Unsupervised machine learning models reveal predictive clinical markers of glioblastoma patient survival using white blood cell counts prior to initiating chemoradiation.

Background: Glioblastoma is a malignant brain tumor requiring careful clinical monitoring even after primary management. Personalized medicine has suggested the use of various molecular biomarkers as predictors of patient prognosis or factors utilized for clinical decision-making. However, the accessibility of such molecular testing poses a constraint for various institutes requiring identification of low-cost predictive biomarkers to ensure equitable care. Methods: We collected retrospective data from patients seen at Ohio State University, University of Mississippi, Barretos Cancer Hospital (Brazil), and FLENI (Argentina) who were managed for glioblastoma-amounting to 581 patient records documented using REDCap. Patients were evaluated using an unsupervised machine learning approach comprised of dimensionality reduction and eigenvector analysis to visualize the inter-relationship of collected clinical features. Results: We discovered that the serum white blood cell (WBC) count of a patient during baseline planning for treatment was predictive of overall survival with an over 6-month median survival difference between the upper and lower quartiles of WBC count. By utilizing an objective PD-L1 immunohistochemistry quantification algorithm, we were further able to identify an increase in PD-L1 expression in glioblastoma patients with high serum WBC counts. Conclusions: These findings suggest that in a subset of glioblastoma patients the incorporation of WBC count and PD-L1 expression in the brain tumor biopsy as simple biomarkers predicting glioblastoma patient survival. Moreover, machine learning models allow the distillation of complex clinical data sets to uncover novel and meaningful clinical relationships.

"Non-Eloquent" brain regions predict neuropsychological outcome in tumor patients undergoing awake craniotomy.

Supratotal resection of primary brain tumors is being advocated especially when involving "non-eloquent" tissue. However, there is extensive neuropsychological data implicating functions critical to higher cognition in areas considered "non-eloquent" by most surgeons. The goal of the study was to determine pre-surgical brain regions that would be predictive of cognitive outcome at 4-6 months post-surgery. Cortical reconstruction and volumetric segmentation were performed with the FreeSurfer-v6.0 image analysis suite. Linear regression models were used to regress cortical volumes from both hemispheres, against the total cognitive z-score to determine the relationship between brain structure and broad cognitive functioning while controlling for age, sex, and total segmented brain volume. We identified 62 consecutive patients who underwent planned awake resections of primary (n = 55, 88%) and metastatic at the University of New Mexico Hospital between 2015 and 2019. Of those, 42 (23 males, 25 left hemispheric lesions) had complete pre and post-op neuropsychological data available and were included in this study. Overall, total neuropsychological functioning was somewhat worse (p = 0.09) at post-operative neuropsychological outcome (Mean = -.20) than at baseline (Mean = .00). Patients with radiation following resection (n = 32) performed marginally worse (p = .036). We found that several discrete brain volumes obtained pre-surgery predicted neuropsychological outcome post-resection. For the total sample, these volumes included: left fusiform, right lateral orbital frontal, right post central, and right paracentral regions. Regardless of lesion lateralization, volumes within the right frontal lobe, and specifically right orbitofrontal cortex, predicted neuropsychological difference scores. The current study highlights the gaps in our current understanding of brain eloquence. We hypothesize that the volume of tissue within the right lateral orbital frontal lobe represents important cognitive reserve capacity in patients undergoing tumor surgery. Our data also cautions the neurosurgeon when considering supratotal resections of tumors that do not extend into areas considered "non-eloquent" by current standards.

The Survival Benefit of Postoperative Bacterial Infections in Patients With Glioblastoma Multiforme: Myth or Reality?

Glioblastoma multiforme (GBM), the most common malignant brain tumor, universally carries a poor prognosis. Despite aggressive multimodality treatment, the median survival is ~18-20 months, depending on molecular subgroups. A long history of observations suggests antitumor effects of bacterial infections against malignant tumors. The present review summarizes and critically analyzes the clinical data providing evidence for or against the survival benefit of post-operative bacterial infections in GBM patients. Furthermore, we explore the probable underlying mechanism(s) from basic science studies on the topic. There are plausible explanations from immunobiology for the mechanism of the "favorable effect" of bacterial infections in GBM patients. However, available clinical literature does not provide a definitive association between postoperative bacterial infection and prolonged survival in GBM patients. The presently available, single-/multi-center and national database retrospective case-control studies on the topic provide conflicting results. A prospective randomized study on the subject is clearly not possible. Immunobiology literature supports development of genetically modified bacteria as part of multimodal regimen against GBM.

Necessity of brain imaging in COVID-19 infected patients presenting with acute neurological deficits.

BACKGROUND: Patients undergoing cardiopulmonary stabilization in the intensive care unit for novel coronavirus (COVID-19) are often sedated, placing timely assessment of a neurological decline at risk. CASE DESCRIPTION: Here, we present two cases of COVID-19 infected young patients transferred to our facility in a cardio-pulmonary crisis, with a poor neurological exam. While there was significant delay in obtaining brain imaging in the first patient, the second patient had timely recognition of her ischemic infarct, underwent emergent surgery, and is now doing well. CONCLUSIONS: These cases highlight the importance of early head imaging in COVID-19 patients with a poor neurological exam. While lungs remain the primary target of COVID-19, these cases alert the medical community to suspect involvement of the central nervous system, since there may be life-saving surgical interventions available.

5-Aminolevulinic acid fluorescence guided surgery for recurrent high-grade gliomas.

INTRODUCTION: Fluorescence guided surgery (FGS) with five-aminolevulinic acid (5-ALA) is expected to revolutionize neurosurgical care of patients with high-grade gliomas (HGG). After the recent landmark FDA approval, this optical agent is now available to neurosurgeons in the United States. METHODS: This review is designed to highlight the evidence for the use of 5-ALA in recurrent HGG surgery for the neurosurgical community. The manuscript was prepared in accordance with the PRISMA guidelines. RESULTS: Intra-operatively, a strong fluorescent signal is highly correlated with the presence of cellular tumor in recurrent HGG, giving it a high positive predictive value (PPV). Similar to what is observed in primary HGG surgery, false-negative results can occur if tumor cells do not emit fluorescence. In addition, false-positive fluorescence signals in tissues devoid of tumor cells can be observed more frequently in recurrent HGG compared to the primary setting. However, these areas overwhelmingly contain reactive/regressive tissue, resection of which is unlikely to cause functional deficits. The safety profile of 5-ALA is similarly favorable in primary and recurrent HGG. CONCLUSIONS: 5-ALA FGS is a powerful adjunct in the resection of recurrent HGG with a high PPV and favorable safety profile. It is therefore the authors' opinion to routinely employ this fluorescent agent as a standard of care.

Surgical Decompression of High-Grade Spinal Cord Compression from Hormone Refractory Metastatic Prostate Cancer.

BACKGROUND: Spine and nonspine skeletal metastases occur in more than 80% of patients with prostate cancer. OBJECTIVE: To examine the characteristics of the patient population undergoing surgery for the treatment of prostate cancer metastatic to the spine. METHODS: A retrospective chart review was performed on all patients treated at our institution from June 1993 to August 2014 for surgical management of metastatic spine disease from prostate cancer. RESULTS: During the study period, 139 patients with 157 surgical lesions underwent surgery for metastatic spine disease. Decompression for high-grade epidural spinal cord compression was required for 126 patients with 143 lesions. Preoperatively, 69% had a motor deficit and 21% were nonambulatory, with 32% due to motor weakness. At surgery, 87% of patients had hormone-refractory prostate cancer (HRPC) and 61% failed prior radiation. Median overall survival for HRPC patients was 6.6 mo (95% confidence interval [CI]: 5.6-8.6) while the median overall survival for hormone-sensitive patients was 16.3 mo (95% CI: 4.0-26.6). CONCLUSION: The majority of patients undergoing surgery for prostate cancer metastases to the spine were refractory to hormone therapy, indicating that patients with hormone-sensitive prostate cancer are unlikely to develop symptomatic spinal cord compression or spinal instability. A significant number of HRPC patients presented with neurological deficits attributable to spinal cord compression. Vigilant monitoring for the development of signs and symptoms of epidural spinal cord compression and spinal instability in hormone-refractory patients is recommended. Surgical decision making may be affected by the much shorter postoperative survival for HRPC patients as compared to patients with hormone-sensitive cancer.

Microsurgical Vascular Manipulation in Aneurysm Surgery and Delayed Ischemic Injury.

BACKGROUND: The role of aggressive surgical manipulation with clot evacuation, arachnoid dissection, and papaverine-guided adventitial dissection of large vessels during ruptured aneurysm surgery in reducing vasospasm is controversial. Here we describe a single-institution experience in aneurysm surgery outcomes with and without aggressive surgery. METHODS: We performed retrospective analysis of all patients >18 years of age with subarachnoid hemorrhage (SAH) from anterior circulation aneurysms between 2008 and 2013 at the University of New Mexico Hospital. Vasospasm was characterized on days 3 through 14 after SAH based on: (1) angiography, (2) vasospasm requiring angiographic intervention, (3) development of delayed ischemic neurologic deficit (DIND), and (4) radiological appearance of new strokes. RESULTS: Of 159 patients, 114 (71.6%) had "aggressive" and 45 (28.3%) had standard microsurgery. More than 60% of patients presented with a Hunt and Hess score of ≥3 and a Fisher grade (FG) of 4. Compared with standard surgery, there was a statistically significant decrease in the incidence of DIND in patients undergoing aggressive surgery (18.4% vs 37.8%, p=0.01). Moreover, there was a reduction in the number of new strokes by 30% in the aggressive surgery group with moderate or higher degrees of vasospasm (46.0% vs 76.5%, p=0.06). In the same group with FG 4 SAH, however, this difference was more than 50% (30% vs 64.7%, p=0.02). CONCLUSIONS: We conclude that aggressive surgical manipulation during aneurysm surgery results in lower incidence of DIND and new strokes. This effect is most pronounced in patients with FG 4 SAH.

Three-dimensional volumetric measurements in defining endoscope-guided giant adenoma surgery outcomes.

PURPOSE: Maximum two-dimensional (2D) diameter has been used to define giant pituitary adenoma (GPA) surgery outcomes as has volume using an ellipsoid approximation of volumetrics. Cross sectional length can be measured in several different planes. We sought to compare the accuracy of different 2D cross sectional measurements with the 3D volumetric measurements for predicting GPA surgery outcomes. METHODS: Retrospective analysis was performed on a prospectively collected database. Tumors with >3 cm diameter were identified and classified based on maximal cross sectional measurements in three separate co-axial planes, i.e. transverse (TV), antero-posterior (AP) and cranio-caudal (CC). Volume was calculated using both MRI-guided volumetrics and an ellipsoid approximation (TV × AP × CC/2). Univariate and multivariate analysis was used to evaluate the relationship between cross sectional and volumetric data and extent of resection (EOR). RESULTS: In 62 subjects, median tumor volume using 3D volumetrics was 13.74 cm(3), which was overestimated by 16 % by the ellipsoid calculation (p = 0.0029), particularly for tumors >20 cm(3). Gross total resection (GTR) was 46.7 % and median EOR was 99.57 %. At 22-month follow-up, visual and anterior pituitary functions were stable (90 %) or improved (87 %). Pre-operative tumor volume >10 cm(3) (p = 0.02) and Knosp grade 3-4 (p = 0.04) were independent predictors of EOR. Knosp grade 3-4 (p < 0.0001), TV measurement >4 cm (p = 0.007) and maximum cross sectional length >4 cm (p = 0.04) were predictors of not achieving GTR. Only TV measurement (p = 0.02) predicted permanent diabetes insipidis. The smallest significant thresholds for predicting decreased GTR were TV measurement >25 mm, AP measurement >35 mm and volume >19 cm(3). CONCLUSION: We propose a new volumetric threshold of 20 cm(3) as most accurate for predicting GTR in the EEA era. CC measurement is the least useful predictor. Cavernous sinus invasion remains the best predictor of incomplete resection.

Enhancement of neurogenesis and memory by a neurotrophic peptide in mild to moderate traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a risk factor for Alzheimer disease (AD), a neurocognitive disorder with similar cellular abnormalities. We recently discovered a small molecule (Peptide 6) corresponding to an active region of human ciliary neurotrophic factor, with neurogenic and neurotrophic properties in mouse models of AD and Down syndrome. OBJECTIVE: To describe hippocampal abnormalities in a mouse model of mild to moderate TBI and their reversal by Peptide 6. METHODS: TBI was induced in adult C57Bl6 mice using controlled cortical impact with 1.5 mm of cortical penetration. The animals were treated with 50 nmol/d of Peptide 6 or saline solution for 30 days. Dentate gyrus neurogenesis, dendritic and synaptic density, and AD biomarkers were quantitatively analyzed, and behavioral tests were performed. RESULTS: Ipsilateral neuronal loss in CA1 and the parietal cortex and increase in Alzheimer-type hyperphosphorylated tau and A-ß were seen in TBI mice. Compared with saline solution, Peptide 6 treatment increased the number of newborn neurons, but not uncommitted progenitor cells, in dentate gyrus by 80%. Peptide 6 treatment also reversed TBI-induced dendritic and synaptic density loss while increasing activity in tri-synaptic hippocampal circuitry, ultimately leading to improvement in memory recall on behavioral testing. CONCLUSION: Long-term treatment with Peptide 6 enhances the pool of newborn neurons in the dentate gyrus, prevents neuronal loss in CA1 and parietal cortex, preserves the dendritic and synaptic architecture in the hippocampus, and improves performance on a hippocampus-dependent memory task in TBI mice. These findings necessitate further inquiry into the therapeutic potential of small molecules based on neurotrophic factors.

Cranial radiation exposure during cerebral catheter angiography.

BACKGROUND: Radiation exposure to patients and personnel remains a major concern in the practice of interventional radiology, with minimal literature available on exposure to the forehead and cranium. OBJECTIVE: In this study, we measured cranial radiation exposure to the patient, operating interventional neuroradiologist, and circulating nurse during neuroangiographic procedures. We also report the effectiveness of wearing a 0.5 mm lead equivalent cap as protection against radiation scatter. DESIGN: 24 consecutive adult interventional neuroradiology procedures (six interventional, 18 diagnostic) were prospectively studied for cranial radiation exposures in the patient and personnel. Data were collected using electronic detectors and thermoluminescent dosimeters. RESULTS: Mean fluoroscopy time for diagnostic and interventional procedures was 8.48 (SD 2.79) min and 26.80 (SD 6.57) min, respectively. Mean radiation exposure to the operator's head was 0.08 mSv, as measured on the outside of the 0.5 mm lead equivalent protective headgear. This amounts to around 150 mSv/year, far exceeding the current deterministic threshold for the lens of the eye (ie, 20 mSv/year) in high volume centers performing up to five procedures a day. When compared with doses measured on the inside of the protective skullcap, there was a statistically significant reduction in the amount of radiation received by the operator's skull. CONCLUSIONS: Our study suggests that a modern neurointerventional suite is safe when equipped with proper protective shields and personal gear. However, cranial exposure is not completely eliminated with existing protective devices and the addition of a protective skullcap eliminates this exposure to both the operator and support staff.

Lack of functional patency of the lamina terminalis after fenestration following clipping of anterior circulation aneurysms.

OBJECT: Fenestration of the lamina terminalis (FLT) during aneurysm surgery for subarachnoid hemorrhage can, in theory, improve CSF circulation from the lateral and third ventricles to the cortical subarachnoid space, which may, in turn, decrease the incidence of hydrocephalus and vasospasm. However, the actual effects of FLT on CSF circulation have been difficult to determine, due to confounding factors. In addition, it is unclear whether the lamina terminalis remains functionally patent when the brain resumes its normal position. The goal of this study was to assess the functional patency of the fenestrated lamina terminalis in patients who underwent surgery for ruptured aneurysms. METHODS: This prospective study included 15 patients who underwent surgical clipping of ruptured anterior circulation aneurysms, with FLT performed during surgery. On postoperative Day 1, the external ventricular drain of each patient was closed, and 1 ml of Omnipaque 300, an iodine based contrast agent, was injected intraventricularly, accompanied by cranial maneuvering designed to position the contrast agent adjacent to the lamina terminalis. Three to 5 minutes after cranial maneuvering, the flow of contrast agent into the basal cisterns was assessed with CT imaging. Flow was verified by an increase in Hounsfield units in a prespecified "region of interest" within the basal cisterns on the CT scan. This procedure was performed using a standardized protocol designed in consultation with the Department of Radiology and approved by the institutional review board. One patient who underwent endoscopic third ventriculostomy was recruited as a positive control to validate the technique, and 1 patient who underwent aneurysm clipping but not FLT was recruited as a negative control. RESULTS: Seventeen patients consented to study participation. In the 15 patients who underwent aneurysm clipping and FLT, and the negative control patient who underwent aneurysm clipping but not FLT, the contrast agent followed the normal ventricular pathway from the lateral ventricles into the fourth ventricle, and did not appear in the basal cisterns. In the positive control patient, the contrast agent robustly and immediately filled the basal cisterns. CONCLUSIONS: Fenestration of the lamina terminalis did not result in functional patency of the lamina terminalis when performed as part of surgical clipping for ruptured aneurysms.

16 month-old female with intraventricular mass.

Pediatric meningiomas are rare and account for about 1.5% of all intracranial tumors. When compared to adults, intraventricular location of childhood meningiomas is four to ten times as high. Atypical pathology of these lesions is very uncommon and indicates an aggressive nature. They are usually associated with Neurofibromatosis 2 (NF2) or previous cranial irradiation. Here, we present an interesting case of an unusually large, congenital intraventricular meningioma of atypical pathology in a 16 month old child with subsequently diagnosed NF2. A brief review of literature is also presented with this case illustration.

Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide.

Pharmacological enhancement of hippocampal neurogenesis is a therapeutic approach for improvement of cognition in learning and memory disorders such as Alzheimer's disease. Here we report the development of an 11-mer peptide that we designed based on a biologically active region of the ciliary neurotrophic factor. This peptide, Peptide 6, induced proliferation and increased survival and maturation of neural progenitor cells into neurons in the dentate gyrus of normal adult C57BL6 mice. Furthermore, Peptide 6 increased the MAP2 and synaptophysin immunoreactivity in the dentate gyrus. Thirty-day treatment of the mice with a slow release bolus of the peptide implanted subcutaneously improved reference memory of the mice in Morris water maze. Peptide 6 has a plasma half life of over 6 h, is blood-brain barrier permeable, and acts by competitively inhibiting the leukemia inhibitory factor signaling. The fact that Peptide 6 is both neurogenic and neurotrophic and that this peptide is effective when given peripherally, demonstrates its potential for prevention and treatment of learning and memory disorders.

Metastatic epithelioid trophoblastic tumor involving the spine.

STUDY DESIGN: This is a single case-based report. OBJECTIVE: We report the first case of epithelioid trophoblastic tumor (ETT) presenting as primary metastasis to the spine. SUMMARY OF BACKGROUND DATA: ETT is an extremely rare form of gestational trophoblastic neoplasm with less than 100 cases reported in the literature. A 36-year-old, postpartum woman presented with severe low back pain and was found to have a contrast-enhancing lesion in lower thoracic spine subsequently confirmed as ETT. METHODS: The patient data, history, clinical examination findings, laboratory, and histopathology data and imaging studies were retrospectively reviewed and findings reported. A literature search using Pubmed and Cochrane database was conducted. RESULT: We described the first case of an ETT to present as a primary metastasis to the spine. CONCLUSION: This first report of metastasis of ETT to the spine adds significant new information to the growing literature of this rare and newly identified tumor. It also alerts the neurosurgeon into considering the diagnosis with appropriate clinical presentation. As more number of cases of nervous system involvement with this tumor are reported, crucial information on prognostic factors and treatment regimens will emerge.

Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice.

Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGLAG-NH2, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome.

Two groups of tau, 3R- and 4R-tau, are generated by alternative splicing of tau exon 10. Normal adult human brain expresses equal levels of them. Disruption of the physiological balance is a common feature of several tauopathies. Very early in their life, individuals with Down syndrome (DS) develop Alzheimer-type tau pathology, the molecular basis for which is not fully understood. Here, we demonstrate that Dyrk1A, a kinase encoded by a gene in the DS critical region, phosphorylates alternative splicing factor (ASF) at Ser-227, Ser-234, and Ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration. Imbalance of 3R- and 4R-tau in DS brain by Dyrk1A-induced dysregulation of alternative splicing factor-mediated alternative splicing of tau exon 10 represents a novel mechanism of neurofibrillary degeneration and may help explain early onset tauopathy in individuals with DS.

Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau.

Hyperphosphorylated tau has long been proposed as the key molecule disrupting normal neuronal microtubule dynamics and leading to neurofibrillary degeneration in Alzheimer disease. Here we provide a direct evidence of hyperphosphorylated tau-induced disruption of microtubule network. Using Nocodozole-treated and detergent-extracted cells, we created a neuronal environment in mouse embryonic fibroblasts, 3T3 cells, by replacing their cytoplasm with adult rat brain cytosol. By recreating neuronal microtubule network in these cells, we were able to follow the effects of hyperphosphorylated tau on microtubule dynamics in real time. Whereas recombinant human brain tau promoted assembly and bundling of microtubules, abnormally hyperphosphorylated tau isolated from Alzheimer disease brain cytosol (AD P-tau) inhibited the assembly and disrupted preformed microtubule network by sequestering normal brain tau and MAP2. This breakdown of the microtubule network was reversed by treatment of the extracted cells with protein phosphatase-2A. This study, for the first time, provides direct mechanistic insights into the molecular basis of both axonal and dendritic neurodegeneration seen in Alzheimer disease.

Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by Memantine.

The activity of protein phosphatase (PP)-2A, which regulates tau phosphorylation, is compromised in Alzheimer disease brain. Here we show that the transient transfection of PC12 cells with inhibitor-2 (I2PP2A) of PP2A causes abnormal hyperphosphorylation of tau at Ser396/Ser404 and Ser262/Ser356. This hyperphosphorylation of tau is observed only when a sub-cellular shift of I2PP2A takes place from the nucleus to the cytoplasm and is accompanied by cleavage of I2PP2A into a 20 kDa fragment. Memantine, an un-competitive inhibitor of N-methyl-D-aspartate receptors, inhibits this abnormal phosphorylation of tau and cell death and prevents the I2PP2A-induced inhibition of PP2A activity in vitro. These findings demonstrate novel mechanisms by which I2PP2A regulates the intracellular activity of PP2A and phosphorylation of tau, and by which Memantine modulates PP2A signaling and inhibits neurofibrillary degeneration.