Correction: Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS.

More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma.

Ectopic adrenocorticotropin (ACTH) secretion accounts for less than 10% of all causes of endogenous Cushing's syndrome (CS) and is usually associated with neuroendocrine tumors and small cell carcinoma of the lung. We report the case of a 62-year-old man with CS due to ectopic ACTH production by small cell carcinoma of the prostate. He presented with severe hypercortisolism and associated symptoms. Plasma neuron specific enolase (NSE) was grossly elevated. Despite performing a laparoscopic bilateral adrenalectomy, the patient died as a result of sepsis with multi-organ failure. Post-mortem immunohistochemical staining of prostate tumor tissue showed ACTH expression. ACTH staining was also performed in four additional patients with small cell carcinoma of the urinary tract without CS. None of these additional cases showed a positive staining for ACTH. Although a rare cause of ectopic ACTH production, neuroendocrine prostate carcinoma should be considered in male patients with Cushing's syndrome, in particular in those with an occult source of ACTH overproduction.

Assessment of fracture risk: who should be treated for osteoporosis?

The clinical significance of osteoporosis arises from the fractures that occur. Of these, the hip fracture in particular is associated with high morbidity, mortality and socio-economic costs. The primary goal of osteoporosis treatment is fracture prevention. In this chapter we try to answer the question of how to assess fracture risk and how to identify those above a given risk threshold so that treatment can be given to those in whom fractures can be prevented (cost-) effectively. At first, the two main strategies for fracture prevention--population screening and case finding--are discussed. Then a fracture risk assessment score, based on easily identifiable clinical risk factors, is proposed. This clinical risk factor analysis can guide the decisions whether additional bone assessment is relevant and whether treatment should be started. Finally, we advocate that absolute fracture risk is important for communication with the patient about the decision whether or not to initiate treatment.

Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study.

The aim of this study was to determine the association between type-2 diabetes mellitus (DM), BMD and fractures in 6,655 men and women aged 55 years and over from the Rotterdam Study. We compared subjects with type-2 DM to subjects without DM. Additionally, subset analyses were performed, dividing subjects on the basis of the glucose tolerance test into already treated DM, newly diagnosed DM, impaired glucose tolerance (IGT) and normal glucose tolerance (NGT, reference). Femoral neck and lumbar spine BMD were measured using DEXA. Nonvertebral fracture ascertainment was performed using an automated record system involving GPs and local hospitals. Although subjects with DM had higher BMD, they had an increased nonvertebral fracture risk: hazard ratio (HR) 1.33 (1.00-1.77). In subset analysis, the increased fracture risk appeared restricted to treated DM subjects only: HR 1.69 (1.16-2.46). Subjects with IGT had a higher BMD, but contrary to treated DM, they had a lower fracture risk: HR 0.80 (0.63-1.00). In conclusion, subjects with type-2 DM and IGT both have a higher BMD. Whereas, subjects with IGT have a decreased fracture risk, subjects with DM (primarily those with already established and treated DM) had an increased fracture risk, probably due to long-term complications associated with DM.

Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study.

The incidence of all non-vertebral fractures, as well as the relation to bone mineral density (BMD), was quantified in 7806 men and women from the Rotterdam Study, a prospective, population-based cohort study of men and women aged 55 years and older. In addition, the sensitivity of using a T-score at or below -2.5 for identifying subjects at risk for fractures was assessed. At baseline, between 1990 and 1993, femoral neck BMD was measured by dual energy X-ray absorptiometry (DXA). Subsequently, gender-specific T-scores were calculated using the NHANES reference population. During a mean follow-up of 6.8 years, information on incident non-vertebral fractures was gathered. In general, hip, wrist and upper humerus fractures are the most frequent fractures in both men and women. Femoral neck BMD appears to be an equally important risk factor in both genders, and is especially related to hip fractures. For all non-vertebral fractures, the age-adjusted hazard ratio (95% confidence interval) per standard deviation decrease in femoral neck BMD was 1.5 (1.4-1.6) for women and 1.4 (1.2-1.6) for men. For hip fractures, the hazard ratios were 2.1 (1.7-2.5) for women and 2.3 (1.6-3.3) for men. Only 44% of all non-vertebral fractures occurred in women with a T-score below -2.5; in men, this percentage was even lower (21%). Thus, there is a clear need for the development of more sensitive risk assessment tools, using not only BMD, but also other clinical predictors of fractures.

Bone mineral density and the risk of peripheral arterial disease: the Rotterdam Study.

Low estrogen exposure throughout life is thought to result in low bone mineral density (BMD) and an increased incidence of cardiovascular disease. In the Rotterdam Study we cross-sectionally examined the relation between BMD and peripheral arterial disease (PAD), as assessed by an ankle-arm index (AAI) of <0.9 in either leg. Data on BMD and PAD were available for 5268 individuals (3053 women, 2215 men). From the BMD, Z-scores were calculated and subsequently divided into tertiles. Logistic regression analysis was used to compute odds ratios (OR) for PAD in tertiles of BMD, using the upper tertile as a reference. When adjusting for age, women with a low femoral neck BMD had a significantly increased risk of PAD (OR = 1.49, 95% CI 1.16-1.91). This could not be found for men (1.14, 0.84-1.53). The mid-tertile did not differ from the reference in either men or women. In women, additional adjustment for several potential confounders resulted in a somewhat lowered risk estimate (1.35, 1.02-1.79). In contrast, no association between lumbar spine BMD and PAD could be observed in either men or women. Our study shows an association between low femoral neck BMD and PAD in women only, an association unlikely to be causal. Estrogen deficiency may be the common denominator in osteoporosis and PAD, resulting in clustering of these two major diseases in postmenopausal women.

Bone mineral density and mortality in elderly men and women: the Rotterdam Study.

Recent studies have shown that a low bone mineral density (BMD) is associated with a higher risk of mortality. Most studies have investigated this relationship in women only and presented their risk estimates per standard deviation change in BMD. However, when using this approach, a BMD threshold might be missed when relative risks are presented in the traditional manner. Therefore, in this study our aim was to model the relation between BMD and all-cause mortality. In the Rotterdam Study, follow-up was complete for 5819 men and women aged > or =55 years for whom BMD data were available. During an average follow-up of 5.4 years, 399 men and 317 women died. We calculated BMD Z scores using measurements performed at the femoral neck. Cox proportional hazards regression was used to fit the model. An average BMD, reflected by a Z score = 0, was used as the reference. For women, no significant relationship between BMD and overall mortality was observed. For men, however, a cubic model best fitted the relationship under study, also after adjusting for age and body mass index (BMI). The risk of mortality increased when BMD was below average. Similar results were found when separate curves were made for diabetics and nondiabetics, smokers (ever or never), and tertiles of BMI. Excluding subjects who had suffered hip fractures, or adjusting for the number of drugs used and for lower limb disability, essentially did not change results. This suggests that low BMD is not mainly due to morbidity and impaired mobility in our cohort, which makes this a less likely explanation for the observed relation with mortality. The results of our study suggest that, in men, a nonlinear relationship between BMD and mortality exists, which is independent of comorbidity, whereas, in women, no significant relationship was observed.