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.

Correction to: Automatic identification of atypical clinical fMRI results.

The above article was published online with an incorrect affiliation.

Automatic identification of atypical clinical fMRI results.

PURPOSE: Functional MRI is not routinely used for neurosurgical planning despite potential important advantages, due to difficulty of determining quality. We introduce a novel method for objective evaluation of fMRI scan quality, based on activation maps. A template matching analysis (TMA) is presented and tested on data from two clinical fMRI protocols, performed by healthy controls in seven clinical centers. Preliminary clinical utility is tested with data from low-grade glioma patients. METHODS: Data were collected from 42 healthy subjects from seven centers, with standardized finger tapping (FT) and verb generation (VG) tasks. Copies of these "typical" data were deliberately analyzed incorrectly to assess feasibility of identifying them as "atypical." Analyses of the VG task administered to 32 tumor patients assessed sensitivity of the TMA method to anatomical abnormalities. RESULTS: TMA identified all atypical activity maps for both tasks, at the cost of incorrectly classifying 3.6 (VG)-6.5% (FT) of typical maps as atypical. For patients, the average TMA was significantly higher than atypical healthy scans, despite localized anatomical abnormalities caused by a tumor. CONCLUSION: This study supports feasibility of TMA for objective identification of atypical activation patterns for motor and verb generation fMRI protocols. TMA can facilitate the use and evaluation of clinical fMRI in hospital settings that have limited access to fMRI experts. In a clinical setting, this method could be applied to automatically flag fMRI scans showing atypical activation patterns for further investigation to determine whether atypicality is caused by poor scan data quality or abnormal functional topography.

Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging.

OBJECTIVE: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers. METHODS: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery. RESULTS: A total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI. CONCLUSION: A minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of ≤ 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET. IMPORTANCE OF THE STUDY: We believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed "minimal core of imaging" in clinical routine will facilitate future cooperative studies.

Evaluation of a New Brain Tissue Probe for Intracranial Pressure, Temperature, and Cerebral Blood Flow Monitoring in Patients with Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To evaluate an intraparenchymal probe for intracranial pressure (ICP) and temperature (TEMP) monitoring as well as determination of cerebral hemodynamics using a near-infrared spectroscopy (NIRS) and indocyanine green (ICG) dye dilution method (NIRS-ICP probe). METHODS: The NIRS-ICP probe was applied after aneurysmal subarachnoid hemorrhage if multimodal monitoring was established due to poor neurological condition. ICP and TEMP values were obtained from ventricular catheters and systemic temperature sensors. Repeated NIRS-ICG measurements (2 injections within 30 min) were performed daily for determination of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time of ICG (mttICG). Secondary neurologic dysfunction was defined as brain tissue oxygen tension <20 mmHg and/or lactate/pyruvate ratio >35 obtained from cerebral probing. RESULTS: A total of 128 NIRS-ICG measurements were performed in ten patients. The correlation coefficients between ICP and TEMP values obtained with the NIRS-ICP probe and values from routine monitoring were r = 0.72 and r = 0.96, respectively. The mean values were 30.3 ± 13.6 ml/100 g/min for CBF, 3.3 ± 1.2 ml/100 g for CBV, and 6.8 ± 1.6 s for mttICG. The coefficients of variation from repeated NIRS-ICG measurements were 10.9 % for CBF, 11.7 % for CBV, and 3.8 % for mttICG. The sensitivity for detection of secondary neurologic dysfunction was 85 % and the specificity 83 % using a CBF-threshold of 25 ml/100 g/min. CONCLUSION: Multimodal monitoring using the NIRS-ICP probe is feasible with high reproducibility of measurement values and the ability to detect secondary neurologic dysfunction. No safety concerns exist for the routine clinical use of the NIRS-ICP probe.

5-Aminolevulinic acid-induced protoporphyrin IX fluorescence as immediate intraoperative indicator to improve the safety of malignant or high-grade brain tumor diagnosis in frameless stereotactic biopsies.

BACKGROUND: Frameless stereotactic biopsies are replacing frame-based stereotaxy as a diagnostic approach to brain lesions. In order to avoid a sampling bias or negative histology, multiple specimens are often taken. This in turn increases the risk of hemorrhagic complications. OBJECTIVE: We present the use of 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX fluorescence in frameless stereotaxy to improve the procedure duration and yield, and thereby reduce the risk of complications. METHODS: Patients with suspected high-grade brain tumors are given 5-ALA 4 h prior to stereotactic biopsy. The biopsy needle is guided to the target using frameless stereotaxy based either on preoperative images or combined with intraoperative MRI sequences. The specimen is illuminated with blue light to look for fluorescence. In case of a positive fluorescence within the tissue sample, no frozen sections are obtained, and no further specimens are taken. RESULTS: The samples of 13 patients revealed a positive fluorescence and were histologically confirmed as malignant or high-grade brain neoplasms. four cases were fluorescence-negative, requiring frozen section confirmation and/or multiple samples. In theses cases histology was either nonspecific gliotic changes or low-grade tumors. There were no complications related to the additional use of 5-ALA. CONCLUSION: 5-ALA fluorescence in stereotactic biopsies can increase the safety and accuracy of these procedures by reducing sampling errors and eliminating the need for multiple samples and/or frozen section verification, creating a more accurate, faster and safer procedure for cases of suspected malignant or high-grade brain tumors situated in deep or eloquent areas.

MRI Response Assessment in Glioblastoma Patients Treated with Dendritic-Cell-Based Immunotherapy.

Introduction: In this post hoc analysis we compared various response-assessment criteria in newly diagnosed glioblastoma (GB) patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression-free survival (PFS) and overall survival (OS). Methods: 76 patients enrolled in a multicenter phase II trial receiving standard of care (SOC, n = 40) or SOC + Audencel vaccine (n = 36) were included. MRI scans were evaluated using MacDonald, RANO, Vol-RANO, mRANO, Vol-mRANO and iRANO criteria. Tumor volumes (T1 contrast-enhancing as well as T2/FLAIR volumes) were calculated by semiautomatic segmentation. The Kruskal-Wallis-test was used to detect differences in PFS among the assessment criteria; for correlation analysis the Spearman test was used. Results: There was a significant difference in median PFS between mRANO (8.6 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.0 months), RANO (4.2 months) and Vol-RANO (5.4 months). For the vaccination arm, median PFS by iRANO was 6.2 months. There was no difference in PFS between SOC and SOC + Audencel. The best correlation between PFS/OS was detected for mRANO (r = 0.65) and Vol-mRANO (r = 0.69, each p < 0.001). A total of 16/76 patients developed a pure T2/FLAIR progressing disease, and 4/36 patients treated with Audencel developed pseudoprogression. Conclusion: When comparing different response-assessment criteria in GB patients treated with dendritic cell-based immunotherapy, the best correlation between PFS and OS was observed for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel.

Synthetic skull bone defects for automatic patient-specific craniofacial implant design.

Patient-specific craniofacial implants are used to repair skull bone defects after trauma or surgery. Currently, cranial implants are designed and produced by third-party suppliers, which is usually time-consuming and expensive. Recent advances in additive manufacturing made the in-hospital or in-operation-room fabrication of personalized implants feasible. However, the implants are still manufactured by external companies. To facilitate an optimized workflow, fast and automatic implant manufacturing is highly desirable. Data-driven approaches, such as deep learning, show currently great potential towards automatic implant design. However, a considerable amount of data is needed to train such algorithms, which is, especially in the medical domain, often a bottleneck. Therefore, we present CT-imaging data of the craniofacial complex from 24 patients, in which we injected various artificial cranial defects, resulting in 240 data pairs and 240 corresponding implants. Based on this work, automatic implant design and manufacturing processes can be trained. Additionally, the data of this work build a solid base for researchers to work on automatic cranial implant designs.

Automatic skull defect restoration and cranial implant generation for cranioplasty.

A fast and fully automatic design of 3D printed patient-specific cranial implants is highly desired in cranioplasty - the process to restore a defect on the skull. We formulate skull defect restoration as a 3D volumetric shape completion task, where a partial skull volume is completed automatically. The difference between the completed skull and the partial skull is the restored defect; in other words, the implant that can be used in cranioplasty. To fulfill the task of volumetric shape completion, a fully data-driven approach is proposed. Supervised skull shape learning is performed on a database containing 167 high-resolution healthy skulls. In these skulls, synthetic defects are injected to create training and evaluation data pairs. We propose a patch-based training scheme tailored for dealing with high-resolution and spatially sparse data, which overcomes the disadvantages of conventional patch-based training methods in high-resolution volumetric shape completion tasks. In particular, the conventional patch-based training is applied to images of high resolution and proves to be effective in tasks such as segmentation. However, we demonstrate the limitations of conventional patch-based training for shape completion tasks, where the overall shape distribution of the target has to be learnt, since it cannot be captured efficiently by a sub-volume cropped from the target. Additionally, the standard dense implementation of a convolutional neural network tends to perform poorly on sparse data, such as the skull, which has a low voxel occupancy rate. Our proposed training scheme encourages a convolutional neural network to learn from the high-resolution and spatially sparse data. In our study, we show that our deep learning models, trained on healthy skulls with synthetic defects, can be transferred directly to craniotomy skulls with real defects of greater irregularity, and the results show promise for clinical use. Project page: https://github.com/Jianningli/MIA.

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.

Targeted Chemotherapy of Glioblastoma Spheroids with an Iontronic Pump.

Successful treatment of glioblastoma multiforme (GBM), the most lethal tumor of the brain, is presently hampered by (i) the limits of safe surgical resection and (ii) "shielding" of residual tumor cells from promising chemotherapeutic drugs such as Gemcitabine (Gem) by the blood brain barrier (BBB). Here, the vastly greater GBM cell-killing potency of Gem compared to the gold standard temozolomide is confirmed, moreover, it shows neuronal cells to be at least 104-fold less sensitive to Gem than GBM cells. The study also demonstrates the potential of an electronically-driven organic ion pump ("GemIP") to achieve controlled, targeted Gem delivery to GBM cells. Thus, GemIP-mediated Gem delivery is confirmed to be temporally and electrically controllable with pmol min-1 precision and electric addressing is linked to the efficient killing of GBM cell monolayers. Most strikingly, GemIP-mediated GEM delivery leads to the overt disintegration of targeted GBM tumor spheroids. Electrically-driven chemotherapy, here exemplified, has the potential to radically improve the efficacy of GBM adjuvant chemotherapy by enabling exquisitely-targeted and controllable delivery of drugs irrespective of whether these can cross the BBB.

AutoImplant 2020-First MICCAI Challenge on Automatic Cranial Implant Design.

The aim of this paper is to provide a comprehensive overview of the MICCAI 2020 AutoImplant Challenge. The approaches and publications submitted and accepted within the challenge will be summarized and reported, highlighting common algorithmic trends and algorithmic diversity. Furthermore, the evaluation results will be presented, compared and discussed in regard to the challenge aim: seeking for low cost, fast and fully automated solutions for cranial implant design. Based on feedback from collaborating neurosurgeons, this paper concludes by stating open issues and post-challenge requirements for intra-operative use. The codes can be found at https://github.com/Jianningli/tmi.

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.

Chemotherapy and diffuse low-grade gliomas: a survey within the European Low-Grade Glioma Network.

BACKGROUND: Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. METHODS: An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. RESULTS: The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. CONCLUSIONS: The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.

Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: A Phase II Randomized Trial.

Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3⁻20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, p = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436⁻671 versus control: 568 days, 95% CI: 349⁻680; p = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC.

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.

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.

Interactive reconstructions of cranial 3D implants under MeVisLab as an alternative to commercial planning software.

In this publication, the interactive planning and reconstruction of cranial 3D Implants under the medical prototyping platform MeVisLab as alternative to commercial planning software is introduced. In doing so, a MeVisLab prototype consisting of a customized data-flow network and an own C++ module was set up. As a result, the Computer-Aided Design (CAD) software prototype guides a user through the whole workflow to generate an implant. Therefore, the workflow begins with loading and mirroring the patients head for an initial curvature of the implant. Then, the user can perform an additional Laplacian smoothing, followed by a Delaunay triangulation. The result is an aesthetic looking and well-fitting 3D implant, which can be stored in a CAD file format, e.g. STereoLithography (STL), for 3D printing. The 3D printed implant can finally be used for an in-depth pre-surgical evaluation or even as a real implant for the patient. In a nutshell, our research and development shows that a customized MeVisLab software prototype can be used as an alternative to complex commercial planning software, which may also not be available in every clinic. Finally, not to conform ourselves directly to available commercial software and look for other options that might improve the workflow.