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Purpose: Peripheral neuropathy (PN) is common in patients with multiple myeloma (MM). We hypothesized that the relationship between hypovitaminosis D and PN described in diabetes mellitus patients may also be present in MM patients. Methods: To study this potential association, we assessed the incidence of hypovitaminosis D (vitamin D < 75 nmol/L [= 30 ng/mL]) in smouldering and active MM patients in two Dutch hospitals. Furthermore, a validated questionnaire was used to distinguish different PN grades. Results: Of the 120 patients included between January 2017 and August 2018, 84% had an inadequate vitamin D level (median vitamin D level 49.5 nmol/L [IQR 34–65 nmol/L]; mean age: 68 years [SD ± 7.7]; males: 58%). PN was reported by 69% of patients (n = 83); however, of these 83 patients, PN was not documented in the medical records of 52%. An association was found between lower vitamin D levels and higher incidence of PN in the total population (P = 0.035), and in the active MM patients (P = 0.016). Conclusion: This multi-centre cohort study showed that PN and hypovitaminosis D are common in MM patients, and addressing low vitamin D levels in the treatment of MM patients might be beneficial in reducing the risk of PN. More attention for PN is warranted, as PN is underreported by clinicians. Further research is needed to fully understand the implications of vitamin D in the development of PN in patients with MM. Clinical trial registration: Netherland Trial Register NL5835, date of registration July 28, 2016 [ABSTRACT FROM AUTHOR]

Several clinical studies have shown superiority of azacitidine compared to conventional care regimens in frail patients with MDS and AML [[1]]. In 57 (65%) of 87 patients without HI, and in 51 (81%) of the 63 patients that stopped treatment within 6 cycles, no BME was performed. In 13 out of 22 patients, the dose reduction was done before HI was reached, in 3 of them a BME was done before dose reduction (1 patient had CRi, and 2 patients had SD). Thirteen (6%) patients stopped treatment after the 1st cycle of azacitidine and 63 (37%) patients stopped within 6 cycles. [Extracted from the article]

BACKGROUND The correct dose of therapeutic low molecular weight heparins (LMWHs) in patients with a body mass index ≥ 30 kg/m2 is uncertain. Literature and guidelines are not clear and consistent about the correct dose. DESIGN and METHODS In this review, an overview of the literature on therapeutic use of LMWHs in this population is provided. Sixteen pharmacokinetic and pharmacodynamic or clinical studies were included. RESULTS Based on these results, obese patients should receive therapeutic doses of LMWHs, based on their total body weight without a dose cap as recommended in the Summary of Product Characteristics. In patients with morbid obesity, anti-Xa level monitoring and subsequently an adjusted dosage on the base of supratherapeutic anti- Xa levels is recommended. [ABSTRACT FROM AUTHOR]

Background. Preliminary studies report no negative and a possible positive impact of deep brain stimulation (DBS) on cognition of patients with treatment-resistant depression (TRD). However, these studies neither controlled for practice effects nor compared active with sham stimulation. Method. To address these limitations, we compared 25 TRD patients, who underwent DBS of the ventral anterior limb of the internal capsule (vALIC), with 21 healthy controls (HCs) matched on gender, age and education level. Both groups did subtests of the Cambridge Neuropsychological Test Automated Battery assessing verbal and visuospatial memory, attention, cognitive flexibility, psychomotor functioning, planning and object naming. TRD patients were tested 3 weeks prior to DBS surgery (baseline), 3 weeks following surgery (T1) and following 52 weeks of DBS optimization (T2). HCs were tested at baseline, 6 weeks following baseline (T1) and 20-24 weeks following baseline (T2). Subsequently, TRD patients entered a randomized, double-blind crossover phase, in which they were tested in an active and a sham stimulation phase. Results. TRD patients did not improve on a test of immediate verbal recognition from baseline to T1, whereas HCs did (group x time: p = 0.001). Both TRD patients and HCs improved over sessions on tests measuring delayed verbal recall, visuospatial memory, planning and object naming (all p < 0.01). Active and sham stimulation did not have an impact on any of the tests differentially. Conclusions. vALIC DBS neither has a lasting positive nor negative impact on cognition in TRD patients. DBS surgery might have a temporary negative effect on verbal memory. [ABSTRACT FROM AUTHOR]

Purpose: This prospective, observational population-based cohort study was performed to determine overall survival (OS) in multiple myeloma (MM) patients in Friesland, the Netherlands, in the era of novel agents and to analyse the influence of first-line treatment, MM-related end-organ damage and comorbidities at initial presentation on OS. Methods: Detailed clinical information was obtained from the population-based registry 'HemoBase' during the period January 2005 to January 2013, with a follow-up to January 2014. Results: Overall, the symptomatic MM patients ( n = 225) had a median OS of 40 months. In the age categories <65, 65-75 and ≥75 years, 99, 94 and 87% of the patients received treatment, with a median OS of 92, 42 and 31 months, respectively. OS for patients with or without treatment was 43 and 3 months, respectively. In multivariable analysis, risk factors for worse OS were increasing age (<65: reference; 65-75: HR = 2.2 (95% CI 1.3-3.7) and ≥75: HR = 2.8 (95% CI 1.7-4.8); P < 0.001), not receiving initial treatment (HR = 4.0 (95% CI 2.1-7.7); P < 0.001), hypercalcaemia ( P < 0.001, HR = 1.7 (95% CI 1.2-2.6), P = 0.006) and impaired renal function (HR = 2.6 (95% CI 1.7-4.0); P < 0.001). Conclusions: Increasing age, not receiving initial treatment, hypercalcaemia and impaired renal function at initial presentation were independent risk factors for worse OS. Comorbidity according to Charlson comorbidity index score was not an independent variable predicting OS. [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to determine the total medical costs for treating displaced femoral neck fractures with hemi- or total hip arthroplasty in fit elderly patients. The mean total costs per patient at 2 years of follow-up were €26,399. These results contribute to cost awareness. Introduction: The absolute number of hip fractures is rising and increases the already significant burden on society. The aim of this study was to determine the mean total medical costs per patient for treating displaced femoral neck fractures with hemi- or total hip arthroplasty in fit elderly patients. Methods: The population was the Dutch sample of an international randomized controlled trial consisting of femoral neck fracture patients treated with hemi- or total hip arthroplasty. Patient data and health care utilization were prospectively collected during a total follow-up period of 2 years. Costs were separated into costs for hospital care during primary stay, hospital costs for clinical follow-up, and costs generated outside the hospital during rehabilitation. Multiple imputations were used to account for missing data. Results: Data of 141 participants (mean age 81 years) were included in the analysis. The 2-year mortality rate was 19 %. The mean total cost per patient after 10 weeks of follow-up was €15,216. After 1 and 2 years of follow-up the mean total costs were €23,869 and €26,399, respectively. Rehabilitation was the main cost determinant, and accounted for 46 % of total costs. Primary hospital admission days accounted for 22 % of the total costs, index surgery for 11 %, and physical therapy for 7 %. Conclusions: The main cost determinants for hemi- or total hip arthroplasty after treatment of displaced femoral neck fractures (€26,399 per patient until 2 years) were rehabilitation and nursing homes. Most of the costs were made in the first year. Reducing costs after hip fracture surgery should focus on improving the duration and efficiency of the rehabilitation phase. [ABSTRACT FROM AUTHOR]

Aim To detect features that might lead to the early diagnosis and treatment of aceruloplasminemia, as initiation of treatment before the onset of neurological symptoms is likely to prevent neurological deterioration. Methods The PubMed and OMIM databases were searched for published cases of aceruloplasminemia. Diagnostic criteria for aceruloplasminemia were undetectable or very low serum ceruloplasmin, hyperferritinemia and low transferrin saturation. Clinical, biochemical and radiological data on the presentation and follow-up of the cases were extracted and completed through e-mail contact with all authors. Results We present an overview of 55 aceruloplasminemia cases, including three previously unreported cases. Diabetes mellitus was the first symptom related to aceruloplasminemia in 68.5% of the patients, manifesting at a median age of 38.5 years, and often accompanied by microcytic or normocytic anaemia. The combination preceded neurological symptoms in almost 90% of the neurologically symptomatic patients and was found 12.5 years before the onset of neurological symptoms. Conclusions There is a diagnostic window during which diabetes and anaemia are present although there is an absence of neurological symptoms. Screening for aceruloplasminemia in adult non-obese individuals presenting with antibody-negative, insulin-dependent diabetes mellitus and unexplained anaemia is recommended. The combination of ferritin and transferrin saturation provides a sensitive initial measure for aceruloplasminemia. [ABSTRACT FROM AUTHOR]

Elderly patients with diffuse large B-cell lymphoma (DLBCL) are frequently not treated with standard immunochemotherapy, and this influences survival negatively. The purpose of this study was to gain more insight into treatment decision-making by hematologists. Case vignettes concerning patients with DLBCL were presented to hematologists in the Netherlands. Patient characteristics (age, comorbidity) differed per case. Respondents were asked in each case if they would treat the patient with curative intent by means of full-dose chemotherapy or chemotherapy with dose reduction or if they would not treat the patient with curative intent. The vast majority of respondents would treat an elderly patient diagnosed with DLBCL without a relevant medical history with full-dose chemotherapy irrespective of age. In the presence of comorbidity, lack of social support, cognitive disorders, and untreated depression dose reductions in advance are frequently applied or patients are not treated with curative intent. This is most pronounced for patients aged older than 80 years. Respondents working in a university hospital more frequently refrain form full-dose chemotherapy with curative intent compared to respondents working in tertiary medical teaching hospitals or general hospitals. Patients without a relevant medical history are generally treated with curative intent irrespective of age. Cognitive disorders, comorbidity, and depression reduce the change of being treated with curative intent. This is most prominent in the eldest patient category. [ABSTRACT FROM AUTHOR]

Rationale: Delirium incidence in intensive care unit (ICU) patients is high and associated with poor outcome. Identification of high-risk patients may facilitate its prevention. Purpose: To develop and validate a model based on data available at ICU admission to predict delirium development during a patient's complete ICU stay and to determine the predictive value of this model in relation to the time of delirium development. Methods: Prospective cohort study in 13 ICUs from seven countries. Multiple logistic regression analysis was used to develop the early prediction (E-PRE-DELIRIC) model on data of the first two-thirds and validated on data of the last one-third of the patients from every participating ICU. Results: In total, 2914 patients were included. Delirium incidence was 23.6 %. The E-PRE-DELIRIC model consists of nine predictors assessed at ICU admission: age, history of cognitive impairment, history of alcohol abuse, blood urea nitrogen, admission category, urgent admission, mean arterial blood pressure, use of corticosteroids, and respiratory failure. The area under the receiver operating characteristic curve (AUROC) was 0.76 [95 % confidence interval (CI) 0.73-0.77] in the development dataset and 0.75 (95 % CI 0.71-0.79) in the validation dataset. The model was well calibrated. AUROC increased from 0.70 (95 % CI 0.67-0.74), for delirium that developed <2 days, to 0.81 (95 % CI 0.78-0.84), for delirium that developed >6 days. Conclusion: Patients' delirium risk for the complete ICU length of stay can be predicted at admission using the E-PRE-DELIRIC model, allowing early preventive interventions aimed to reduce incidence and severity of ICU delirium. [ABSTRACT FROM AUTHOR]

Background: There are few empirical studies on the valuation of health profiles that describe the short-term fluctuations of chronic diseases.Objective: This study aimed to value chronic obstructive pulmonary disease (COPD) health profiles, which describe the health of these patients over the course of 1 year from a societal perspective.Methods: We developed 16 COPD health profiles. Each profile combined a description of the severity of COPD during the stable phase with a description of the exacerbation profile in terms of severity, frequency and duration. These profiles were valued by a representative sample of 239 Dutch adults using the visual analogue scale (VAS) and time trade-off (TTO) methods. Value functions were estimated using random effects regression analysis.Results: Both VAS and TTO values consistently decreased as severity of the COPD profiles increased. Estimated TTO values ranged from 0.97 for mild COPD without exacerbations to 0.43 for very severe COPD with one non-serious and one serious exacerbation per year. The estimated decrements in TTO values ranged from 0.010 for having one non-serious exacerbation to 0.088 for having one non-serious plus one serious exacerbation per year.Conclusions: The value function may be an alternative way to model the joint impact of COPD severity and exacerbations on utility values in health economic modelling studies. [ABSTRACT FROM AUTHOR]

Several lines of evidence, including expression analyses, brain imaging and genetic studies suggest that the integrity of myelin is disturbed in schizophrenia patients. In this study, we first reconstructed a pathway of 138 myelin-related genes, all involved in myelin structure, composition, development or maintenance. Then we performed a two-stage association analysis on these 138 genes using 771 single nucleotide polymorphisms (SNPs). Analysis of our data from 310 cases vs 880 controls demonstrated association of 10 SNPs from six genes. Specifically, we observed highly significant P-values for association in PIK4CA (observed P=6.1 × 10−6). These findings remained significant after Bonferroni correction for 771 tests. The PIK4CA gene is located in the chromosome 22q11 deletion syndrome region, which is of particular interest because it has been implicated in schizophrenia. We also report weak association of SNPs in PIK3C2G, FGF1, FGFR1, ARHGEF10 and PSAP (observed P0.01). Our approach—of screening genes involved in a particular pathway for association—resulted in identification of several, mostly novel, genes associated with the risk of developing schizophrenia in the Dutch population.Molecular Psychiatry (2008) 13, 1060–1068; doi:10.1038/sj.mp.4002080; published online 25 September 2007 [ABSTRACT FROM AUTHOR]

Objective: To examine the cost-effectiveness of varenicline, a new pharmacotherapy to support smoking cessation, compared with the currently available pharmacologic alternatives in the Netherlands.Methods: The BENESCO-model was used to estimate the long-term health and economic benefits of smoking cessation for a cohort of smokers making a one-time quit attempt. The cohort represented the population of Dutch smokers with respect to gender, age, and prevalence of the smoking-related diseases included in the model: COPD, lung cancer, CHD, stroke, and asthma exacerbations. The model compared the cumulative incidence of smoking-related diseases, (quality-adjusted) life years, intervention costs, and direct medical costs between the cohort treated with varenicline and the same cohort either untreated (unaided cessation) or treated with bupropion, nortriptyline or NRT. The time horizon was lifetime. Future costs were discounted at 4%, health outcomes at 1.5%.Results: The cost of varenicline per additional quitter ranged from 1030 Euro compared with NRT to 4270 Euro compared with nortriptyline. When including the savings due to the reduction in incidence of smoking-related diseases, varenicline generated net savings compared with bupropion and NRT. Compared with nortriptyline and unaided cessation, varenicline was estimated to cost 1650 Euro/QALY and 320 Euro/QALY gained, respectively. At a willingness-to-pay as low as 5000/QALY gained, the probability that varenicline was cost-effective was more than 80% compared to bupropion, NRT, and unaided cessation and about 60% compared to nortriptyline.Conclusion: Treatment with varenicline for smoking cessation is cost-effective compared with nortriptyline and unaided cessation and even cost-saving compared with bupropion and NRT. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the characteristics of graft-versus-leukemia responses in patients with chronic lymphocytic leukemia (CLL).

Several putative schizophrenia susceptibility genes have recently been reported, but it is not clear whether these genes are associated with schizophrenia in general or with specific disease subtypes. In a previous study, we found an association of the neuregulin 1 ( NRG1) gene with non-deficit schizophrenia only. We now report an association study of four schizophrenia candidate genes in patients with and without deficit schizophrenia, which is characterized by severe and enduring negative symptoms. Single-nucleotide polymorphisms (SNPs) were genotyped in the DTNBP1 (dysbindin), G72/G30 and RGS4 genes, and the relatively unknown PIP5K2A gene, which is located in a region of linkage with both schizophrenia and bipolar disorder. The sample consisted of 273 Dutch schizophrenia patients, 146 of whom were diagnosed with deficit schizophrenia and 580 controls. The strongest evidence for association was found for the A-allele of SNP rs10828317 in the PIP5K2A gene, which was associated with both clinical subtypes ( P = 0.0004 in the entire group; non-deficit P = 0.016, deficit P = 0.002). Interestingly, this SNP leads to a change in protein composition. In RGS4, the G-allele of the previously reported SNP RGS4-1 (single and as part of haplotypes with SNP RGS4-18) was associated with non-deficit schizophrenia ( P = 0.03) but not with deficit schizophrenia ( P = 0.79). SNPs in the DTNBP1 and G72/G30 genes were not significantly associated in any group. In conclusion, our data provide further evidence that specific genes may be involved in different schizophrenia subtypes and suggest that the PIP5K2A gene deserves further study as a general susceptibility gene for schizophrenia. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation following reduced-intensity conditioning is being evaluated in patients with advanced B-cell chronic lymphocytic leukemia (B-CLL). The curative potential of this procedure is mediated by donor-derived alloreactive T cells, resulting in a graft-versus-leukemia effect. However, B-CLL may escape T-cell-mediated immune reactivity since these cells lack expression of costimulatory molecules. We examined the most optimal method to transform B-CLL cells into efficient antigen-presenting cells (APC) using activating cytokines, by triggering toll-like receptors (TLRs) using microbial pathogens and by CD40 stimulation with CD40L-transfected fibroblasts. CD40 activation in the presence of IL-4 induced strongest upregulation of costimulatory and adhesion molecules on B-CLL cells and induced the production of high amounts of IL-12 by the leukemic cells. In contrast to primary B-CLL cells as stimulator cells, these malignant APCs were capable of inducing the generation of B-CLL-reactive CD8+ CTL lines and clones from HLA class I-matched donors. These CTL lines and clones recognized and killed primary B-CLL as well as patient-derived lymphoblasts, but not donor cells. These results show the feasibility of ex vivo generation of B-CLL-reactive CD8+ CTLs. This opens new perspectives for adoptive immunotherapy, following allogeneic stem cell transplantation in patients with advanced B-CLL.Leukemia (2004) 18, 1278-1287. doi:10.1038/sj.leu.2403358 Published online 29 April 2004 [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the association of the neuregulin 1 gene with schizophrenia in patients with and without the deficit syndrome.