Low holotranscobalamin and cobalamins predict incident fractures in elderly men: the MrOS Sweden.

UNLABELLED: In a population-based study on cobalamin status and incident fractures in elderly men (n = 790) with an average follow-up of 5.9 years, we found that low levels of metabolically active and total cobalamins predict incident fractures, independently of body mass index (BMI), bone mineral density (BMD), plasma total homocysteine (tHcy), and cystatin C. INTRODUCTION: Cobalamin deficiency in elderlies may affect bone metabolism. This study aims to determine whether serum cobalamins or holotranscobalamin (holoTC; the metabolic active cobalamin) predict incident fractures in old men. METHODS: Men participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) Sweden cohort and without ongoing vitamin B medication were included in the present study (n = 790; age range, 70-81 years). RESULTS: During an average follow-up of 5.9 years, 110 men sustained X-ray-verified fractures including 45 men with clinical vertebral fractures. The risk of fracture (adjusted for age, smoking, BMI, BMD, falls, prevalent fracture, tHcy, cystatin C, 25-OH-vitamin D, intake of calcium, and physical activity (fully adjusted)), increased per each standard deviation decrease in cobalamins (hazard ratio (HR), 1.38; 95% confidence intervals (CI), 1.11-1.72) and holoTC (HR, 1.26; 95% CI, 1.03-1.54), respectively. Men in the lowest quartile of cobalamins and holoTC (fully adjusted) had an increased risk of all fracture (cobalamins, HR = 1.67 (95% CI, 1.06-2.62); holoTC, HR = 1.74 (95% CI, 1.12-2.69)) compared with quartiles 2-4. No associations between folate or tHcy and incident fractures were seen. CONCLUSIONS: We present novel data showing that low levels of holoTC and cobalamins predicting incident fracture in elderly men. This association remained after adjustment for BMI, BMD, tHcy, and cystatin C. However, any causal relationship between low cobalamin status and fractures should be explored in a prospective treatment study.

No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease.

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

Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish Lymphoma Registry study.

Treatment for follicular lymphoma (FL) improved with rituximab. In Sweden, first-line rituximab was gradually introduced between 2003 and 2007, with regional differences. The first national guidelines for FL were published in November 2007, recommending rituximab in first-line therapy. Using the population-based Swedish Lymphoma Registry, 2641 patients diagnosed with FL from 2000 to 2010 were identified and characterized by year and region of diagnosis, age (median, 65 years), gender (50% men), first-line therapy and clinical risk factors. Overall and relative survivals were estimated by calendar periods (2000-2002, 2003-2007 and 2008-2010) and region of diagnosis. With each period, first-line rituximab use and survival increased. Survival was superior in regions where rituximab was quickly adopted and inferior where slowly adopted. These differences were independent in multivariable analyses. Ten-year relative survival for patients diagnosed 2003-2010 was 92%, 83%, 78% and 64% in the age groups 18-49, 50-59, 60-69 and ⩾70, respectively. With increasing rituximab use, male sex emerged as an adverse factor. Survival improved in all patient categories, particularly in elderly women. The introduction and the establishment of rituximab have led to a nationwide improvement in FL survival. However, rituximab might be inadequately dosed in younger women and men of all ages.

Trofosfamide as salvage therapy for anaplastic large cell lymphoma relapsing after high-dose chemotherapy.

Patients with relapsed aggressive lymphoma after high dose chemotherapy have a very poor prognosis and long-term survival is rare. Most patients are not eligible for allogeneic stem cell transplantation in this setting and treatment, therefore, becomes palliative. A few studies have shown that trofosfamide, an oral alkylating agent, may be effective as palliative treatment in non-Hodgkin's lymphoma. Trofosfamide therapy is considered rather non-toxic with an overall response rate from 50 to 80%. Most responses are, however, partial and their duration is short. We report a patient with a very aggressive ALK + anaplastic large cell lymphoma (ALCL), relapsing shortly after high dose chemotherapy. Unrelated allogeneic transplantation was hot possible. After several radio/chemotherapy regimens trofosfamide was started as palliative treatment. This therapy resulted in a complete remission, still ongoing, 27 months after termination of intravenous cytotoxic therapy and 16 months after withdrawal of trofosfamide. Thus, in this particular case, trofosfamide turned out to be an unexpectedly effective salvage therapy for an otherwise very aggressive relapsing ALCL.

Bullous pyoderma gangrenosum in a patient with myelodysplastic syndrome during granulocyte colony-stimulating factor therapy.

An unusual case of bullous pyoderma gangrenosum in a patient with myelodysplastic syndrome during treatment with granulocyte colony-stimulating factor (G-CSF) is reported. The possible relationship between G-CSF therapy and pyoderma gangrenosum, as well as the beneficial effect of cyclosporin A therapy, is discussed.

Age-related changes in cobalamin (vitamin B12) handling. Implications for therapy.

Cobalamin (vitamin B12) deficiency is more common in the elderly than in younger patients. This is because of the increased prevalence of cobalamin malabsorption in this age group, which is mainly caused by (autoimmune) atrophic body gastritis. Cobalamin supplementation is affordable and nontoxic, and it may prevent irreversible neurological damage if started early. Elderly individuals with cobalamin deficiency may present with neuropsychiatric or metabolic deficiencies, without frank macrocytic anaemia. An investigation of symptoms and/or signs includes the diagnosis of deficiency as well as any underlying cause. Deficiency states can still exist even when serum cobalamin levels are higher than the traditional lower reference limit. Cobalamin-responsive elevations of serum methylmalonic acid (MMA) and homocysteine are helpful laboratory tools for the diagnosis. The health-related reference ranges for homocysteine and MMA appear to vary with age and gender. Atrophic body gastritis is indirectly diagnosed by measuring serum levels of gastrin and pepsinogens, and it may cause dietary cobalamin malabsorption despite a normal traditional Schilling's test. The use of gastroscopy may also be considered to diagnose dysplasia, bacterial overgrowth and intestinal villous atrophy in healthy patients with atrophic body gastritis or concomitant iron or folic acid deficiency. Elderly patients respond to cobalamin treatment as fully as younger patients, with complete haematological recovery and complete or good partial resolution of neurological deficits. Chronic dementia responds poorly but should, nevertheless, be treated if there is a metabolic deficiency (as indicated by elevated homocysteine and/or MMA levels). Patients who are at risk from cobalamin deficiency include those with a gastrointestinal predisposition (e.g. atrophic body gastritis or previous partial gastrectomy), autoimmune disorders [type 1 (insulin-dependent) diabetes mellitus and thyroid disorders], those receiving long term therapy with gastric acid inhibitors or biguanides, and those undergoing nitrous oxide anaesthesia. To date, inadequate cobalamin intake has not proven to be a major risk factor. Intervention trials of cobalamin, folic acid and pyridoxine (vitamin B6) in unselected elderly populations are currently under way.

Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B12 and vitamin B6: a randomised trial.

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 B(12)/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 B(6). RESULTS: High P- tHcys was found in 64% of men and 45% of women, high S-MMA in 11% of both. Vitamin B(12) 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 B(12) 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.

Anaemia and other haematological abnormalities in patients admitted to long-term care.

We investigated the occurence and causes of anaemia and other haematological abnormalities in 142 elderly patients (43 men, 99 women; median age 79 and 80 years), admitted to long-term care. Healthy 81-year-old subjects (n = 220) were used as reference group. Anaemia according to the WHO definition was much more common in the studied population (41%) than in a representative sample of 81-year-old subjects (10%). Somatically fit patients were less often anaemic (30%) than those with somatic illness (68%). The main causes for anaemia were: chronic disease (14.9%), recent haemorrhage (7.8%), iron deficiency (5.7%); and often multifactorial. Secondary leuko- or thrombocytosis occurred in 14 and 23%, drug-induced thrombocytopenia in 2.8% of the patients. Anaemia and other haematological abnormalities seen in elderly patients hospitalized for long-term care are often secondary to chronic or acute disorders. However, they also occur in patients without severe somatic impairment and many of them are reversible. Such findings should therefore not be neglected, but properly investigated, and if possible treated.

Glomerular filtration rate as measured by serum cystatin C is an important determinant of plasma homocysteine and serum methylmalonic acid in the elderly.

OBJECTIVES: To explore the dependence of glomerular filtration rate (GFR) on plasma total homocysteine (tHcy) and serum methylmalonic acid (MMA), as well as the consequences for the diagnosis of cobalamin and/or folic acid deficiency in an elderly community-dwelling population. DESIGN AND SETTING: Population-based study of 209 community-dwelling subjects, mean age 76 years. INTERVENTIONS: Four months' treatment study with oral vitamin B(12), folic acid and B(6) or placebo. MAIN OUTCOME MEASURES: Determinants of tHcy and MMA: cystatin C as a marker of GFR and serum/plasma concentrations of vitamin B(12) and folate, age and sex. RESULTS: Elevated cystatin C (>1.55 mg L(-1)) was found in 31.3% (men) and 13.0% (women). Elevated tHcy (> or = 16 micromol L(-1)) occurred in 53% and elevated MMA (> or = 0.34 micromol L(-1)) in 11% of all subjects. When GFR was taken into consideration, the proportion of elevated tHcy was reduced to 10% (20/209), whilst the proportion of elevated MMA was unchanged. Cystatin C was correlated with tHcy (r = 0.45, P < 0.001) and with MMA (r =0.28, P < 0.001), independently of vitamin B(12)- and folate status. According to multiple regression, independent predictors for tHcy were plasma folate (15%), cystatin C (11%) and vitamin B(12) (4%), and for MMA, cystatin C (8%) and vitamin B(12) (2%). CONCLUSIONS: The prevalence of elevated tHcy may be overestimated in elderly populations unless GFR is taken into account. Nomograms for evaluation of tHcy and MMA in relation to both cystatin C and serum creatinine are presented.

Bone scintigraphy in the diagnosis of skeletal involvement and metastatic calcification in multiple myeloma.

The contribution of bone scintigraphy to the diagnosis of skeletal involvement in multiple myeloma was evaluated in a consecutive, unselected series of 25 previously untreated patients. Definite scintigraphic abnormalities were found in 11 patients (localized in 4, generalized in 7) (44%). In the majority of patients the clinical value of the information gained from scintigraphy was roughly equal to that found by radiography. However, 2 patients with normal and 2 with questionable bone scans had X-ray evidence of skeletal involvement, and the extent of bone destruction in 4 cases was seriously underestimated in the bone scans. Small osteolytic lesions were as a rule not detected by scintigraphy. On the other hand, in 8 patients the bone scan added information of involvement of ribs, pelvis and vertebrae, not clearly visualized by X-ray. In 2 patients, both with IgA myeloma, hypercalcemia and uremia, a massive extraskeletal uptake of the bone-seeking isotope was observed. Autopsy verified in one case the presence of a disseminated metastatic calcification.

Blood haemoglobin declines in the elderly: implications for reference intervals from age 70 to 88.

The objective was to determine whether Hb declines in healthy elderly men and women and if this influences health-related reference intervals. A representative population sample, comprising 30% of all 70-yr-old subjects in a Swedish city with 420,000 inhabitants (n = 1148, participation rate 85%), was followed at 1-5-yr intervals for 18 yr within a longitudinal population study. Age-related changes in Hb were calculated after exclusion of non-healthy probands and by multivariate analyses in the total study group. Mean Hb declined between age 70 and 88 from 149 to 138 g/L in men (annual decline 0.69 g/L, p = 0.000), and from 139 to 135 g/L in women (annual decline 0.06 g/L, n.s.). Healthy men declined from 152 to 141 g/L (annual decline 0.53 g/L, p = 0.038), for women from 140 to 138 g/L (annual decline 0.05 g/L, n.s.). Age and body mass index correlated, in multivariate analysis, independently to Hb in both men and women, as did variables indicating a non-healthy state. Epidemiological decision limits for anaemia declined for men from 128 to 116 g/L, for women from 118 to 114 g/L. Anaemia, thus defined, occurred in 3.2 to 9.7% of the subjects, whereas 28.3% of the 88-yr-old men had anaemia according to the WHO definition. In conclusion, there is a significant age-related decline in Hb from age 70 to 88 among healthy men, and a less pronounced decline among women. This justifies the use of lower epidemiological decision limits for anaemia of about 115 g/L for both men and women from age 80-82.

Bone marrow progenitor cell growth and karyotype changes in healthy 88-year-old subjects.

Previous studies have indicated a decline in bone marrow progenitor cell function in subjects aged 75-82 years, possibly causing lower Hb concentrations. We studied the bone marrow with in vitro colony assays and cytogenetic analysis in 24 apparently healthy 88-year-olds with Hb concentrations ranging from moderate anaemia to normal levels. Twenty-two healthy younger subjects, aged 21-57 years, were used as a control group. The 88-year-olds showed significantly lower numbers of myeloid bone marrow progenitors than the controls, and the elderly men had lower numbers of both erythroid and myeloid progenitors than the elderly women. There were no in vitro growth differences between elderly subjects with "low" or "normal" Hb concentrations. Ten out of 14 men had bone marrow cells with a missing Y-chromosome, which did not seem to have any relationship to the erythroid function. No morphological or other cytogenetic indications of a clonal progenitor cell disorder were found. A more rapid decline in Hb concentrations in healthy elderly men as compared to elderly women might be explained by differences in bone marrow progenitor cell function. However, progenitor cell abnormalities do not seem to explain differences in Hb concentrations within groups of apparently healthy men and women of advanced age.

Haematological abnormalities and reference intervals in the elderly. A cross-sectional comparative study of three urban Swedish population samples aged 70, 75 and 81 years.

We compared three representative population samples aged 70 (n = 312), 75 (n = 486) and 81 (n = 404) years. Anaemia defined either as blood haemoglobin concentration below the corresponding health-related lower reference limits or according to WHO was, in the total study groups, more common at age 81. Anaemia of unknown cause was rare, but somewhat more common at age 81. Mean blood haemoglobin concentrations in subsamples without definable disorders were significantly lower at age 81 than at ages 70 and 75, whereas the lower health-related reference limits did not differ significantly. White blood cell counts tended to be lower and iron deficiency was somewhat more common at age 81. No significant differences were found in platelet counts or in the prevalence of low plasma cobalamin concentrations. These results indicate a fall in blood haemoglobin with advancing age. The arbitrary WHO criteria for anaemia are clinically applicable at age 70-81.

Serum cobalamins in the elderly: a longitudinal study of a representative population sample from age 70 to 81.

In a representative population sample (n = 973) born 1901-1902 and examined at the ages of 70, 75, 79, and 81, the change in serum cobalamins with increasing age was studied by trend analysis using values obtained in single individuals at all four examinations. In subsamples without definable disorders, the mean annual decline was: among men 3.4 pmol/l (p less than 0.05), among women 3.2 pmol/l (n.s.). The decline was possibly more pronounced among individuals with low and intermediate concentrations. The health-related lower reference limits (the 2.5 percentile values of subsamples without definable disorders) did not differ significantly between sexes and age groups, but low concentrations or ongoing cobalamin medication became more common with advancing age. The results indicate a slight fall in serum cobalamins between age 70 and 81 but do not call for age-related lower reference limits.

Haematological abnormalities in a 75-year-old population. Consequences for health-related reference intervals.

A representative sample (n = 486) of a 75-year-old population was studied, and probands with defined laboratory aberrations were re-investigated. Anaemia was present in 6% of the men and 3% of the women; in 17/22 anaemic subjects a cause was found. The prevalence of plasma cobalamin concentrations less than 130 pmol/l was 6%, of iron deficiency approximately 6%. Divergences in white blood cell and platelet counts were rare. The observed haematological aberrations were almost always caused by disease. Reference intervals for haematological components were calculated in the total study group and two reference sample groups after exclusions based on anamnestic and/or laboratory screening criteria or anamnestic criteria and/or verified disease. The lower reference limits for B-Hb and P-B12 in a group obtained after exclusions based on anamnestic and screening data were considered to be minimum values for healthy subjects. The WHO criteria for anaemia were applicable.