Cognitive functioning in glioblastoma patients during radiotherapy and temozolomide treatment: initial findings

The aim of this study was to evaluate cognitive functioning in newly-diagnosed glioblastoma multiforme (GBM) patients during treatment with radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ). Cognitive assessment took place following surgery, but prior to the start of RT (baseline), after 6 weeks of RT and concomitant TMZ (1st follow-up), and after three cycles of adjuvant TMZ (2nd follow-up). Standardized cognitive summary measures and delta scores for six cognitive domains were calculated at the individual level. Cognitive functioning of progression-free GBM patients was compared to that of matched healthy controls. Analyses were performed on a group of 13 GBM patients that were progression-free during follow-up. The results showed that the majority of patients had deficits in multiple cognitive domains at baseline. Between baseline and 1st follow-up, four patients improved in one cognitive domain, four patients deteriorated in one domain, one patient improved in one domain and deteriorated in another, and four patients remained stable in all six domains. Between 1st and 2nd follow-up, the majority of patients (11) remained stable in all six cognitive domains, whereas one patient declined in one domain, and one patient showed a deterioration in two domains. Overall, between baseline and 2nd follow-up, three patients improved in one cognitive domain, two patients deteriorated in two domains, one patient improved in one domain and deteriorated in another, and seven patients remained stable in all six cognitive domains. In conclusion, preceding treatment, the majority of GBM patients show clear-cut deficits in cognitive functioning. In the course of the first 6 months of their disease, however, progression-free GBM patients undergoing radiotherapy plus concomitant and adjuvant temozolomide treatment do not deteriorate in cognitive functioning

The Short-term Car Flow Planning Model in Rail Freight Company – Case Study

AbstractWith the promotion of the environmentally friendly transportation modes (the European Commission supports the freight transport operations in the rail sector), an increase in the diversification of the demand is observed. While most rail freight companies tend to apply fixed schedules, this approach is not effective turns out to be ineffective due to the need to meet the customer's specific requirements.The purpose of this paper is to present a case study of empty wagon flow planning over a medium term horizon and to discuss the opportunities of improvement of this plans by discrete optimization. In order to increase the utilization and availability of wagons, the planning procedure with a rolling horizon has to be implemented. Unfortunately, since the plan has to be updated ca. every 4hours, this planning approach needs effective optimization tools. Our hybrid two-stage approach is designed to be implemented in such business environment. This formulation allows us to solve real life instances even for a 7-day time horizon

Treatments and costs for recurrent and/or metastatic squamous cell carcinoma of the head and neck in the Netherlands

__Abstract__ For patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), chemotherapy can prolong life and alleviate symptoms. However, expected gains may be small, not necessarily outweighing considerable toxicity and high costs. Treatment choice is to a large extent dependent on preferences of doctors and patients and data on these choices are scarce. The purpose of this study is to obtain real-world information on palliative systemic treatment and costs of R/M SCCHN in the Netherlands. In six Dutch head and neck treatment centers, data were collected on patient and tumor characteristics, treatment patterns, disease progression, survival, adverse events, and resource use for R/M SCCHN, between 2006 and 2013. 125 (14 %) out of 893 R/M SCCHN patients received palliative, non-trial first-line systemic treatment, mainly platinum + 5FU + cetuximab (32 %), other platinum-based combination therapy (13 %), methotrexate monotherapy (27 %) and capecitabine monotherapy (14 %). Median progression-free survival and overall survival were 3.4 and 6.0 months, respectively. 34 (27 %) patients experienced severe adverse events. Mean total hospital costs ranged from €10,075 (±€9,891) (methotrexate monotherapy) to €39,459 (±€21,149) (platinum + 5FU + cetuximab). Primary cost drivers were hospital stays and anticancer drug treatments. Major health care utilization and costs are involved in systemically treating R/M SCCHN patients with a limited survival

Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients:Results From the TransplantLines Biobank and Cohort Study

Rationale &amp; Objective: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. Study Design: Cross-sectional study. Setting &amp; Participants: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. Exposure: PPI use, PPI type, PPI dosage, and duration of PPI use. Outcome: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. Analytical Approach: Logistic and linear regression. Results: We included 937 kidney transplant recipients (mean age 56 ± 13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P &lt; 0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P &lt; 0.001), lower physical HRQoL (regression coefficient −8.54, 95% CI, −11.54 to −5.54, P &lt; 0.001), and lower mental HRQoL (regression coefficient −4.66, 95% CI, −7.15 to −2.17, P &lt; 0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. Limitations: Residual confounding and inability to assess causal relationships. Conclusions: PPI use is independently associated with fatigue and lower HRQoL among kidney transplant recipients. PPI use might be an easily accessible target for alleviating fatigue and improving HRQoL among kidney transplant recipients. Further studies examining the effect of PPI exposure in this population are warranted. Plain-Language Summary: In this observational study, we investigated the association of proton pump inhibitors with fatigue and health-related quality of life among kidney transplant recipients. Our data showed that proton pump inhibitors were independently associated with fatigue severity, severe fatigue, and lower physical and mental health-related quality of life. These associations were present among all individually assessed proton pump inhibitor types and were dose dependent. While we await future studies on this topic, proton pump inhibitor use might be an easily accessible target for alleviating fatigue and improving health-related quality of life among kidney transplant recipients.</p

The EGFRvIII transcriptome in glioblastoma, a meta-omics analysis.

BACKGROUND: EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being amongst its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signalling compared with wildtype EGFR. METHODS: To better understand the oncogenic role of EGFRvIII, we leveraged four large datasets into one large glioblastoma transcriptome dataset (n=741) alongside 81 whole-genome samples from two datasets. RESULTS: The EGFRvIII/EGFR expression ratios differ strongly between tumours and ranges from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII positive and negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (p=0.007), which may point towards crosstalk between these pathways. EGFRvIII-expressing tumours have an upregulation of 'classical' subtype genes compared to those with EGFR-amplification only (p=3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference towards the 3' end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. CONCLUSIONS: These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumours

Loss of Dopamine Transporter Binding and Clinical Symptoms in Dementia With Lewy Bodies

Little is known about the underlying mechanisms of clinical symptoms in dementia with Lewy bodies. The aim of this study was to explore the association between loss of striatal dopamine transporter binding and symptoms in dementia with Lewy bodies. Thirty-five patients with dementia with Lewy bodies underwent single-photon emission computerized tomography brain imaging with N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([(123) I]FP-CIT). Associations between striatal binding ratios and motor (UPDRS), psychiatric (Neuropsychiatric Inventory; [NPI]), and cognitive (Mini-Mental State Examination [MMSE] and neuropsychological tests) symptoms were assessed by linear regression analysis. The explorative analysis showed that the motor UPDRS was negatively associated with putamen dopamine transporter binding, whereas no association with striatal dopamine transporter binding was found for total NPI, hallucinations, apathy, depression, anxiety, and MMSE scores. However, in post-hoc analysis, executive impairment was positively associated with dopamine transporter loss after adjustment of age and gender. Dopamine deficiency in patients with dementia with Lewy bodies was associated with severity of motor symptoms, but did not correlate significantly with ratings of neurobehavioral disturbances or overall cognitio

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OBJECTIVES: Little is known regarding the ‘false-negative’ or ‘false-positive’ striatal dopamine transporter binding on SPECT for the diagnosis of dementia with Lewy bodies (DLB). We explored the clinical course in patients fulfilling the criteria for clinical DLB with a normal ((123)I)FP-CIT SPECT (ie, SPECT scan negative, clinical features positive (S−CF+)) and patients not fulfilling DLB criteria with an abnormal scan (S+CF−). DESIGN: Longitudinal case study over 2–5 years. SETTING: Consecutive referrals of patients with mild dementia to dementia clinics in western Norway. PARTICIPANTS: 50 patients (27 men and 23 women; mean age at baseline of 74 (range 52–88)) with ((123)I)FP-CIT SPECT images underwent cluster analysis: 20/50 patients allocated to a ‘DLB’ and 8 to a ‘non-DLB’ cluster were included. OUTCOME MEASURES: Scores on standardised clinical rating scales for hallucinations, parkinsonism, fluctuations, rapid eye movement (REM) sleep behaviour disorder and visually rated ((123)I)FP-CIT SPECT. RESULTS: During the follow-up period, in the S+CF− group (n=7), frequency and severity of DLB symptoms tended to increase, particularly parkinsonism (7/7) and cognitive fluctuations (7/7), while severity of visual hallucinations and REM sleep behaviour disorder remained stable. The S−CF+ (n=3) fulfilled the operationalised criteria for probable DLB both at baseline and at the end of the follow-up. CONCLUSIONS: The findings suggest that systematic visual analyses of ((123)I)FP-CIT SPECT can detect people with DLB prior to the development of the full clinical syndrome. In addition, the study indicates that some patients fulfilling clinical criteria for probable DLB have a normal scan, and further studies are required to characterise these patients better

(123I)FP-CIT SPECT in suspected dementia with Lewy bodies: a longitudinal case study

Little is known regarding the 'false-negative' or 'false-positive' striatal dopamine transporter binding on SPECT for the diagnosis of dementia with Lewy bodies (DLB). We explored the clinical course in patients fulfilling the criteria for clinical DLB with a normal ((123)I)FP-CIT SPECT (ie, SPECT scan negative, clinical features positive (S-CF+)) and patients not fulfilling DLB criteria with an abnormal scan (S+CF-). Longitudinal case study over 2-5 years. Consecutive referrals of patients with mild dementia to dementia clinics in western Norway. 50 patients (27 men and 23 women; mean age at baseline of 74 (range 52-88)) with ((123)I)FP-CIT SPECT images underwent cluster analysis: 20/50 patients allocated to a 'DLB' and 8 to a 'non-DLB' cluster were included. Scores on standardised clinical rating scales for hallucinations, parkinsonism, fluctuations, rapid eye movement (REM) sleep behaviour disorder and visually rated ((123)I)FP-CIT SPECT. During the follow-up period, in the S+CF- group (n=7), frequency and severity of DLB symptoms tended to increase, particularly parkinsonism (7/7) and cognitive fluctuations (7/7), while severity of visual hallucinations and REM sleep behaviour disorder remained stable. The S-CF+ (n=3) fulfilled the operationalised criteria for probable DLB both at baseline and at the end of the follow-up. The findings suggest that systematic visual analyses of ((123)I)FP-CIT SPECT can detect people with DLB prior to the development of the full clinical syndrome. In addition, the study indicates that some patients fulfilling clinical criteria for probable DLB have a normal scan, and further studies are required to characterise these patients bette