First-line treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience

Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly diagnosed malignant glioma. But these studies and subsequent non-phase III studies have also shown risks associated with local chemotherapy within the central nervous system. The introduction of concomitant radiochemotherapy with temozolomide (TMZ) has later demonstrated a survival benefit in a phase III trial and has become the current treatment standard for newly diagnosed malignant glioma patients. Lately, this has resulted in clinical protocols combining local chemotherapy with BCNU wafers and concomitant radiochemotherapy with TMZ although this may carry the risk of increased toxicity. We have compiled the treatment experience of seven neurosurgical centers using implantation of carmustine wafers at primary surgery followed by 6 weeks of radiation therapy (59–60 Gy) and 75 mg/m²/day TMZ in patients with newly diagnosed glioblastoma followed by TMZ monochemotherapy. We have retrospectively analyzed the postoperative clinical course, occurrence and severity of adverse events, progression-free interval, and overall survival in 44 patients with newly diagnosed glioblastoma multiforme. All patients received multimodal treatment including tumor resection, BCNU wafer implantation, and concomitant radiochemotherapy. Of 44 patients (mean age 59?±?10.8 years) with glioblastoma who received Gliadel wafer at primary surgery, 28 patients (64%) had died, 16 patients (36%) were alive, and 15 patients showed no evidence of clinical or radiographic progression after a median follow-up of 15.6 months. At time of analysis of adverse events in this patient population, the median overall survival was 12.7 months and median progression-free survival was 7.0 months. Surgical, neurological, and medical adverse events were analyzed. Twenty-three patients (52%) experienced adverse events of any kind including complications that did not require treatment. Nineteen patients (43%) experienced grade 3 or grade 4 adverse events. Surgical complications included cerebral edema, healing abnormalities, cerebral spinal fluid leakage, meningitis, intracranial abscess, and hydrocephalus. Neurological adverse events included newly diagnosed seizures, alteration of mental status, and new neurological deficits. Medical complications were thromboembolic events (thrombosis, pulmonary embolism) and hematotoxicity. Combination of both treatment strategies, local chemotherapy with BCNU wafer and concomitant radiochemotherapy, appears attractive in aggressive multimodal treatment schedules and may utilize the sensitizing effect of TMZ and carmustine on MGMT and AGT on their respective drug resistance genes. Our data demonstrate that combination of local chemotherapy and concomitant radiochemotherapy carries a significant risk of toxicity that currently appears underestimated. Adverse events observed in this study appear similar to complication rates published in the phase III trials for BCNU wafer implantation followed by radiation therapy alone, but further add the toxicity of concomitant radiochemotherapy with systemic TMZ. Save use of a combined approach will require specific prevention strategies for multimodal treatments.     

Evaluation of new colorimetric vitek 2 yeast identification card by use of different source media

The new colorimetric Vitek 2 YST card was evaluated for identification of yeasts (136 strains) with respect to the influence of different source media. The Vitek 2 YST card achieved satisfactory results for all yeast species tested, with the exception of Candida guilliermondii, Candida norvegensis, Candida parapsilosis, Candida rugosa, and Candida tropicalis. After simple additional tests, 93.7% of all the strains tested were correctly identified. A significant influence of the isolation medium on the identification rate could not be observed.     

The molecular profile of adult T‐cell acute lymphoblastic leukemia: Mutations in RUNX1 and DNMT3A are associated with poor prognosis in T‐ALL

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive and heterogeneous disease. The diagnosis is predominantly based on immunophenotyping. In addition to known cytogenetic abnormalities molecular mutations were recently identified. Here, 90 adult T‐ALL cases were investigated for mutations in NOTCH1, FBXW7, PHF6, CDKN2A, DNMT3A, FLT3, PTEN, and RUNX1 using 454 next‐generation amplicon sequencing and melting curve analyses. These data were further complemented by FISH, chromosome banding, array CGH, and CDKN2B promoter methylation analyses. NOTCH1 was the most frequently mutated gene with a 71.1% frequency followed by FBXW7 (18.9%), PHF6 (39.5%), DNMT3A (17.8%), RUNX1 (15.5%), PTEN (10.0%), CDKN2A (4.4%), FLT3‐ITD (2.2%), and FLT3‐TKD (1.1%). In total, 84/90 (93.3%) cases harbored at least one mutation. Combining these data with CDKN2A/B deletions and CDKN2B methylation status, we detected minimum one aberration in 89/90 (98.9%) patients. Survival analyses revealed the subtype as defined by the immunophenotype as the strongest independent prognostic factor. When restricting the survival analysis to the early T‐ALL subtype, a strong association of RUNX1 (P = 0.027) and DNMT3A (P = 0.005) mutations with shorter overall survival was observed. In conclusion, RUNX1 and DNMT3A are frequently mutated in T‐ALL and are associated with poor prognosis in early T‐ALL. © 2013 Wiley Periodicals, Inc.     

Interaction of pregnancy and autoimmune rheumatic disease

During pregnancy, the fetus represents a natural allograft that is not normally rejected. While the maternal immune system retains the ability to respond to foreign antigens, tolerance mechanisms are up-regulated to protect the fetus from immunologic attacks by the mother. The profound immunologic adaptations during and after pregnancy do influence maternal autoimmune rheumatic diseases in several ways. One is triggering the onset of a rheumatic disease in the post partum period, the other influencing disease activity of established rheumatic disease. The review will discuss the mechanisms of increased susceptibility of rheumatoid arthritis (RA) in the first year post partum with a specific emphasis on the role of fetal cells or antigens persisting in the maternal circulation (so called microchimerism). Furthermore, the different influences of pregnancy on established rheumatic diseases will be highlighted. A marked beneficial effect of pregnancy is observed on RA whereas several other rheumatic diseases as ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) show either no particular effect or an aggravation of symptoms during pregnancy. Differences emerging in regard to modulation of disease symptoms during pregnancy seem related to response to hormones, the type of cytokine profile and immune response prevailing as well as further downstream interactions of molecular pathways that are important in disease pathogenesis.     

Higher body mass index is associated with reduced posterior default mode connectivity in older adults

Obesity is a complex neurobehavioral disorder that has been linked to changes in brain structure and function. However, the impact of obesity on functional connectivity and cognition in aging humans is largely unknown. Therefore, the association of body mass index (BMI), resting‐state network connectivity, and cognitive performance in 712 healthy, well‐characterized older adults of the Leipzig Research Center for Civilization Diseases (LIFE) cohort (60–80 years old, mean BMI 27.6 kg/m² ± 4.2 SD, main sample: n = 521, replication sample: n = 191) was determined. Statistical analyses included a multivariate model selection approach followed by univariate analyses to adjust for possible confounders. Results showed that a higher BMI was significantly associated with lower default mode functional connectivity in the posterior cingulate cortex and precuneus. The effect remained stable after controlling for age, sex, head motion, registration quality, cardiovascular, and genetic factors as well as in replication analyses. Lower functional connectivity in BMI‐associated areas correlated with worse executive function. In addition, higher BMI correlated with stronger head motion. Using 3T neuroimaging in a large cohort of healthy older adults, independent negative associations of obesity and functional connectivity in the posterior default mode network were observed. In addition, a subtle link between lower resting‐state connectivity in BMI‐associated regions and cognitive function was found. The findings might indicate that obesity is associated with patterns of decreased default mode connectivity similar to those seen in populations at risk for Alzheimer's disease. Hum Brain Mapp 38:3502–3515, 2017. © 2017 Wiley Periodicals, Inc.     

Effectiveness of telephone-assisted parent-administered behavioural family intervention for preschool children with externalizing problem behaviour: a randomized controlled trial

Externalizing problem behaviour is one of the most common childhood disorders. Parent training is an effective treatment for these children and there is growing interest in the effects of parent-administered interventions with minimal therapist contact. This randomized controlled study examined the efficacy of a telephone-assisted parent-administered behavioural intervention (bibliotherapy) in families with preschool children with externalizing problem behaviour. Families were randomly assigned to a treatment group (n = 26) and an untreated waitlist control group (n = 22). The intervention comprised the reading of an 11 chapter self-help book and 11 weekly telephone consultations. Compared to the control group, the treatment group demonstrated significant decreases in parent-reported externalizing and internalizing child problem behaviour and dysfunctional parenting practices. Moreover, treated parents reported less parenting-related strains and decreases in parental depression, anxiety, and stress. The results suggest that telephone-assisted self-administered parent training is an effective alternative to more intensive forms of behavioural family intervention for preschool children with externalizing problem behaviour.     

A Stratified Model for Psychosis Prediction in Clinical Practice

Objective: Impaired cognition is an important dimension in psychosis and its at-risk states. Research on the value of impaired cognition for psychosis prediction in at-risk samples, however, mainly relies on study-specific sample means of neurocognitive tests, which unlike widely available general test norms are difficult to translate into clinical practice. The aim of this study was to explore the combined predictive value of at-risk criteria and neurocognitive deficits according to test norms with a risk stratification approach. Method: Potential predictors of psychosis (neurocognitive deficits and at-risk criteria) over 24 months were investigated in 97 at-risk patients. Results: The final prediction model included (1) at-risk criteria (attenuated psychotic symptoms plus subjective cognitive disturbances) and (2) a processing speed deficit (digit symbol test). The model was stratified into 4 risk classes with hazard rates between 0.0 (both predictors absent) and 1.29 (both predictors present). Conclusions: The combination of a processing speed deficit and at-risk criteria provides an optimized stratified risk assessment. Based on neurocognitive test norms, the validity of our proposed 3 risk classes could easily be examined in independent at-risk samples and, pending positive validation results, our approach could easily be applied in clinical practice in the future.Key words: prediction, psychosis, neurocognition, processing speed, at-risk criteria, risk estimation     

Polyspecific immunoglobulins (IVIg) suppress proliferation of human (auto)antigen-specific T cells without inducing apoptosis

Polyspecific immunoglobulins (IVIg) have been shown to reduce disease activity in multiple sclerosis (MS). To investigate the mechanisms of action of IVIg, we studied the impact of IVIg on growth and death (apoptosis) of human (auto)antigen-specific T cells. We observed a substantial suppression of proliferation of specifically activated T cells, in absence of caspase activation or DNA fragmentation. Further, neither susceptibility of T cells to undergo CD95-mediated apoptosis nor expression of apoptosis-blocking bcl-2 was modulated by IVIg. We conclude that IVIg may inhibit the reactivity of antigen-specific T cells in MS through suppression of proliferation rather than modulation of apoptosis.