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.

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.

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.

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.

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

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.

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.

Effects of opioids on driving ability.

Driving has been regarded as an activity of daily living that is important in maintaining a person's independence in the community, access to employment, and social activities. Many patients, however, using opioid medications on a regular basis (Chronic Opioid Analgesic Therapy: COAT) to ameliorate their intractable pain have been restricted from driving out of concern that skills would be impaired and driving safety compromised by these medications. Yet there are no driving studies which have explored the effects of using opioid analgesics for an extended period of time. This pilot study was designed to determine the effects of medically prescribed, stable opioid use on the driving abilities of patients with persistent, nonmalignant pain. Sixteen patients with chronic nonmalignant pain on COAT, who met criteria for participation in the study, underwent a comprehensive off-road driving evaluation using measures which have been shown to be sensitive in predicting on-road driving performance. The evaluation consisted of a pre-driver evaluation (PDE), a simulator evaluation (SDE), and behavioral observation during simulator performance. Patients in the COAT group were compared to a historical control group of 327 cerebrally compromised patients (CComp) who had undergone the same evaluation and then passed an on-road, behind-the-wheel evaluation (BTW Pass; n = 162) or failed (BTW Fail; n = 165). Results revealed that COAT patients generally outperformed the CComp patients as a group by equaling or exceeding PDE and SDE scores of the BTW Fail patients as well as the BTW Pass patients on all measures that differentiated the groups. Notably, COAT patients had a relatively poorer performance than CComp patients on specific neuropsychometric tests in the PDE; however, the differences were not statistically significant and did not imply a systematic pattern of scores that reflected domain-specific deficits. Behaviorally, COAT patients were generally superior to CComp patients, also; however, COAT patients had greater difficulty in following instructions and as well as a tendency toward impulsivity, like the BTW fail group. While there was general support for the notion that COAT did not significantly impair the perception, cognition, coordination, and behavior measured in off-road tests that have been regarded as requisite for on-road driving, methodological problems may limit the generalizability of results and recommendations are made for research beyond a pilot study.

Evaluating fitness to drive after cerebral injury: basic issues and recommendations for medical and legal communities.

Specialists in rehabilitation are typically called upon to evaluate and render an opinion about whether or not a person can be entrusted to resume driving. And, because driving is an individual privilege to be balanced against the public's right to safety and protection from the dangers of a driver whose residual deficits may impede ability to drive safely, these specialists have developed a number of methods to assess fitness to drive. Unfortunately, many evaluators remain unfamiliar with research used as basis for evaluations or lack understanding of the strengths and weaknesses of tests in use. Therefore, there may be unquestioning trust in tests and methods that leads to errors of significant consequence in decisions about fitness to drive as well as unawareness of expanding risks of litigation that can emanate from inappropriate recommendations. This article intends to draw attention to issues, considerations, and problems underlying the conduct of driver evaluations, including focus on ways in which the legal and medical communities approach question of fitness, legal and medical definitions and terminology, responsibility for assessment as well as tests and methods used in evaluations. Conclusions are drawn from discussion of these matters and recommendations are outlined for addressing identified problems at the interface between medical and legal communities.

Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients.

Treatment with erythropoietin (epo) may improve the anemia of myelodysplastic syndromes (MDS) in approximately 20% of patients. Previous studies have suggested that treatment with the combination of granulocyte colony-stimulating factor (G-CSF) and epo may increase this response rate. In the present phase II study, patients with MDS and anemia were randomized to treatment with G-CSF + epo according to one of two alternatives; arm A starting with G-CSF for 4 weeks followed by the combination for 12 weeks, and arm B starting with epo for 8 weeks followed by the combination for 10 weeks. Fifty evaluable patients (10 refractory anemia [RA], 13 refractory anemia with ring sideroblasts [RARS], and 27 refractory anemia with excess blasts [RAEB]) were included in the study, three were evaluable only for epo as monotherapy and 47 for the combined treatment. The overall response rate to G-CSF + epo was 38%, which is identical to that in our previous study. The response rates for patients with RA, RARS, and RAEB were 20%, 46%, and 37%, respectively. Response rates were identical in the two treatment groups indicating that an initial treatment with G-CSF was not neccessary for a response to the combination. Nine patients in arm B showed a response to the combined treatment, but only three of these responded to epo alone. This suggests a synergistic effect in vivo by G-CSF + epo. A long-term follow-up was made on 71 evaluable patients from both the present and the preceding Scandinavian study on G-CSF + epo. Median survival was 26 months, and the overall risk of leukemic transformation during a median follow-up of 43 months was 28%. Twenty patients entered long-term maintenance treatment and showed a median duration of response of 24 months. The international prognostic scoring system (IPSS) was effective to predict survival, leukemic transformation, and to a lesser extent, duration of response, but had no impact on primary response rates.

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.

Estimates of driving abilities and skills in different conditions.

OBJECTIVES: This research was a preliminary effort to determine whether various driving situations seemed to require different driving skills and abilities and to identify the relative demands of specific physical, perceptual, cognitive, behavioral, and operational skills and abilities in different driving situations. METHOD: Experienced driver evaluators and trainers estimated the magnitude of driving abilities and skills for different photographed driving situations. Pictures of driving scenarios were counterbalanced for road type, traffic condition, and weather condition. RESULTS: A multifactorial analysis of variance of the total score for each scenario revealed significant main effects for road type and traffic condition but not for weather condition. Highway and city driving were rated as significantly more demanding overall than residential driving, but no difference was found between city and highway driving. Estimates of the overall demands for driving in heavy traffic were significantly greater than in light traffic. However, driving in inclement weather was not regarded as significantly more demanding than driving in sunny weather. Additionally, significant interaction effects were found for road type by weather condition and traffic by weather condition but not for road type by traffic condition. Through multivariate methods to evaluate the significance of individual abilities and skills across conditions, significant main and interactive effects were found for road type, traffic condition, and weather condition. Post hoc analyses showed the impact of these effects on such abilities and skills as scanning, attention and concentration, information-processing speed, and others. CONCLUSION: Evaluators' quantified estimates of driving demands showed driving as a complex task that (a) requires high levels of abilities and skills in all situations; (b) demands greater abilities in some situations than in others; and (c) involves different kinds and various degrees of abilities and skills, depending on the demand characteristics of the situation.

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.

Off-road driving evaluations for persons with cerebral injury: a factor analytic study of predriver and simulator testing.

OBJECTIVES: Off-road evaluations composed of psychometric testing and simulator driving are commonly used in rehabilitation settings to assess a person's fitness to resume driving after a cerebral injury. Although the results of these evaluation methods separately provide information about ability to drive, there is no clear understanding about what is measured in comprehensive off-road evaluations as a whole. This study explored the interrelationship of perceptual, cognitive, behavioral, and operational variables that form the basis for off-road evaluations in order to determine whether there are basic dimensions underlying performance in these evaluations and to derive a small set of variables that could help in refining methods for evaluating persons with cerebral injuries. METHODS: One-hundred six persons with cerebral damage due to brain injury or cerebrovascular accident were administered a predriver evaluation that consisted of selected neuropsychometric tests. Subjects were also evaluated in a driving simulator that measured their operational responses to filmed driving situations and assessed their behaviors. Principal component analysis was used to identify manifest and latent variables contributing to the results of the evaluations. RESULTS: The analysis produced a model with five independent (orthogonal) eigenvectors, or factors, for this population: Higher Order Visuospatial Abilities, Basic Visual Recognition and Responding, Anticipatory Braking, Defensive Steering, and Behavioral Manifestations of Complex Attention. These factors accounted for 66.14% of the total variance in the subjects' responses to comprehensive off-road evaluations. CONCLUSION: These factors were useful in understanding driving performance and the role of predriver and simulator testing in driver evaluations.

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.

Prediction of behind-the-wheel driving performance in patients with cerebral brain damage: a discriminant function analysis.

Rehabilitation specialists, particularly occupational therapists, are often involved in evaluating clients' fitness to resume driving after cerebral damage due to head injury or stroke. Their available methods include separate or combined administration of predriver, simulator, and behind-the-wheel evaluations. However, use of these methods without a theoretical model on which to base test selection has yielded some criticism and little research about the effectiveness of these methods in predicting driving performance. Using the authors' Cybernetic Model of Driving as the basis for assessing abilities and behaviors relevant to driving outcome, this study sought to determine the effectiveness of the evaluation methods by discriminant analysis and measurements of sensitivity in predicting behind-the-wheel failures. Comprehensive evaluations of 106 patients revealed that residual deficits in cognition per se did not render a person unfit to drive and underscored the importance of considering behaviors in determining fitness. The methods of evaluation were shown to be relatively sensitive in predicting outcome; off-road and on-road evaluation reached sensitivities of 90% and 92% with the inclusion of behavioral measures. Formulae for predicting outcome based on methods of evaluation are provided and reasons for failures in behind-the-wheel evaluations are discussed.

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.

Driving after cerebral damage: a model with implications for evaluation.

Evaluation of the ability of cerebrally injured patients to return to driving is an important task for rehabilitation specialists. These evaluations require predictively valid methods of assessment based on identification of relevant skills and abilities. The present study tested a hypothetical model for driving after cerebral injury and determined its use in evaluating fitness to drive. Thirty-five patients with cerebral damage due to head injury or cerebrovascular accident participated in the study. All were administered (a) a predriver evaluation, that is, a battery of neuropsychological tests chosen a priori to test the model, (b) a simulator evaluation, and (c) a behind-the-wheel evaluation consisting of driving on a protected course and in traffic. The results showed that 93% of the driving outcome in traffic was explained cumulatively by findings from the predriver and simulator evaluations as well as from behavioral and operational measures during evaluation on the protected lot. These results supported the predictive validity of the model and are discussed in terms of methodology for evaluation of return to driving.