (CI 1.18-1.56) and for men 1.61 (CI 1.37-1.88). From 2005 onwards, when differentiation in the registry between allo- and auto-HSCT was possible, the observed number of hip fracture and MOF in allo-HSCT (n = 1865) were significantly increased (observed/expected hip fracture 5.24 (95% CI 3.28-7.93) and observed/expected MOF 2.08 (95% CI 1.63-2.62)). Fractures occurred in mean 2.7 (hip) and 2.5 (MOF) years after allo-HSCT. Graft-versus-host disease (GVHD) was not associated with an increased risk of fracture., Conclusion: Patients who underwent HSCT had an increased risk of both hip and major osteoporotic fracture compared with the Swedish population and occurred in 4.3% of patients. GVHD was not statistically significantly associated with fracture risk., (© 2024. The Author(s).)

Background and Purpose: The Swedish Lymphoma Register (SLR) was initiated in the year 2000 with the aim to monitor quality of care in diagnostics, treatment and outcome of all lymphomas diagnosed nationally among adults. Here, we present the first systematic validation of SLR records as a basis for improved register quality and patient care., Patients and Methods: We evaluated timeliness and completeness of register records among patients diagnosed with lymphoma in the SLR (n = 16,905) compared with the National Cancer Register for the period 2013-2020. Comparability was assessed through evaluation of coding routines against national and international guidelines. Accuracy of 42 variables was evaluated through re-abstraction of data from medical records among 600 randomly selected patients diagnosed in 2016-2017 and treated across all six Swedish healthcare regions.  Results: Completeness was high, >95% per year for the period 2013-2018, and >89% for 2019-2020 compared to the National Cancer Register. One in four patients was registered within 3 months, and 89.9% within 2 years of diagnosis. Registration instructions and coding procedures followed the prespecified guidelines. Missingness was generally low (<5%), but high for occasional variables, for example, those describing maintenance and consolidative treatment. Exact agreement of categorical variables was high overall (>80% for 24/34 variables), especially for treatment-related data (>80% for 17/19 variables)., Interpretation: Completeness and accuracy are high in the SLR, while timeliness could be improved. Finetuning of variable registration guided by this validation can further improve reliability of register reports and advance service to lymphoma patients and health care in the future.

Sézary syndrome (SS) is a rare primary cutaneous T-cell lymphoma variant. Despite various treatment options, it remains incurable, with a poor prognosis. There is an urgent need for additional descriptive research to enhance our understanding and treatment of SS. The aim of this retrospective register-based study was to outline patients' demographic characteristics; investigate the clinical, histopathological, and molecular findings; and assess treatment effectiveness with a focus on time to next treatment (TTNT) and disease progression. Data on 17 patients with SS were obtained from the primary cutaneous lymphoma register in West Sweden between 2012 and 2024. The results revealed that not all patients exhibited the classical triad of symptoms at diagnosis, emphasizing the need for personalized diagnostic approaches. The median survival was only 2.1 years, which reflects the aggressive nature of SS. The longest median TTNT was observed in triple therapy involving retinoids, interferon alpha, and extracorporeal photopheresis (ECP). There was no significant difference in TTNT between various lines of treatment. Early initiation of ECP treatment did not result in improved outcomes. This study highlights the importance of combination therapy for improved outcomes and underscores the need for future studies to identify optimal treatment approaches.

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

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., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

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., Competing Interests: MJ: Honoraria: Kite/Gilead, Janssen, Abbvie, AstraZeneca, Pierre Fabre, Roche, Genmab, MSD. Research support: Roche, Abbvie, AstraZeneca, BMS, Janssen. IG: Honoraria: Janssen, Takeda. Research support: Lokon Pharma. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

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., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

(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.

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., (© 2022. The Author(s).)

Background/aims: The diagnostic work-up of lymphadenopathy is challenging but important to determine the correct therapy. Nevertheless, few studies have addressed the topic of endosonography (EUS)-guided tissue acquisition in lymphadenopathy. Therefore, we aimed to evaluate the accuracy and safety of EUS-guided fine-needle biopsy sampling (EUS-FNB) in intrathoracic and intraabdominal lymphadenopathy., Methods: In a tertiary care center, patients with lymphadenopathy referred for EUS-guided sampling were included prospectively from 2014 to 2019 (NCT02360839). In all cases, EUS-FNB (22 gauge) and EUS-guided fine-needle aspiration (EUS-FNA) (25 gauge) were performed. The patients were randomized to the first needle pass with FNB or FNA. Study outcomes were the diagnostic accuracy and adverse event rate., Results: Forty-eight patients were included (median age: 69 years [interquartile range, 59-76]; 24/48 females [50%]). The final diagnoses were metastasis (n=17), lymphoma (n=11), sarcoidosis (n=6), and inflammatory disease (n=14). The diagnostic performance of the two modalities was comparable, including a high sensitivity for metastatic nodes (EUS-FNB: 87% vs. EUSFNA: 100%, p=0.5). The sensitivity for lymphoma was borderline superior in favor of EUS-FNB (EUS-FNB: 55% vs. EUS-FNA: 9%, p=0.06). No adverse events were recorded., Conclusion: In lymphadenopathy, both EUS-FNB and EUS-FNA are safe and highly sensitive for metastatic lymph node detection. Lymphoma diagnosis is challenging regardless of the needle used.

The risk for hip and vertebral fracture was determined in 10,752 patients diagnosed with myeloproliferative neoplasms (MPN) in Sweden 1995-2015. The mean follow-up time were 6.34 years. Five percent developed hip fracture and 1.3% a vertebral fracture. There was a significant increased risk for fracture among the MPN patients compared with the Swedish population. The ratio of observed (obs) and expected (exp) number of hip fracture in all MPN patients, polycythemia vera (PV), essential thrombocythemia and MPN undetermined (MPNu) was 1.20 (95% confidence interval (CI): 1.10-1.31), 1.37 (95% CI: 1.19-1.58), 1.02 (95% CI: 0.87-1.19), and 1.28 (95% CI: 1.07-1.52), respectively. Corresponding figures for vertebral fractures were 1.94 (95% CI: 1.64-2.29), 2.09 (95% CI: 1.56-2.75), 1.50 (95% CI: 1.06-2.07) and 2.47 (95% CI: 1.77-3.35), respectively. Patients with MPN had an increased risk of hip and vertebral fracture, especially patients with PV and MPNu in comparison with the entire Swedish population.

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., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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.

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., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2019 American Society for Bone and Mineral Research.)

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., (© 2018 American Society for Bone and Mineral Research.)

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 β-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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

"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., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

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.

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.

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.