Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival.

Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.

[Glial fibrillary acidic protein in patients with symptoms of acute stroke: diagnostic marker of cerebral hemorrhage]. / Saures Gliafaserprotein beim Patienten mit akuten Schlaganfallsymptomen : Diagnostischer Marker einer Hirnblutung.

Glial fibrillary acidic protein (GFAP) is a highly brain-specific protein that is expressed in large quantities in astrocytes and has important functions in terms of maintaining and stabilizing the cytoskeleton. Acute intracerebral hemorrhage leads to an immediate mechanical destruction of astroglial cells with the subsequent release of GFAP into the extracellular space and the bloodstream. On the other hand, necrosis, cytolysis and GFAP release does not occur before 6-12 h after symptom onset in ischemic stroke. Thus, in the early hours after stroke increased GFAP values could indicate intracerebral hemorrhage. This review article describes the underlying pathophysiology of the test and guides the reader through the available data. Potential implications regarding the prehospital triage of acute stroke patients are discussed, including the possibility to initiate hyperacute treatment, such as blood pressure reduction in patients with intracerebral hemorrhage. Other areas of interest for a potential GFAP test include traumatic brain injury and malignant gliomas.

Notes on the normalizer of a finite subgroup of GL(n,d,Z) in GL(n,d,Z).

A finite algorithm for calculating a finite set of generators for the normalizer of a finite subgroup G of GL(n,d,Z) in GL(n,d,Z) is presented. It is based on an algorithm for the normalizer of a finite subgroup G in GL(n,Z), which has been developed recently by Opgenorth. The normalizer of G in GL(n,d,Z) plays a role for superspace groups analogous to the role that the normalizer of G in GL(n,Z) plays for n-dimensional space groups. It is important for calculating superspace groups with the Zassenhaus algorithm and is needed for testing equivalence of superspace groups.

Response to methylphenidate in boys with attention-deficit hyperactivity disorder.

The response to methylphenidate was examined in 36 boys, aged 7-11 y, with attention-deficit hyperactivity disorder (ADHD) in a double-blind, placebo-controlled, crossover design. Hyperactivity and conduct problems were significantly reduced during methylphenidate treatment. Stimulant medication was associated with improvements on tests of sustained attention, working memory and motor steadiness. When individual changes were studied, it was found that 83% showed a significant improvement in their hyperactivity at home or at school, and for 60% their levels of hyperactive behaviour were within the normal range. High levels of hyperactivity at school and relatively low age were significant predictors of normalization of hyperactivity in at least one setting. However, these predictors could only classify correctly 71% of the children. In clinical practice a trial with stimulants is indicated in ADHD children who show symptoms that are sufficiently severe to cause impairment at home and at school.

Altered reinforcement mechanisms in attention-deficit/hyperactivity disorder.

The present study tested eight boys with attention-deficit/hyperactivity disorder (ADHD) and 12 normal boys (comparison group), aged 7-12 years, to investigate the hypothesis that ADHD is associated with a steeper and shorter delay-of-reinforcement gradient than is normal. A two-component schedule of reinforcement was used to deliver trinkets or coins as reinforcers in a game-like test. One component was marked by a signal. During this period reinforcers (coins or trinkets) were delivered every 30 s. This component is called a 30-s fixed interval (FI) schedule of reinforcement and measures changes in reactivity to reinforcers. The other component was in effect when the signal was turned off. Then no reinforcer was ever delivered. This is called an extinction (EXT) component and measures primarily sustained attention. The ADHD children gradually developed hyperactivity to a large extent consisting of bursts of responses with short interresponse times (IRTs) during both schedule components. The response bursts not only constituted a substantial portion of the ADHD overactivity, but may well be a key component of the behaviour commonly described as impulsiveness, the key behavioural characteristic of ADHD. In addition, the ADHD children showed behaviour during the extinction component that may well be described as a sustained-attention deficit: initially stopping when the signal was turned off and then resuming responding some time thereafter as if the signal had been turned on again. The comparison group ceased responding during extinction and did not show impulsiveness. The findings were in accordance with a steeper and shorter delay gradient in ADHD.

No vigilance deficit found in either young schizophrenic or ADHD subjects.

Vigilance deficits have been found in both schizophrenic and ADHD subjects. The two patient groups have never been directly compared on any vigilance measure, however. In the present study 20 early-onset schizophrenics were compared to 20 ADHD adolescents on a Degraded Stimulus Continuous Performance Test (DS-CPT). A comparison group of 30 normal adolescents was also included. Results showed no significant differences between the three groups on any of the DS-CPT measures. Different hypotheses are put forth to explain the findings, among them that the task may be insensitive to identifying sustained attention deficits in adolescent populations.

Parent-reported symptoms of hyperactivity and attention deficits predict teacher-reported symptoms.

The object of the study was to examine whether symptoms of attention problems and hyperactivity reported by parents predicted teacher-reported symptoms in a referred sample of boys with the DSM-III-R diagnosis of Attention-deficit Hyperactivity Disorder (ADHD). Data from 48 boys, 7-12 years, were gathered independently from parents and teachers using the Child Behavior Checklist, Teacher's Report Form and the ADHD Rating Scale. Base rate, positive predictive power and negative predictive power were calculated for each symptom and for clusters of symptoms. The positive predictive power for individual symptoms was reasonably high with a mean score of 80%, while the parent-teacher agreement (measured by phi correlations) was low. Our results indicate that in most children referred because of hyperactivity, inattention and impulsivity, parent reports are sufficient to make a diagnostic evaluation. However, when multiple informants are available, data should be obtained from different sources.