Decreased eukaryotic initiation factors expression upon temozolomide treatment-potential novel implications for eIFs in glioma therapy.

PURPOSE: Since glioma therapy is currently still limited until today, new treatment options for this heterogeneous group of tumours are of great interest. Eukaryotic initiation factors (eIFs) are altered in various cancer entities, including gliomas. The purpose of our study was to evaluate the potential of eIFs as novel targets in glioma treatment. METHODS: We evaluated eIF protein expression and regulation in 22 glioblastoma patient-derived xenografts (GBM PDX) after treatment with established cytostatics and with regards to mutation profile analyses of GBM PDX. RESULTS: We observed decreased expression of several eIFs upon temozolomide (TMZ) treatment independent from the phosphatidylinositol 3-kinase (PI3K)/ AKT/ mammalian target of the rapamycin (mTOR) signalling pathway. These effects of TMZ treatment were not present in TMZ-resistant PDX. Combination therapy of regorafenib and TMZ re- established the eIF/AKT/mTOR axis. CONCLUSION: Our study provides novel insights into chemotherapeutic effects on eIF regulation in gliomas and suggests that eIFs are interesting candidates for future research to improve glioma therapy.

Comparing the Impact of Multi-Session Left Dorsolateral Prefrontal and Primary Motor Cortex Neuronavigated Repetitive Transcranial Magnetic Stimulation (nrTMS) on Chronic Pain Patients.

Repetitive transcranial stimulation (rTMS) has been shown to produce an analgesic effect and therefore has a potential for treating chronic refractory pain. However, previous studies used various stimulation parameters (including cortical targets), and the best stimulation protocol is not yet identified. The present study investigated the effects of multi-session 20 Hz (2000 pulses) and 5 Hz (1800 pulses) rTMS stimulation of left motor cortex (M1-group) and left dorsolateral prefrontal cortex (DLPFC-group), respectively. The M1-group (n = 9) and DLPFC-group (n = 7) completed 13 sessions of neuronavigated stimulation, while a Sham-group (n = 8) completed seven sessions of placebo stimulation. The outcome was measured using the German Pain Questionnaire (GPQ), Depression, Anxiety and Stress Scale (DASS), and SF-12 questionnaire. Pain perception significantly decreased in the DLPFC-group (38.17%) compared to the M1-group (56.11%) (p ≤ 0.001) on the later sessions. Health-related quality of life also improved in the DLPFC-group (40.47) compared to the Sham-group (35.06) (p = 0.016), and mental composite summary (p = 0.001) in the DLPFC-group (49.12) compared to M1-group (39.46). Stimulation of the left DLPFC resulted in pain relief, while M1 stimulation was not effective. Nonetheless, further studies are needed to identify optimal cortical target sites and stimulation parameters.

A Profound Basic Characterization of eIFs in Gliomas: Identifying eIF3I and 4H as Potential Novel Target Candidates in Glioma Therapy.

Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients' overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I-IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients' survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients.

The vertical superior longitudinal fascicle and the vertical occipital fascicle.

Association fibers of the human brain have long been considered to exclusively follow an anterior-posterior direction. Using magnetic resonance imaging techniques that allow in-vivo fiber dissection, vertically oriented association fibers have been rediscovered or newly described. Aside from the frontal aslant tract (FAT) in the frontal lobe, the vertical occipital fascicle (VOF) and the vertical portion of the superior longitudinal fascicle system (vSLF) have been studied in recent years. The aim of this review was to give an overview on the current knowledge regarding these two fiber tracts. A review of the available literature in the Medline database was conducted to gather all available publications dealing with either the VOF or the vSLF. One thousand two hundred seventy-three articles were obtained from the literature search of which a total of 71 articles met the final inclusion criteria of this review. We describe the history of the discovery of the respective fiber tract, its anatomical course and its boundaries integrating blunt fiber dissection studies and functional MRI/tractography studies. We discuss the functional properties of the respective fiber tract and its relevance in neurosurgery. The VOF is a fiber tract that has been discovered in the late XIX century and long been forgotten before being rediscovered in the 1970's. It lies lateral to the fibers of the sagittal stratum and mainly connects the superior and inferior occipital lobe. It plays a major role in reading and visual word and language comprehension and is said to be the main link between dorsal and ventral visual streams. The vSLF has many synonyms and is part of the superior longitudinal fascicle system. Recent studies were able to provide more insight into this set of fiber tracts showing distinct connections running from the superior and inferior parietal lobule to the posterior part of the temporal lobe. Its functional role is still not completely cleared. It is said to play a role in visual and auditory semantic language comprehension. It lies directly lateral to the arcuate fascicle. The VOF and the vSLF are vertically oriented fiber tracts connecting the temporo-parieto-occipital region and play a major role in the communication of dorsal and ventral visual streams (VOF), reading (VOF, vSLF) and visual and auditory semantic language comprehension (vSLF). They can consistently be identified using ex vivo blunt dissection techniques and in-vivo fiber tractography. Because of their localization and orientation these two fiber tracts can be combined to a fiber bundle system called posterior transverse system (PTS).

Dissociating Arithmetic Operations in the Parietal Cortex Using 1 Hz Repetitive Transcranial Magnetic Stimulation: The Importance of Strategy Use.

The triple-code model (TCM) of number processing suggests the involvement of distinct parietal cortex areas in arithmetic operations: the bilateral horizontal segment of the intraparietal sulcus (hIPS) for arithmetic operations that require the manipulation of numerical quantities (e.g., subtraction) and the left angular gyrus (AG) for arithmetic operations that require the retrieval of answers from long-term memory (e.g., multiplication). Although neuropsychological, neuroimaging, and brain stimulation studies suggest the dissociation of these operations into distinct parietal cortex areas, the role of strategy (online calculation vs. retrieval) is not yet fully established. In the present study, we further explored the causal involvement of the left AG for multiplication and left hIPS for subtraction using a neuronavigated repetitive transcranial magnetic stimulation (rTMS) paradigm. Stimulation sites were determined based on an fMRI experiment using the same tasks. To account for the effect of strategy, participants were asked whether they used retrieval or calculation for each individual problem. We predicted that the stimulation of the left AG would selectively disrupt the retrieval of the solution to multiplication problems. On the other hand, stimulation of the left hIPS should selectively disrupt subtraction. Our results revealed that left AG stimulation was detrimental to the retrieval and online calculation of solutions for multiplication problems, as well as, the retrieval (but not online calculation) of the solutions to subtraction problems. In contrast, left hIPS stimulation had no detrimental effect on both operations regardless of strategy.

Impact of Priming on Effectiveness of TMS in Detecting Language-eloquent Brain Areas in Tumor Patients.

BACKGROUND AND STUDY AIMS: Language is characteristically human, and preserving it is critical when resecting tumors in language-eloquent brain areas. Navigated repetitive transcranial magnetic stimulation (nrTMS) has been used in recent years as a noninvasive technique to identify preoperatively the language-eloquent cortical areas in tumor patients. An important objective is to increase the sensitivity and specificity of nrTMS in detecting language-related areas and increase the positive correlation of its results to that of intraoperative direct cortical stimulation (DCS). Although the technical aspects of the procedure have received enormous interest, factors related to the targeted cortical area such as previous cortical history or activity have been neglected. Therefore, the present study explores the impact of previous cortical history or activity on the effectiveness of a subsequent nrTMS mapping paradigm. MATERIALS AND METHODS: Twelve right-handed patients with a left hemispheric glioma underwent presurgical nrTMS language mapping and intraoperative language mapping with DCS. nrTMS was performed using a continuous theta burst stimulation paradigm to inhibit possible language relevant areas in the vicinity of the tumor, determined anatomically or based on functional magnetic resonance imaging hotspots. The nrTMS was applied in two separate sessions. One of the sessions randomly included a priming paradigm to precondition the targeted cortical areas. RESULTS: Priming stimulation decreased the error detection of the subsequent nrTMS mapping paradigm. This effect was more robust on major types of errors such as speech arrest and hesitation. CONCLUSION: Prior cortical activity as induced by the priming stimulation has a profound impact on the responsiveness to the nrTMS mapping paradigm. Our findings further showed that metaplasticity, a type of homeostatic plastic process, could be elicited even in cortical areas affected by a growing tumor.

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space.

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.

Symmetry of the arcuate fasciculus and its impact on language performance of patients with brain tumors in the language-dominant hemisphere.

OBJECTIVE Cerebral damage in frontal, parietal, and temporal brain areas and, probably more importantly, their interconnections can lead to deficits in language. However, neural plasticity and repair allow the brain to partly compensate for neural injury, mediated by both functional and structural changes. In this study, the authors sought to systematically investigate the relationship between language performance in brain tumor patients and structural perisylvian pathways (i.e., the arcuate fasciculus [AF]) using probabilistic fiber tracking on diffusion tensor imaging. The authors used a previously proposed model in which the AF is divided into anterior, long, and posterior segments. The authors hypothesized that right-handed patients with gliomas in the language-dominant (left) hemisphere would benefit from a more symmetrical or right-lateralized language pathway in terms of better preservation of language abilities. Furthermore, they investigated to what extent specific tumor characteristics, including proximity to the AF, affect language outcome in such patients. METHODS Twenty-seven right-handed patients (12 males and 15 females; mean age 52 ± 16 years) with 11 low-grade and 16 high-grade gliomas of the left hemisphere underwent 3-T diffusion-weighted MRI (30 directions) and language assessment as part of presurgical planning. For a systematic quantitative evaluation of the AF, probabilistic fiber tracking with a 2 regions of interest approach was carried out. Volumes of the 3 segments of both hemispheric AFs were evaluated by quantifying normalized and thresholded pathways. Resulting values served to generate the laterality index of the AFs. RESULTS Patients without language deficits tended to have an AF that was symmetric or lateralized to the right, whereas patients with deficits in language significantly more often demonstrated a left-lateralized posterior segment of the AF. Patients with high-grade gliomas had more severe language deficits than those with low-grade gliomas. Backward logistic regression revealed the laterality index of the posterior AF segment and tumor grade as the only independent statistically significant predictors for language deficits in this cohort. CONCLUSIONS In addition to the well-known fact that tumor entity influences behavioral outcome, the authors' findings suggest that the right homologs of structural language-associated pathways could be supportive for language function and facilitate compensation mechanisms after brain damage in functionally eloquent areas. This further indicates that knowledge about preoperative functional redistribution (identified by neurofunctional imaging) increases the chance for total or near-total resections of tumors in eloquent areas. In the future, longitudinal studies with larger groups are mandatory to overcome the methodological limitations of this cross-sectional study and to map neuroplastic changes associated with language performance and rehabilitation in brain tumor patients.

Pre- and postoperative neurocognitive deficits in brain tumor patients assessed by a computer based screening test.

Neurocognitive assessment becomes increasingly important in neuro-oncology. The presence and degree of neurocognitive deficits in patients with brain tumors appear to be important not only as outcome measures but also in treatment planning and as possible prognostic markers for tumor-progression. Common screening methods for neurocognitive deficits are often insufficient in uncovering subtle changes or harbor the risk of being observer-dependent and time-consuming. We present data of brain tumor patients screened by a computer-based neurocognitive assessment tool before and after surgery. 196 patients with tumor resections were tested at our institution using the NeuroCog Fx® software 2days before and 3-4months after surgery. Additionally to the test results, patient-related information, such as age, sex, handedness, level of education, pre- and postoperative neurological status, KPS, location and histopathological diagnosis were recorded. These prospectively collected results were correlated in the here presented retrospective study. The majority of patients with malignant gliomas, metastases and meningiomas showed significant deficits in various neurocognitive domains, most of them improved or did not decline in their postoperative neurocognitive performances. Interestingly, there was no significant correlation of neurocognitive deficits and brain tumor location. In future, standardized neuropsychological assessment should become an essential part of the management and care of patients with brain tumors to provide a more personalized and tailored treatment. Further studies will improve the understanding of the influence of various treatment modalities on neuro-cognition.

Prognostic value of pigment epithelium-derived factor in patients with advanced heart failure.

OBJECTIVE: Whereas angiogenesis, the formation of new blood vessels from preexisting vessels, may be beneficial in restoring failing myocardium, apoptosis may contribute to the progression of heart failure (HF). We investigated the role of pigment epithelium-derived factor (PEDF), a recently discovered antiangiogenic factor with additional proapoptotic effects, in patients with advanced HF. METHODS: We assayed PEDF levels in 351 patients with advanced HF at baseline. During the median follow-up time of 16 months, 50% of patients experienced the composite end point of rehospitalization and/or death. RESULTS: The risk of a clinical event increased with concentrations of the antiangiogenic marker PEDF, with a 1.94-fold higher risk in the third tertile compared with the first tertile (95% CI, 1.33-2.84). This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model (P = .015). Experimental data revealed that PEDF may contribute to the progression of HF by inducing apoptosis in human cardiac myocytes and fibroblasts via activation of caspase 3. CONCLUSIONS: We suggest a role of PEDF in the progression of HF by inducing apoptosis of human cardiac myocytes and fibroblasts. Our clinical data suggest that PEDF concentrations may have the potential to become a valuable marker of the prognosis of HF, in addition to BNP.