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Purpose Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumors in adults. Patients invariably relapse during or after first-line therapy and the median overall survival is 14.6 months. Such poor clinical response is partly ascribed to the activity of ATP-binding cassette (ABC) transporters. The activity of these proteins, severely reduces the amount of therapeutics that penetrates the tumor cells. We hypothesized that ABC transporter expression could correlate with survival surrogates. In this study, we assessed the expression of four commonly expressed ABC transporters in GBM samples and investigated if mRNA levels could serve as a prognostic biomarker. Methods Human specimens were analyzed by qPCR to assess ABCB1, ABCC1/3 and ABCG2 expression. Kaplan-Meier and multivariate analyses were then used to evaluate the correlation with overall survival (OS) and progression-free survival (PFS). Results Our cohort included 22 non-tumoral samples as well as 159 GBM tumor specimens. ABC transporters were significantly more expressed in GBM samples compared to non-tumoral tissue. Moreover ABCC1 and 3 mRNA expression were significantly increased at recurrence. Statistical analyses revealed that increased expression of either ABCC1 or ABCC3 did not confer a poorer prognosis. However, increased ABCC1 mRNA levels did correlate with a significantly shorter PFS. Conclusion In this manuscript, the analyses we conducted suggest that the expression of the four ABC transporters evaluated would not be suitable prognostic biomarkers. We believe that, when estimating prognosis, the plethora of mechanisms implicated in chemoresistance should be analyzed as a multi-facetted entity rather than isolated units.

Background High-grade gliomas (HGG) are aggressive brain tumors associated with short median patient survival and limited response to therapies, driving the need to develop tools to improve patient outcomes. Patient-derived xenograft (PDX) models, such as mouse PDX, have emerged as potential Avatar platforms for personalized oncology approaches, but the difficulty for some human grafts to grow successfully and the long time required for mice to develop tumors preclude their use for HGG. Methods We used a rapid and efficient ex-ovo chicken embryo chorioallantoic membrane (CAM) culture system to evaluate the efficacy of oncologic drug options for HGG patients. Results Implantation of fresh glioma tissue fragments from 59 of 60 patients, that include difficult-to-grow IDH-mutated samples, successfully established CAM tumor xenografts within 7 days, with a tumor take rate of 98.3%. These xenografts faithfully recapitulate the histological and molecular characteristics of the primary tumor, and the ability of individual fragments to form tumors was predictive of poor patient prognosis. Treatment of drug-sensitive or drug-resistant xenografts indicates that the CAM-glioma assay enables testing tumor sensitivity to temozolomide and carboplatin at doses consistent with those administered to patients. In a proof-of-concept study involving 14 HGG patients, we observed a correlation of 100% between the CAM xenograft response to temozolomide or carboplatin and the clinical response of patients. Conclusion The CAM-glioma model is a fast and reliable assay that has the potential to serve as a complementary model to drug discovery and a real-time Avatar platform to predict the best treatment for HGG patients.

Despite extensive paleoenvironmental research on the postglacial history of the Kenai Peninsula, Alaska, uncertainties remain regarding the region's deglaciation, vegetation development, and past hydroclimate. To elucidate this complex environmental history, we present new proxy datasets from Hidden and Kelly lakes, located in the eastern Kenai lowlands at the foot of the Kenai Mountains, including sedimentological properties (magnetic susceptibility, organic matter, grain size, and biogenic silica), pollen and macrofossils, diatom assemblages, and diatom oxygen isotopes. We use a simple hydrologic and isotope mass balance model to constrain interpretations of the diatom oxygen isotope data. Results reveal that glacier ice retreated from Hidden Lake's headwaters by ca. 13.1 cal ka BP, and that groundwater was an important component of Kelly Lake's hydrologic budget in the Early Holocene. As the forest developed and the climate became wetter in the Middle to Late Holocene, Kelly Lake reached or exceeded its modern level. In the last ca. 75 years, rising temperature caused rapid changes in biogenic silica content and diatom oxygen isotope values. Our findings demonstrate the utility of mass balance modeling to constrain interpretations of paleolimnologic oxygen isotope data, and that groundwater can exert a strong influence on lake water isotopes, potentially confounding interpretations of regional climate.

Background The impact of glioma location on quality of life (QOL) has not been conclusively studied, possibly due to the prohibitively high sample size that standard statistical analyses would require and the inherent heterogeneity of this disease. By using a novel algorithm, we investigated the impact of tumor location on QOL in a limited set of 53 consecutive patients. Methods The glial tumors of 53 consecutive patients were segmented and registered to a standardized atlas. The Euclidian distance between 90 brain regions and each tumor's margin was calculated and correlated to the patient's self-reported QOL as measured by the Sherbrooke Neuro-Oncology Assessment Scale questionnaire. Results QOL was not correlated to tumor volume, though a significant correlation was observed with its proximity to these areas: right supramarginal gyrus, right rolandic operculum, right superior temporal gyrus, right middle temporal gyrus, right angular gyrus, and right inferior parietal lobule. Interestingly, all identified areas are in the right hemisphere, and localized in the temporoparietal region. We postulate that the adverse relation between proximity to these areas and QOL results from disruption in visuospatial functioning. Conclusions Although the areas identified in this study are traditionally considered non-eloquent areas, tumor proximity to these regions showed more impact on QOL than any other brain regions. We postulate that this effect is mediated via an adverse impact on the visuospatial functioning.

3D printing is an additive manufacturing method that involves successive deposition of layers of materials to create a construct from a digital model. 3D-printing technologies have widespread applications in medicine and are increasingly used for solving a wide variety of medical problems. In this review, we summarize existing 3D-printing technologies and explore recent advances in the development and characterization of bioinks and biomaterial inks. We will then explain characterization methods for determining the rheological and mechanical properties of printing inks and 3D-printed constructs using invasive and noninvasive methods. Lastly, four core uses in recent innovations in medicine, including tissue and organoid engineering, disease modeling, drug delivery, biosensing, patient-specific implants and challenges along with future prospects will be discussed.

Glass composition-based correlations of volcanic ash (tephra) traditionally rely on extensive manual plotting. Many previous statistical methods for testing correlations are limited by using geochemical means, masking diagnostic variability. We suggest that machine learning classifiers can expedite correlation, quickly narrowing the list of likely candidates using well-trained models. Eruptives from Alaska's Aleutian Arc-Alaska Peninsula and Wrangell volcanic field were used as a test environment for 11 supervised classification algorithms, trained on nearly 2000 electron probe microanalysis measurements of glass major oxides, representing 10 volcanic sources. Artificial neural networks and random forests were consistently among the top-performing learners (accuracy and kappa > 0.96). Their combination as an average ensemble effectively improves their performance. Using this combined model on tephras from Eklutna Lake, south-central Alaska, showed that predictions match traditional methods and can speed correlation. Although classifiers are useful tools, they should aid expert analysis, not replace it. The Eklutna Lake tephras are mostly from Redoubt Volcano. Besides tephras from known Holocene-active sources, Holocene tephra geochemically consistent with Pleistocene Emmons Lake Volcanic Center (Dawson tephra), but from a yet unknown source, is evident. These tephras are mostly anchored by a highly resolved varved chronology and represent new important regional stratigraphic markers.

Datasets from a 4-year monitoring effort at Lake Peters, a glacier-fed lake in Arctic Alaska, are described and presented with accompanying methods, biases, and corrections. Three meteorological stations documented air temperature, relative humidity, and rainfall at different elevations in the Lake Peters watershed. Data from ablation stake stations on Chamberlin Glacier were used to quantify glacial melt, and measurements from two hydrological stations were used to reconstruct continuous discharge for the primary inflows to Lake Peters, Carnivore and Chamberlin creeks. The lake's thermal structure was monitored using a network of temperature sensors on moorings, the lake's water level was recorded using pressure sensors, and sedimentary inputs to the lake were documented by sediment traps. We demonstrate the utility of these datasets by examining a flood event in July 2015, though other uses include studying intra- and inter-annual trends in this weather–glacier–river–lake system, contextualizing interpretations of lake sediment cores, and providing background for modeling studies. All DOI-referenced datasets described in this paper are archived at the National Science Foundation Arctic Data Center at the following overview web page for the project: https://arcticdata.io/catalog/view/urn:uuid:df1eace5-4dd7-4517-a985-e4113c631044 (last access: 13 October 2019; Kaufman et al., 2019f).

Chemoattraction is a normal and essential process, but it can also be involved in tumorigenesis. This phenomenon plays a key role in glioblastoma (GBM). The GBM tumor cells are extremely difficult to eradicate, due to their strong capacity to migrate into the brain parenchyma. Consequently, a complete resection of the tumor is rarely a possibility, and recurrence is inevitable. To overcome this problem, we proposed to exploit this behavior by using three chemoattractants: CXCL10, CCL2 and CCL11, released by a biodegradable hydrogel (GlioGel) to produce a migration of tumor cells toward a therapeutic trap. To investigate this hypothesis, the agarose drop assay was used to test the chemoattraction capacity of these three chemokines on murine F98 and human U87MG cell lines. We then studied the potency of this approach in vivo in the well-established syngeneic F98-Fischer glioma-bearing rat model using GlioGel containing different mixtures of the chemoattractants. In vitro assays resulted in an invasive cell rate 2-fold higher when chemokines were present in the environment. In vivo experiments demonstrated the capacity of these specific chemoattractants to strongly attract neoplastic glioblastoma cells. The use of this strong locomotion ability to our end is a promising avenue in the establishment of a new therapeutic approach in the treatment of primary brain tumors.

The superior longitudinal fasciculus (SLF) is part of the longitudinal association fiber system, which lays connections between the frontal lobe and other areas of the ipsilateral hemisphere. As a dominant association fiber bundle, it should correspond to a well-defined structure with a clear anatomical definition. However, this is not the case, and a lot of confusion and overlap surrounds this entity. In this review/opinion study, we survey relevant current literature on the topic and try to clarify the definition of SLF in each hemisphere. After a comparison of postmortem dissections and data obtained from diffusion MRI studies, we discuss the specifics of this bundle regarding its anatomical landmarks, differences in lateralization, as well as individual variability. We also discuss the confusion regarding the arcuate fasciculus in relation to the SLF. Finally, we recommend a nomenclature based on the findings exposed in this review and finalize with a discussion on relevant functional correlates of the structure.

BACKGROUND AND PURPOSE: Current guidelines proposed for the measurement of primary central nervous system lymphoma in 2005 have indicated that unidimensional and bidimensional measurements may be used, using the same threshold for response categorization, because no clinical study has evaluated the agreement among the measurement techniques. Hence, our study assessed the agreement among different measurements. MATERIALS AND METHODS: In this retrospective study, primary central nervous system lymphoma lesions were measured with different techniques (longest 1D, axial 1D, 2D, 3D, and the Response Evaluation Criteria in Solid Tumor) on consecutive MR images. Intra- and interobserver correlations were calculated with intraclass correlation coefficients. Correlations between raw measurements and variations in size compared with baseline were evaluated with the Spearman rank correlation, and agreement among response categories was evaluated. RESULTS: A total of 304 examinations obtained in 40 patients was assessed. The intraobserver intraclass correlation coefficient for 3D, 2D, and longest 1D were ≥0.993. The interobserver intraclass correlation coefficient was ≥0.967. The correlations in raw measurements and size variation in comparison with 3D were respectively; 0.99 and 0.98 for 2D; 0.94 and 0.92 for longest 1D; 0.94 and 0.83 for axial 1D; and 0.90 and 0.79 for Response Evaluation Criteria in Solid Tumor. With 20%–30% and 25%–50% thresholds for unidimensional techniques, response categorizations were 95% and 95% for 2D, 92.5% and 90% for the longest 1D, 87.5% and 82.5% for axial 1D, and 90% and 85% for the Response Evaluation Criteria in Solid Tumor. CONCLUSIONS: Both longest 1D and 2D demonstrated excellent correlations with 3D measurements. The longest 1D could be used for the follow-up of primary central nervous system lymphoma. If unidimensional measurements were used, 20% and 30% cutoffs should be used for defining response categorization instead of the current guidelines.

Sediments that accumulate in high-latitude lakes serve as valuable environmental archives of changing conditions in a region currently undergoing rapid change. A previously unexplored sedimentary sequence reaching back 16,000 years from Lakes Peters and Schrader (Neruokpuk Lakes) in the northeastern Brooks Range (69°N), Alaska, shows distinct changes in accumulation rates and biophysical properties including bulk density (BD), organic matter (OM) content, and grain-size distribution at five widely distributed core sites. The oldest sediments contain little OM and accumulated rapidly as glaciers retreated around 15 ka. OM peaked between 12 and 10 ka along with Northern Hemisphere summer insolation. BD increased and OM decreased until around 5 ka, possibly reflecting a decrease in river-transported terrestrial OM. From 5–2 ka, OM consistently increased, suggesting a rise in river discharge, or a rise in summer temperatures, which led to higher productivity, or both. After 2 ka, sediments increased in BD and decreased in OM, suggesting glacier growth. Evidence for glacier expansion late during the Little Ice Age is weak, but increased sedimentation rates may reflect glacier retreat during the last century. This study provides a framework for future paleoenvironmental research of a rare archive in a relatively pristine Arctic setting.

Developing robust chronological frameworks of lacustrine sediment is central to reconstructing past environmental changes. We present varve chronologies from five sites extending back 2300 years from Eklutna Lake, in the Chugach Mountains of south-central Alaska. The chronologies are built from image analysis of high-resolution photographs and CT scans of sediment cores. The age uncertainty of each record is tested by three methods. We first present varve chronologies from individual sites and reconcile the difference in varve delimitation from two observers. The varve chronologies from each site are then compared to each other using a series of marker beds that can be traced across the lake basin. Finally, using a new Bayesian probabilistic model, we develop age models that incorporate information regarding age uncertainty from the multiple-observer method and the age distribution of marker layers from multiple cores. To evaluate the accuracy of the Bayesian model output, we used seven radiocarbon ages from terrestrial macrofossils and four tephra layers traceable across the core sites. The major-element geochemistry of the tephra layers and their ages are presented here for the first time. The Bayesian age model offers a new approach to quantifying age uncertainty in inter-correlated cores of varved sediment.

International audience; This paper presents a new annually laminated record (varves) from Lake Walker, Quebec North Shore (eastern Canada) spanning the period from similar to 3230 to 2320 +/- 20 cal BP. A similar to 3.5-m-long composite sequence was established with the best regular and continuous laminated intervals using computed tomography and high-resolution photographs. The varve chronology was built based on two methods: manual multi-parameter counting using the PeakCounter software, and manual counting on thin-section images obtained by scanning electron microscopy (SEM). The latter correlates more closely with the ages derived from AMS radiocarbon dating, suggesting that thin-section analysis is here a more reliable counting technique. Varves are clastic, composed of a silt layer deposited in spring and summer, and a clay layer deposited in winter. Annually resolved grain size obtained using image analysis technique on SEM images of thin sections and elemental composition from X-ray microfluorescence analyses performed on the floating varve chronology suggests that the record is sensitive to the North Atlantic Oscillation (NAO), as revealed by the strong co-variability with another lower resolution record from Greenland. This suggests that periods of negative winter NAO promoted a thicker snow cover that resulted in higher river discharges and stronger clastic component in the varves. In modern times, cooling of the North Atlantic in the mid 1970s to the late 1980s was also characterized by concurrent negative phase of NAO, which condition translated into increase snow precipitation over the region. Overall, these results highlight that the new Lake Walker varve record presents remarkable prospects of developing a longer and high-resolution paleoclimatological reconstruction of the NAO in a region where similar records are scarce.

Mechanisms of recurrence in oligodendrogliomas are poorly understood. Recurrence might be driven by telomere dysfunction-mediated genomic instability. In a pilot study, we investigated ten patients with oligodendrogliomas at the time of diagnosis (first surgery) and after recurrence (second surgery) using three-dimensional nuclear telomere analysis performed with quantitative software TeloView&reg, (Telo Genomics Corp, Toronto, Ontario, Canada). 1p/19q deletion status of each patient was determined by fluorescent in situ hybridization on touch preparation slides. We found that a very specific 3D telomeric profile was associated with two pathways of recurrence in oligodendrogliomas independent of their 1p/19q status: a first group of 8 patients displayed significantly different 3D telomere profiles between both surgeries (p &lt, 0.0001). Their recurrence happened at a mean of 231.375 &plusmn, 117.42 days and a median time to progression (TTP) of 239 days, a period defined as short-term recurrence, and a second group of three patients displayed identical 3D telomere profiles between both surgery samples (p &gt, 0.05). Their recurrence happened at a mean of 960.666 &plusmn, 86.19 days and a median TTP of 930 days, a period defined as long-term recurrence. Our results suggest a potential link between nuclear telomere architecture and telomere dysfunction with time to recurrence in oligodendrogliomas, independently of the 1p/19q status.

The blood&ndash, brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.

Dysgeusia is a frequent, yet underreported side effect of chemotherapy for cancer. We report here the first use of gabapentin in two glioblastoma patients who developed dysgeusia following intra-arterial administration of carboplatin or oral administration of lomustine, respectively. Treatment initiation was followed by resolution of taste alteration within weeks. Both patients reported significant improvement in their quality of life and regained weight, allowing further chemotherapy cycles. We hypothesized that in these two cases, chemotherapy impeded gustatory cells turnover and function, resulting in a gustatory “deafferentation-like” syndrome which was successfully addressed by the medication.

Background Smartphones and their apps are used ubiquitously in medical practice. However, in some cases their use can be at odds with current patient data safety regulations such as Canada's Personal Health Information Protection Act of 2004. To assess current practices and inform mobile application development, we sought to better understand mobile device usage patterns among Canadian neurosurgery residents. Methods Through the Canadian Neurosurgery Research Collaborative, an online survey characterizing smartphone ownership and usage patterns was developed and sent to all Canadian neurosurgery resident in April of 2016. Questionnaires were collected and completed surveys analyzed. Results Of 146 eligible residents, 76 returned completed surveys (52% response rate). Of these 99% of respondents owned a smartphone, with 79% running on Apple's iOS. Four general mobile uses were identified: 1) communication between members of the medical team, 2) decision support, 3) medical reference, and 4) documentation through medical photography. Communication and photography were areas where the most obvious breaches in the Canadian Personal Health Information Protection Act were noted, with 89% of respondents taking pictures of patients' radiologic studies and 75% exchanging them with Short Message System. Hospital policies had no impact on user behaviors. Conclusions Smartphones are used daily by most neurosurgery residents. Identified usage patterns are associated with perceived gains in efficacy and challenges in privacy and data reliability. We believe creating and improving workflows that address these usage patterns has a greater potential to improve privacy than changing policies and enforcing regulations.

BACKGROUND Primary central nervous system lymphomas (PCNSL) are considered a rare and aggressive form of central nervous system (CNS) tumors. High-dose methotrexate has become the backbone of PCNSL treatment, and is recommended by the EANO guidelines. In most recent protocols, investigators tend to postpone or even avoid the use of radiotherapy; indeed, its use has become controversial with findings of associated severe neuro-toxicity, especially in elderly patients. To maximize delivery across the BBB, we use cerebral intra-arterial chemotherapy (CIAC) coupled with osmotic blood-brain barrier disruption (OBBBD). We hereby report our single-center experience over 18 years with the CIAC + BBBD technique using 2 different HD-MTX protocols. MATERIAL AND METHODS This phase II study was conducted at the Centre hospitalier Universitaire de Sherbrooke (CHUS) from November 1999 to May 2018. The protocol was approved by the institutional review board, and informed consent was obtained in accordance to institutional regulation in every patient After enrollment and initial evaluation, patients were treated every four weeks (1 cycle) for 12 cycles, unless progression. After general anesthesia, a transfemoral approach was used to catheterize either the right or left internal carotid artery or the dominant vertebral artery, depending on tumor(s) location. OBBBD was performed by infusing 20% mannitol in the selected vascular distribution for 30 seconds at a rate that fills the vascular distribution so as to maximize the contact of the mannitol with the endothelial cells.Two different chemotherapy regimens were sequentially used in this study. High-dose MTX (5 g IV) was the cornerstone of both regimens: the first regimen (1999 to 2007) also included etoposide phosphate IV (400 mg/m²) and cyclophosphamide IV (660 mg/m²), whereas the 2nd regimen (1998 to 2018) also included carboplatin IA (400 mg/m²). RESULTS The present analysis therefore concerns a cohort of 44 naive patients recruited over 18 years in a single center. Median follow-up was 38 months. Overall, a CR was induced in 34 patients (79%). Themedian time to CR was 7.3 months (IQR: 7.8). Of these 34 patients, 11 (25.6%) are still alive, and 9 of these are disease-free after treatment discontinuation. The actuarial median survival (MS) was 46.5 months (95% CI: 30.9–62.2) for the cohort. Survival was 88%, 64%, 54%, 39% and 18% at 1, 2, 3,5 and 10 years (Figure 1 and Table 2).The progression-free survival was 43.4 months (95% CI: 17.9–68.9). Five occurrences of vascular complications related to the treatment were observed (11.6%). Conclusion: CIAC HD-MTX-based protocols with OBBBD is a safe and well-tolerated procedure for the management of primary CNS lymphoma. Our single center data suggests better PFS and survival outcomes compared to IV protocols with less hematologic toxicity and good tolerability, especially in the elderly.

BACKGROUND Glioblastoma (GBM) is a devastating disease with a median survival of 14–16 months. This poor prognosis can be explained by 3 factors. First, the infiltrative nature of the disease prohibits a complete removal of the tumor. Second, some of the tumor cells are brain tumor stem cells, which are highly migratory and highly resistant to treatments. Finally, the presence of the blood-brain barrier prohibits entry of therapeutics. This situation implies that new treatment approaches must be directed toward the infiltrated brain surrounding the resection cavity. To bypass this problem and improve the potency of adjuvant treatment, we have designed a new “GlioGel-device” that will have the ability to: 1- attract the migrating tumor cells into or nearby the device, and 2- subsequently deliver chemotherapy to the locally pooled tumor cells and 3- irradiate these cells with radioisotopes embedded in the GlioGel. MATERIAL AND METHODS In vitro proof of principle of chemoattraction was investigated by agarose drops method releasing chemokines molecules (CCL2, CCL11, CXCL10) with F98 and U87MG GBM cells. In vivo experiments evaluated the efficiency of chemokines and doxorubicin released by the implanted GlioGel on the tumor behaviour in our Fischer-F98 rat glioma model. An histology of tumour behaviour exposed to chemokines and survival of GBM rats treated with doxorubicin were analysed. RESULTS In vitro preliminary results for chemoattraction assays show that up to 2 times more cells invade the gel when it releases chemoattractant compared to PBS. The In vivo chemotherapy experiments with a fast, medium and slow release of doxorubicin from the GlioGel show that a local dose that represent a 1300-fold smaller dose than a normal intravenous systemic dose gave a significant reduction in tumour growth (median survival) compared to a control group. We investigated the effect provided by the GlioGel impregnated with chemokines on tumor cells migration, after implantation in the Fischer-F98 rat glioma model. CONCLUSION This preliminary study shows the ability of GlioGel releasing chemokines and doxorubicin to respectively attract and kill orthotopic glioblastoma cells. These encouraging results will be completed with a combination of short-range (high LET) radiation by embedded radioisotope into the GlioGel aiming for synergistic combination to eradicate as much tumour cells as possible, while limiting systemic side effects.

BACKGROUND Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour in adults. These tumours depict anarchic proliferation and brain infiltration as well as radio- and chemoresistant profiles. The complete surgical resection is unachievable and responses to standard therapy are transitory. Recurrence is thus inevitable and patient prognosis is generally less than 15 months. Transforming growth factor-beta (TGF-β) holds a substantial role in supporting the GBM phenotype. We showed that TGF-β 1 expression levels correlate with overall and progression-free survival in newly diagnosed GBM patient. We also observed that chloroquine (CQ) can reduce the production of TGF-β together with proliferation, invasion, radioresistance and radio-induced invasion in vitro. Unfortunately, little is known regarding the ability of CQ to penetrate the blood-brain barrier (BBB). Therefore, our objective is to determine whether intravenous (IV) or intra-arterial (IA) infusions of CQ and hydroxychloroquine (HCQ), a pharmacological analog of CQ, can yield therapeutic brain concentrations. MATERIAL AND METHODS To assess BBB penetration, the brain, plasma and cerebrospinal fluid (CSF) concentrations of CQ/HCQ were measured by LCMS/MS at different timepoints post-IV or post-IA infusions with 20 mg/kg of CQ/HCQ in tumour-free Wistar rat. For the survival studies, We implanted 10’000 F98 murin glioblastoma cells in the right putamen of Fischer rats. Ten days post-implantation, IA and IV infusion were accomplished through cannulations of the external right carotid and tail vein respectively. RESULTS With IV injections, CQ/HCQ brain concentrations 15 minutes post-injection reached 15.76 mg/g (0.18 µM) and 1.67 mg/g (0.078 µM) respectively. However, following IA infusions, we observed a 1.74 and 20.9 fold increase (20 mg/kg HCQ) as well as 7.1 and 84.7-fold-increase (20 mg/kg CQ) in contra- and ipsilateral brain concentrations respectively. Although brain concentrations gradually decreased over time post-IA infusions, the ipsilateral hemisphere CQ concentration was still 82.81 mg/g (34.52 µM) after 6 hours. Whereas plasma concentrations were very similar following IV and IA infusions, both molecules barely accumulated in the CSF and only when using IA infusions. The median survival of the control group (IA phosphate-buffered saline) and the group treated with 20 mg/kg CQ IV were 23.5 days and 24.5 days respectively. However, rats injected with 20 mg/kg CQ IA had a median survival of 28.5 days. CONCLUSION These results suggest that IA CQ could be used to abrogate the GBM phenotype. As TGF-β is associated with resistance to both radio- and chemotherapy, we plan to characterize the combination of IA infusions of CQ in combination with radiation or chemotherapy (carboplatin).

Datasets from a four-year monitoring effort at Lake Peters, a glacier-fed lake in Arctic Alaska, are described and presented with accompanying methods, biases, and corrections. Three meteorological stations documented air temperature, relative humidity, and rainfall at different elevations in the Lake Peters watershed. Data from ablation stake stations on Chamberlin glacier were used to quantify glacial melt, and measurements from two hydrological stations were used to reconstruct continuous discharge for the two primary inflows to Lake Peters, Carnivore and Chamberlin Creeks. The lake's thermal structure was monitored using a network of temperature sensors on moorings, the lake's water level was recorded using pressure sensors, and sedimentary inputs to the lake were documented by sediment traps. We demonstrate the utility of these datasets by examining a flood event in July 2015, though other uses include studying intra- and inter-annual trends in this weather-glacier-river-lake system, contextualizing interpretations of lakes sediment cores, and providing background for modeling studies. All DOI-referenced datasets described in this manuscript are archived at the National Science Foundation Arctic Data Center at the following overview webpage for the project: https://arcticdata.io/catalog/view/urn:uuid:517b8679-20db-4c89-a29c-6410cbd08afe (Kaufman et al., 2019e).

Primary brain tumors are notoriously hard to resect surgically. Due to their infiltrative nature, finding the optimal resection boundary without damaging healthy tissue can be challenging. One potential tool to help make this decision is diffusion-weighted magnetic resonance imaging (dMRI) tractography. dMRI exploits the diffusion of water molecule along axons to generate a 3D modelization of the white matter bundles in the brain. This feature is particularly useful to visualize how a tumor affects its surrounding white matter and plan a surgical path. This paper reviews the different ways in which dMRI can be used to improve brain tumor resection, its benefits and also its limitations. We expose surgical tools that can be paired with dMRI to improve its impact on surgical outcome, such as loading the 3D tractography in the neuronavigation system and direct electrical stimulation to validate the position of the white matter bundles of interest. We also review articles validating dMRI findings using other anatomical investigation techniques, such as postmortem dissections, manganese-enhanced MRI, electrophysiological stimulations, and phantom studies with known ground truth. We will be discussing the areas of the brain where dMRI performs well and where the future challenges are. We will conclude this review with suggestions and take home messages for neurosurgeons, tractographers, and vendors for advancing the field and on how to benefit from tractography's use in clinical practice.

Background In the past decade, smartphone applications (Apps) have experienced remarkable development across all fields of medicine, including neurosurgery. However, owing to a lack of regulatory oversight and peer review, a clear need exists for a comprehensive review and audit of the existing available Apps. In the present study, we systematically reviewed the existing mobile Apps in neurosurgery, evaluated their clinical use by neurosurgery residents in Canada, and performed a quality audit of the most popular Apps. Methods Indexed Apps were identified from either the Google Play Store or the iOS App Store using a comprehensive list of keywords related to neurosurgery. A subsequent cross-sectional survey of 76 Canadian neurosurgery residents was conducted, including a section on smartphone App use. We next evaluated the most popular Apps among the residents using the Healthcare Smartphone App Evaluation Tool and performed a quality audit of their content using established medical references. Results The survey identified 118 mobile Apps related to neurosurgery. The 3 most used Apps used by the current cohort of Canadian neurosurgery residents were Neurosurgery Survival Guide, Neuromind, and the Journal of Neurosurgery App. Each of these 3 Apps received an excellent score on the Healthcare Smartphone App Evaluation Tool. A quality audit of 30 pages of the Neurosurgery Survival Guide and 40 clinical scores of the Neuromind App, performed by 10 neurosurgery residents, failed to reveal inaccurate or false statements. Conclusion The present study has highlighted the current landscape of neurosurgery mobile Apps and their use among neurosurgery residents.

Purpose: Irradiation of brain stimulates the expression of inflammatory mediators, some of which can modify the ability of cancer cells to infiltrate the brain. In the present study, the time window during which this stimulation occurs was determined. Materials and methods: Brain of Fischer rat was irradiated (15 Gy) and expression of pro-inflammatory mediators IL-1β, IL-6 and TNF-α was measured from 4 h to 20 days post-irradiation. Level of the matrix metalloproteinase 2 (MMP-2) and prostaglandin E2 (PGE2) which can favor cancer cell infiltration were also measured. The F98 glioma cells were implanted either during (4 h post-irradiation) or after (10 days post-irradiation) the pro-inflammatory phase. Infiltration distance of F98 cells in brain parenchyma and the median survival time of the animals were determined. Results: Expression of IL-1β, IL-6 and TNF-α was significantly increased in the irradiated brains with a peak at 4 h post-irradiation. Implantation of F98 glioma cells 4 h post-irradiation reduced the median survival time of Fischer rats to 18 days, compared to 25 days when the F98 were implanted in non-irradiated brain. Irradiation of the brain increased the distance of infiltration of F98 cells and was associated with increased levels of MMP-2 and PGE2. Conversely, F98 cells implanted 10 days post-irradiation have infiltrated the brain over a shorter distance and the median survival time of rats was increased to 35 days. Conclusions: Cancer recurrence is frequently observed in GBM patients. A better understanding of the inflammatory response observed in irradiated brain could contribute to develop new therapeutic modalities to further increase the efficiency of radiotherapy.

Resting state functional magnetic resonance imaging (RS-fMRI) is a popular method of visualizing functional networks in the brain. One of these networks, the default mode network (DMN), has exhibited altered connectivity in a variety of pathological states, including brain tumors. However, very few studies have attempted to link the effect of tumor localization, type and size on DMN connectivity. We collected RS-fMRI data in 73 patients with various brain tumors and attempted to characterize the different effects these tumors had on DMN connectivity based on their location, type and size. This was done by comparing the tumor patients with healthy controls using independent component analysis (ICA) and seed based analysis. We also used a multi-seed approach described in the paper to account for anatomy distortion in the tumor patients. We found that tumors in the left hemisphere had the largest effect on DMN connectivity regardless of their size and type, while this effect was not observed for right hemispheric tumors. Tumors in the cerebellum also had statistically significant effects on DMN connectivity. These results suggest that DMN connectivity in the left side of the brain may be more fragile to insults by lesions.

Results of clinical trials with oxaliplatin in treating glioblastoma are dismal. Previous works showed that intravenous (i.v.) delivery of oxaliplatin did not increase the survival of F98 glioma-bearing Fisher rats. Low accumulation of the drug in tumor cells is presumed to be responsible for the lack of antitumor effect. In the present study, convection-enhanced delivery (CED) was used to directly inject oxaliplatin in brain tumor implanted in rats. Since CED can led to severe toxicity, the liposomal formulation of oxaliplatin (Lipoxal™) was also assessed. The maximum tolerated dose (MTD) of oxaliplatin was 10 μg, while that of Lipoxal™ was increased by 3-times reaching 30 μg. Median survival time (MeST) of F98 glioma-bearing rats injected with 10 μg oxaliplatin by CED was 31 days, 7.5 days longer than untreated control (p = 0.0002); while CED of 30 μg Lipoxal™ reached the same result. Compared to previous study on i.v. delivery of these drugs, their injection by CED significantly increased their tumoral accumulations as well as MeSTs in the F98 glioma bearing rat model. The addition of radiotherapy (15 Gy) to CED of oxaliplatin or Lipoxal™ increased the MeST by 4.0 and 3.0 days, respectively. The timing of radiotherapy (4 h or 24 h after CED) produced similar results. However, the treatment was better tolerated when radiotherapy was performed 24 h after CED. In conclusion, a better tumoral accumulation was achieved when oxaliplatin and Lipoxal™ were injected by CED. The liposomal encapsulation of oxaliplatin reduced its toxic, while maintaining its antitumor potential.