Unveiling the vulnerability of the human abducens nerve: insights from comparative cranial base anatomy in mammals and primates.

The topographic anatomy of the abducens nerve has been the subject of research for more than 150 years. Although its vulnerability was initially attributed to its length, this hypothesis has largely lost prominence. Instead, attention has shifted toward its intricate anatomical relations along the cranial base. Contrary to the extensive anatomical and neurosurgical literature on abducens nerve anatomy in humans, its complex anatomy in other species has received less emphasis. The main question addressed here is why the human abducens nerve is predisposed to injury. Specifically, we aim to perform a comparative analysis of the basicranial pathway of the abducens nerve in mammals and primates. Our hypothesis links its vulnerability to cranial base flexion, particularly around the sphenooccipital synchondrosis. We examined the abducens nerve pathway in various mammals, including primates, humans (N = 40; 60% males; 40% females), and human fetuses (N = 5; 60% males; 40% females). The findings are presented at both the macroscopic and histological levels. To associate our findings with basicranial flexion, we measured the cranial base angles in the species included in this study and compared them to data in the available literature. Our findings show that the primitive state of the abducens nerve pathway follows a nearly flat (unflexed) cranial base from the pontomedullary sulcus to the superior orbital fissure. Only the gulfar segment, where the nerve passes through Dorello's canal, demonstrates some degree of variation. We present evidence indicating that the derived state of the abducens pathway, which is most pronounced in humans from an early stage of development, is characterized by following the significantly more flexed basicranium. Overall, the present study elucidates the evolutionary basis for the vulnerability of the abducens nerve, especially within its gulfar and cavernous segments, which are situated at the main synchondroses between the anterior, middle, and posterior cranial fossae-a unique anatomical relation exclusive to the abducens nerve. The principal differences between the pathways of this nerve and those of other cranial nerves are discussed. The findings suggest that the highly flexed human cranial base plays a pivotal role in the intricate anatomical relations and resulting vulnerability of the abducens nerve.

Frequencies of 4 tumor-infiltrating lymphocytes potently predict survival in glioblastoma, an immune desert.

BACKGROUND: GBM is an aggressive grade 4 primary brain tumor (BT), with a 5%-13% 5-year survival. Most human GBMs manifest as immunologically "cold" tumors or "immune deserts," yet the promoting or suppressive roles of specific lymphocytes within the GBM tumor microenvironment (TME) is of considerable debate. METHODS: We used meticulous multiparametric flow cytometry (FC) to determine the lymphocytic frequencies in 102 GBMs, lower-grade gliomas, brain metastases, and nontumorous brain specimen. FC-attained frequencies were compared with frequencies estimated by "digital cytometry." The FC-derived data were combined with the patients' demographic, clinical, molecular, histopathological, radiological, and survival data. RESULTS: Comparison of FC-derived data to CIBERSORT-estimated data revealed the poor capacity of digital cytometry to estimate cell frequencies below 0.2%, the frequency range of most immune cells in BTs. Isocitrate dehydrogenase (IDH) mutation status was found to affect TME composition more than the gliomas' pathological grade. Combining FC and survival data disclosed that unlike other cancer types, the frequency of helper T cells (Th) and cytotoxic T lymphocytes (CTL) correlated negatively with glioma survival. In contrast, the frequencies of γδ-T cells and CD56bright natural killer cells correlated positively with survival. A composite parameter combining the frequencies of these 4 tumoral lymphocytes separated the survival curves of GBM patients with a median difference of 10 months (FC-derived data; P < .0001, discovery cohort), or 4.1 months (CIBERSORT-estimated data; P = .01, validation cohort). CONCLUSIONS: The frequencies of 4 TME lymphocytes strongly correlate with the survival of patients with GBM, a tumor considered an immune desert.

[EXTENDED ENDONASAL ENDOSCOPIC APPROACH IN TREATING PITUITARY ADENOMAS AND SKULL BASE TUMORS].

INTRODUCTION: The endoscopic endonasal approach (EEA) is a rapidly growing, minimally invasive discipline applied to a broad set of skull base tumors. The introduction of the endoscopic endonasal approach for the management of lesions of the skull base has produced a paradigm shift in the way these complicated lesions are managed. The extended endonasal approach provides the most direct route to the anterior cranial base including sella, cribriform plate, planum sphenoidale, suprasellar cistern, clivus and foramen magnum. Transsphenoidal microscopic pituitary surgery has long been considered the gold standard in surgical treatment of pituitary tumors. Extended endonasal endoscopic pituitary surgery has come into prominence over the last two decades as a superior alternative to microscopic surgery. Gaining experience in this approach has allowed the use of EEA for the surgical treatment of more complex pathologies such as meningiomas, craniopharyngiomas and more.

Toward a theranostic device for gliomas.

BACKGROUND: In the surgical management of glioblastoma, a highly aggressive and incurable type of brain cancer, identification and treatment of residual tissue is the most common site of disease recurrence. Monitoring and localized treatment are achieved with engineered microbubbles (MBs) by combining ultrasound and fluorescence imaging with actively targeted temozolomide (TMZ) delivery. METHODS: The MBs were conjugated with a near-infrared fluorescence probe CF790, cyclic pentapeptide bearing the RGD sequence and a carboxyl-temozolomide, TMZA. The efficiency of adhesion to HUVEC cells was assessed in vitro in realistic physiological conditions of shear rate and vascular dimensions. Cytotoxicity of TMZA-loaded MBs on U87 MG cells and IC50 were assessed by MTT tests. RESULTS: We report on the design of injectable poly(vinyl alcohol) echogenic MBs designed as a platform with active targeting ability to tumor tissues, by tethering on the surface a ligand having the tripeptide sequence, RGD. The biorecognition of RGD-MBs onto HUVEC cells is quantitatively proved. Efficient NIR emission from the CF790-decorated MBs was successfully detected. The conjugation on the MBs surface of a specific drug as TMZ is achieved. The pharmacological activity of the coupled-to-surface drug is preserved by controlling the reaction conditions. CONCLUSIONS: We present an improved formulation of PVA-MBs to achieve a multifunctional device with adhesion ability, cytotoxicity on glioblastoma cells and supporting imaging.

Deoxyhypusine hydroxylase: A novel therapeutic target differentially expressed in short-term vs long-term survivors of glioblastoma.

Glioblastoma (GB) is the most aggressive neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness and drug resistance. Only a small fraction of GB patients survives longer than 24 months from the time of diagnosis (ie, long-term survivors [LTS]). In our study, we aimed to identify molecular markers associated with favorable GB prognosis as a basis to develop therapeutic applications to improve patients' outcome. We have recently assembled a proteogenomic dataset of 87 GB clinical samples of varying survival rates. Following RNA-seq and mass spectrometry (MS)-based proteomics analysis, we identified several differentially expressed genes and proteins, including some known cancer-related pathways and some less established that showed higher expression in short-term (<6 months) survivors (STS) compared to LTS. One such target found was deoxyhypusine hydroxylase (DOHH), which is known to be involved in the biosynthesis of hypusine, an unusual amino acid essential for the function of the eukaryotic translation initiation factor 5A (eIF5A), which promotes tumor growth. We consequently validated DOHH overexpression in STS samples by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. We further showed robust inhibition of proliferation, migration and invasion of GB cells following silencing of DOHH with short hairpin RNA (shRNA) or inhibition of its activity with small molecules, ciclopirox and deferiprone. Moreover, DOHH silencing led to significant inhibition of tumor progression and prolonged survival in GB mouse models. Searching for a potential mechanism by which DOHH promotes tumor aggressiveness, we found that it supports the transition of GB cells to a more invasive phenotype via epithelial-mesenchymal transition (EMT)-related pathways.

[LASER INTERSTITIAL THERMAL THERAPY (LITT) IN NEUROSURGERY].

INTRODUCTION: Laser interstitial thermal therapy (LITT) has emerged as a new treatment option for various conditions within the neurosurgery world, not only due to its minimal invasiveness but also because it has been shown to be safe and effective. Combined with magnetic resonance thermography, LITT gives surgeons the ability to estimate damage in real time and precisely ablate the target tissue while minimizing thermal damage to adjacent structures. In recent years, LITT has become a reality in epilepsy surgery and in neuro-oncology and is emerging as an option in other fields in neurosurgery.

A Highly Sensitive Flow Cytometric Approach to Detect Rare Antigen-Specific T Cells: Development and Comparison to Standard Monitoring Tools.

Personalized vaccines against patient-unique tumor-associated antigens represent a promising new approach for cancer immunotherapy. Vaccine efficacy is assessed by quantification of changes in the frequency and/or the activity of antigen-specific T cells. Enzyme-linked immunosorbent spot (ELISpot) and flow cytometry (FCM) are methodologies frequently used for assessing vaccine efficacy. We tested these methodologies and found that both ELISpot and standard FCM [monitoring CD3/CD4/CD8/IFNγ/Viability+CD14+CD19 (dump)] demonstrate background IFNγ secretion, which, in many cases, was higher than the antigen-specific signal measured by the respective methodology (frequently ranging around 0.05-0.2%). To detect such weak T-cell responses, we developed an FCM panel that included two early activation markers, 4-1BB (CD137) and CD40L (CD154), in addition to the above-cited markers. These two activation markers have a close to zero background expression and are rapidly upregulated following antigen-specific activation. They enabled the quantification of rare T cells responding to antigens within the assay well. Background IFNγ-positive CD4 T cell frequencies decreased to 0.019% ± 0.028% and CD8 T cells to 0.009% ± 0.013%, which are 19 and 13 times lower, respectively, than without the use of these markers. The presented methodology enables highly sensitive monitoring of T-cell responses to tumor-associated antigens in the very low, but clinically relevant, frequencies.

The clinical significance of radiological changes associated with gliadel implantation in patients with recurrent high grade glioma.

Gliadel occasionally induces edema following its implantation. We aimed to correlate such post-surgical radiological changes to its efficacy and subsequent survival. Fifty-six patients with recurrent high grade glioma were treated between 2005 and 2016 with Gliadel implantation. Volumetric measurements of MRI features, including FLAIR abnormalities, tumor bulk (volume of gadolinium enhancement on T1) and resection cavity volumes over time were conducted. To assess dynamics over time, linear regression trendlines for each of these were calculated and examined to correlate with survival. Median follow-up after resection was 21.5 months. Median survival post-Gliadel implantation and overall survival since diagnosis were 12 months and 22 months, respectively. A subgroup of patients (n = 6) with a transient increase in FLAIR changes volume over time survived significantly longer post-Gliadel compared to those who did not demonstrate such change (36 vs 12 months, p = .03). Positive trends, representing overall growth in volume over time, of tumor bulk and resection cavity predicted survival in multivariate analyses (hazard ratios 7.9 and 84, p = .003 and .002, respectively). Increase in tumor bulk and resection cavity over time were associated with decreased survival, while transient FLAIR increase was a favorable prognostic factor. This may represent a transient inflammatory process in the tumor, possibly stemming from a presumed immune-mediated anti-tumor response.

Risk factors and prognostic implications of surgery-related strokes following resection of high-grade glioma.

Surgery-related strokes are an important cause of morbidity following resection of high-grade glioma (HGG). We explored the incidence, risk factors and clinical consequences of intra-operative ischemic strokes in surgeries for resection of HGG. We retrospectively followed a cohort of 239 patients who underwent surgical resection of HGG between 2013 and 2017. Tumor types included both isocitrate dehydrogenase (IDH) wildtype glioblastoma and IDH-mutant WHO grade 4 astrocytoma. We analyzed pre- and post-operative demographic, clinical, radiological, anesthesiology and intraoperative neurophysiology data, including overall survival and functional outcomes. Acute ischemic strokes were seen on postoperative diffusion-weighted imaging (DWI) in 30 patients (12.5%), 13 of whom (43%) developed new neurological deficits. Infarcts were more common in insular (23%, p = 0.019) and temporal surgeries (57%, p = 0.01). Immediately after surgery, 35% of patients without infarcts and 57% of those with infarcts experienced motor deficits (p = 0.022). Six months later, rates of motor deficits decreased to 25% in the non-infarcts group and 37% in the infarcts group (p = 0.023 and 0.105, respectively) with a significantly lower Karnofsky-Performance Score (KPS, p = 0.001). Intra-operative language decline in awake procedures was a significant indicator of the occurrence of intra-operative stroke (p = 0.029). In conclusion, intraoperative ischemic events are more common in insular and temporal surgeries for resection of HGG and their intra-operative detection is limited. These strokes can impair motor and speech functions as well as patients' performance status.

A Prospective Evaluation of Quality of Life in Patients Undergoing Extended Endoscopic Endonasal Surgery for Benign Pituitary Gland Lesion.

Introduction Endoscopic endonasal surgery (EES) has become the preferred approach for pituitary tumor resection. Nevertheless, research on quality of life related to pituitary adenoma surgery is scarce. Objective The aim of the study is to evaluate short-term quality of life in patients after endoscopic endonasal resection of pituitary tumors and to find predictors for poor quality of life (QOL) outcome. Materials and Methods A prospective cohort study was conducted, including all patients who underwent EES for pituitary tumors in a tertiary medical referral center. Recruited patients completed the Anterior Skull Base Disease-Specific QOL (ASBS-Q) questionnaire and the Sinonasal Outcome Test 22 (SNOT-22) questionnaire before surgery, 2 and 4 to 6 months after surgery. Demographic and clinical data was collected. Results Our study included 49 patients. The overall ASBS-Q scores significantly improved 4 to 6 months after surgery (4.46 vs. 4.2, p < 0.05). We found a significant improvement in QOL related to emotional state 2 months post surgery (4.41 vs. 3.87, p < 0.05), which became borderline significant 4 to 6 months post surgery. There was a significant improvement in pain (4.5 vs. 4.08, p < 0.05) and vitality (4.43 vs. 4.16, p < 0.05) domains 4 to 6 months post surgery. SNOT-22 scores did not change significantly postoperatively. Factors such as secreting and non-secreting tumors, tumor size, intraoperative cerebrospinal fluid leak, gross tumor resection, endocrine remission, and the use of nasoseptal flap reconstruction did not have a significant effect on QOL. Conclusion We found that patients after EES reported improved QOL 4 to 6 months post surgery. Specific improvement was noted in the QOL related to pain and vitality.

Clinical and prognostic implications of rim restriction following glioma surgery.

Rim restriction surrounding the resection cavity of glioma is often seen on immediate post-op diffusion-weighted imaging (DWI). The etiology and clinical impact of rim restriction are unknown. We evaluated the incidence, risk factors and clinical consequences of this finding. We evaluated patients that underwent surgery for low-grade glioma (LGG) and glioblastoma (GBM) without stroke on post-operative imaging. Analyses encompassed pre- and postoperative clinical, radiological, intraoperative monitoring, survival, functional and neurocognitive outcomes. Between 2013 and 2017, 63 LGG and 209 GBM patients (272 in total) underwent surgical resection and were included in our cohort. Post-op rim restriction was demonstrated in 68 patients, 32% (n = 20) of LGG and 23% (n = 48) of GBM patients. Risk factors for restriction included temporal tumors in GBM (p = 0.025) and insular tumors in LGG (p = 0.09), including longer surgery duration in LGG (p = 0.008). After a 1-year follow-up, LGG patients operated on their dominant with post-op restriction had a higher rate of speech deficits (46 vs 9%, p = 0.004). Rim restriction on postoperative imaging is associated with longer duration of glioma surgery and potentially linked to brain retraction. It apparently has no direct clinical consequences, but is linked to higher rates of speech deficits in LGG dominant-side surgeries.

Nocardia cyriacigeorgica brain abscess in a patient on low dose steroids: a case report and review of the literature.

BACKGROUND: Nocardia cyriacigeorgica was first described in 2001. It is an emerging pathogen that mainly affects immunocompromised patients. A brain abscess caused by N. cyriacigeorgica has been reported only in immunocompromised hosts. We present a rare case of brain abscess caused by N. cyriacigeorgica in an adult male receiving low dose steroids. CASE PRESENTATION: A 75-year-old male weekend gardener without an immunocompromising condition presented with neurological complaints that were initially attributed to an ischemic stroke. Due to the unusual presentation and rapid progression, his condition was thought to be caused by a cerebral space-occupying lesion. He underwent an emergent right-sided parietal craniotomy and the histopathological report of the specimen was an abscess caused by N. cyriacigeorgica. The patient received appropriate antibiotic treatment and completely recovered without sequelae. CONCLUSIONS: Nocardia species are a rare cause of brain abscess in immunocompetent patients. Their clinical presentation can mimic other more common cerebral diseases, such as brain tumors (primary and secondary) and stroke. The possibility of an abscess caused by N. cyriacigeorgica should also be considered in the differential diagnosis in an immunocompetent patient.

Predicting EGFR mutation status by a deep learning approach in patients with non-small cell lung cancer brain metastases.

PURPOSE: Non-small cell lung cancer (NSCLC) tends to metastasize to the brain. Between 10 and 60% of NSCLCs harbor an activating mutation in the epidermal growth-factor receptor (EGFR), which may be targeted with selective EGFR inhibitors. However, due to a high discordance rate between the molecular profile of the primary tumor and the brain metastases (BMs), identifying an individual patient's EGFR status of the BMs necessitates tissue diagnosis via an invasive surgical procedure. We employed a deep learning (DL) method with the aim of noninvasive detection of the EGFR mutation status in NSCLC BM. METHODS: We retrospectively collected clinical, radiological, and pathological-molecular data of all the NSCLC patients who had been diagnosed with BMs and underwent resection of their BM during 2009-2019. The study population was then divided into two groups based upon EGFR mutational status. We further employed a DL technique to classify the two groups according to their preoperative magnetic resonance imaging features. Augmentation techniques, transfer learning approach, and post-processing of the predicted results were applied to overcome the relatively small cohort. Finally, we established the accuracy of our model in predicting EGFR mutation status of BM of NSCLC. RESULTS: Fifty-nine patients were included in the study, 16 patients harbored EGFR mutations. Our model predicted mutational status with mean accuracy of 89.8%, sensitivity of 68.7%, specificity of 97.7%, and a receiver operating characteristic curve value of 0.91 across the 5 validation datasets. CONCLUSION: DL-based noninvasive molecular characterization is feasible, has high accuracy and should be further validated in large prospective cohorts.

The default network is causally linked to creative thinking.

Creative thinking represents a major evolutionary mechanism that greatly contributed to the rapid advancement of the human species. The ability to produce novel and useful ideas, or original thinking, is thought to correlate well with unexpected, synchronous activation of several large-scale, dispersed cortical networks, such as the default network (DN). Despite a vast amount of correlative evidence, a causal link between default network and creativity has yet to be demonstrated. Surgeries for resection of brain tumors that lie in proximity to speech related areas are performed while the patient is awake to map the exposed cortical surface for language functions. Such operations provide a unique opportunity to explore human behavior while disrupting a focal cortical area via focal electrical stimulation. We used a novel paradigm of individualized direct cortical stimulation to examine the association between creative thinking and the DN. Preoperative resting-state fMRI was used to map the DN in individual patients. A cortical area identified as a DN node (study) or outside the DN (controls) was stimulated while the participants performed an alternate-uses-task (AUT). This task measures divergent thinking through the number and originality of different uses provided for an everyday object. Baseline AUT performance in the operating room was positively correlated with DN integrity. Direct cortical stimulation at the DN node resulted in decreased ability to produce alternate uses, but not in the originality of uses produced. Stimulation in areas that when used as network seed regions produced a network similar to the canonical DN was associated with reduction of creative fluency. Stimulation of areas that did not produce a default-like network (controls) did not alter creative thinking. This is the first study to causally link the DN and creative thinking.

Evaluation of outcomes following subtotal colectomy for the treatment of idiopathic megacolon in cats.

OBJECTIVE: To evaluate outcomes in cats undergoing subtotal colectomy for the treatment of idiopathic megacolon and to determine whether removal versus nonremoval of the ileocecocolic junction (ICJ) was associated with differences in outcome. ANIMALS: 166 client-owned cats. PROCEDURES: For this retrospective cohort study, medical records databases of 18 participating veterinary hospitals were searched to identify records of cats with idiopathic megacolon treated by subtotal colectomy from January 2000 to December 2018. Data collection included perioperative and surgical variables, complications, outcome, and owner perception of the procedure. Data were analyzed for associations with outcomes of interest, and Kaplan-Meier survival time analysis was performed. RESULTS: Major perioperative complications occurred in 9.9% (15/151) of cats, and 14% (12/87) of cats died as a direct result of treatment or complications of megacolon. The median survival time was not reached. Cats with (vs without) a body condition score < 4/9 (hazard ratio [HR], 5.97), preexisting heart disease (HR, 3.21), major perioperative complications (HR, 27.8), or long-term postoperative liquid feces (HR, 10.4) had greater hazard of shorter survival time. Constipation recurrence occurred in 32% (24/74) of cats at a median time of 344 days and was not associated with retention versus removal of the ICJ; however, ICJ removal was associated with long-term liquid feces (OR, 3.45), and a fair or poor outcome on owner assessment (OR, 3.6). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that subtotal colectomy was associated with long survival times and a high rate of owner satisfaction. Removal of the ICJ was associated with less favorable outcomes in cats of the present study.

Microengineered perfusable 3D-bioprinted glioblastoma model for in vivo mimicry of tumor microenvironment.

Many drugs show promising results in laboratory research but eventually fail clinical trials. We hypothesize that one main reason for this translational gap is that current cancer models are inadequate. Most models lack the tumor-stroma interactions, which are essential for proper representation of cancer complexed biology. Therefore, we recapitulated the tumor heterogenic microenvironment by creating fibrin glioblastoma bioink consisting of patient-derived glioblastoma cells, astrocytes, and microglia. In addition, perfusable blood vessels were created using a sacrificial bioink coated with brain pericytes and endothelial cells. We observed similar growth curves, drug response, and genetic signature of glioblastoma cells grown in our 3D-bioink platform and in orthotopic cancer mouse models as opposed to 2D culture on rigid plastic plates. Our 3D-bioprinted model could be the basis for potentially replacing cell cultures and animal models as a powerful platform for rapid, reproducible, and robust target discovery; personalized therapy screening; and drug development.

T Cells Retain Pivotal Antitumoral Functions under Tumor-Treating Electric Fields.

Tumor-treating fields (TTFields) are a localized, antitumoral therapy using alternating electric fields, which impair cell proliferation. Combining TTFields with tumor immunotherapy constitutes a rational approach; however, it is currently unknown whether TTFields' locoregional effects are compatible with T cell functionality. Healthy donor PBMCs and viably dissociated human glioblastoma samples were cultured under either standard or TTFields conditions. Select pivotal T cell functions were measured by multiparametric flow cytometry. Cytotoxicity was evaluated using a chimeric Ag receptor (CAR)-T-based assay. Glioblastoma patient samples were acquired before and after standard chemoradiation or standard chemoradiation + TTFields treatment and examined by immunohistochemistry and by RNA sequencing. TTFields reduced the viability of proliferating T cells, but had little or no effect on the viability of nonproliferating T cells. The functionality of T cells cultured under TTFields was retained: they exhibited similar IFN-γ secretion, cytotoxic degranulation, and PD1 upregulation as controls with similar polyfunctional patterns. Glioblastoma Ag-specific T cells exhibited unaltered viability and functionality under TTFields. CAR-T cells cultured under TTFields exhibited similar cytotoxicity as controls toward their CAR target. Transcriptomic analysis of patients' glioblastoma samples revealed a significant shift in the TTFields-treated versus the standard-treated samples, from a protumoral to an antitumoral immune signature. Immunohistochemistry of samples before and after TTFields treatment showed no reduction in T cell infiltration. T cells were found to retain key antitumoral functions under TTFields settings. Our data provide a mechanistic insight and a rationale for ongoing and future clinical trials that combine TTFields with immunotherapy.

Differentiating Small-Cell Lung Cancer From Non-Small-Cell Lung Cancer Brain Metastases Based on MRI Using Efficientnet and Transfer Learning Approach.

Differentiation between small-cell lung cancer (SCLC) from non-small-cell lung cancer (NSCLC) brain metastases is crucial due to the different clinical behaviors of the two tumor types. We propose the use of a deep learning and transfer learning approach based on conventional magnetic resonance imaging (MRI) for non-invasive classification of SCLC vs. NSCLC brain metastases. Sixty-nine patients with brain metastasis of lung cancer origin were included. Of them, 44 patients had NSCLC and 25 patients had SCLC. Classification was performed with EfficientNet architecture on crop images of lesion areas and based on post-contrast T1-weighted, T2-weighted and FLAIR imaging input data. Evaluation of the model was carried out in a 5-fold cross-validation manner, and based on accuracy, precision, recall, F1 score and area under the receiver operating characteristic curve. The best classification results were obtained with multiparametric MRI input data (T1WI+c+FLAIR+T2WI), with a mean overall accuracy of 0.90 ± 0.04, and F1 score of 0.92 ± 0.05 for NSCLC and 0.87 ± 0.08 for SCLC for the validation data and an accuracy of 0.87 ± 0.05, with an F1 score of 0.88 ± 0.05 for NSCLC and 0.85 ± 0.05 for SCLC for the test dataset. The proposed method provides an automatic noninvasive method for the classification of brain metastasis with high sensitivity and specificity for differentiation between NSCLC vs. SCLC brain metastases. It may be used as a diagnostic tool for improving decision-making in the treatment of patients with these metastases. Further studies on larger patient samples are required to validate the current results.

P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression.

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.

Proteogenomics of glioblastoma associates molecular patterns with survival.

Glioblastoma (GBM) is the most aggressive form of glioma, with poor prognosis exhibited by most patients, and a median survival time of less than 2 years. We assemble a cohort of 87 GBM patients whose survival ranges from less than 3 months and up to 10 years and perform both high-resolution mass spectrometry proteomics and RNA sequencing (RNA-seq). Integrative analysis of protein expression, RNA expression, and patient clinical information enables us to identify specific immune, metabolic, and developmental processes associated with survival as well as determine whether they are shared between expression layers or are layer specific. Our analyses reveal a stronger association between proteomic profiles and survival and identify unique protein-based classification, distinct from the established RNA-based classification. By integrating published single-cell RNA-seq data, we find a connection between subpopulations of GBM tumors and survival. Overall, our findings establish proteomic heterogeneity in GBM as a gateway to understanding poor survival.