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Study Design: A retrospective cohort study.Objective: We performed a retrospective study of patients treated at our institution over the last 7 years to ascertain whether gene expression signatures in patients with advanced metastatic disease are associated with survival, when the disease has progressed to the spine.Summary Of Background Data: Spinal metastases are a major cause of morbidity in patients with cancer. Molecular profiling strategies to characterize lung cancer have identified several genetic biomarkers that may lead to more effective prognostication.Methods: We queried our institutional database for patients with metastatic lung cancer who underwent treatment for spinal metastases between 2011 and 2017. Genetic mutations in ALK, MET, ROS1, EGFR, and KRAS were chosen a priori for study based on availability by standard SNaPshot Lung Tumor Genotyping Analysis. Survival time was the duration between treatment for spinal metastases and death. Kaplan-Meier methods and the log-rank test were applied to characterize survival data.Results: Twenty-six patients met criteria for inclusion. Median survival after surgery was 0.67 years. Median overall survival (OS) after diagnosis was 2.7 years. The presence of molecular abnormalities in patients with spinal metastases was significantly associated with increased OS (HR 0.38, 95% CI 0.12-1.22, P = 0.03).Conclusion: Molecular phenotyping may provide prognostic insight in patients undergoing surgery for spinal metastases. This is the first study to demonstrate an association between genetic mutational data and OS in this patient population. It also represents the largest published series of such patients (n = 26) for which genetic mutational data are reported. Future models estimating survival for patients with spinal metastases may be enhanced by incorporation of molecular criteria.Level Of Evidence: 4. [ABSTRACT FROM AUTHOR]

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX- 1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting. [ABSTRACT FROM AUTHOR]

Study Design: A retrospective cohort study.Objective: We performed a retrospective study of patients treated at our institution over the last 3 years to assess predictive value of immunotherapy exposure on overall survival (OS) of patients with metastatic melanoma to the spine in an effort to better inform surgical decision making.Summary Of Background Data: Modern management of metastatic melanoma includes adjuvant targeted therapies and immunomodulators that have shown to significantly improve OS.Methods: Baseline characteristics were recorded for patients, including performance scores, use of adjuvant therapies, progression-free survival (PFS), and OS. Pre-procedural imaging was reviewed to assign Spinal Instability Neoplastic Score (SINS) and epidural spinal cord compression (ESCC) classification. Kaplan-Meier survival analysis was performed.Results: We identified 18 patients with metastatic melanoma to the spine treated between 2012 and 2015. Instrumented fixation was performed for median SINS 12. Eleven patients undergoing surgery were noted to have ESCC classification of at least 2. Median OS for the entire group was 117 days. Univariate analysis revealed that prior immunotherapy treatment was associated with significantly shorter survival following surgery (median survival 98 vs. 315 days for patients previously on immunotherapies compared to those who were not). Meanwhile, neither BRAF mutation status nor treatments targeting these pathways were associated with this prognostic effect.Conclusion: Progressive metastatic spine disease following immunotherapy may herald a particularly aggressive time point and recognizing this natural history is critical for appropriate multimodal planning.Level Of Evidence: 4. [ABSTRACT FROM AUTHOR]

We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patient's blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment. [ABSTRACT FROM AUTHOR]

Abstract: The amyloid β-protein (Aβ) is believed to play a causal role in Alzheimer''s disease, however, the mechanism by which Aβ mediates its effect and the assembly form(s) of Aβ responsible remain unclear. Several APP transgenic mice have been shown to accumulate Aβ and to develop cognitive deficits. We have studied one such model, the J20 mouse. Using an immunoprecipitation/Western blotting technique we find an age-dependent increase in Aβ monomer and SDS-stable dimer. But prior to the earliest detection of Aβ dimers, immunohistochemical analysis revealed an increase in oligomer immunoreactivity that was coincident with reduced hippocampal MAP2 and synaptophysin staining. Moreover, biochemical fractionation and ELISA analysis revealed evidence of TBS and triton-insoluble sedimentable Aβ aggregates at the earliest ages studied. These data demonstrate the presence of multiple assembly forms of Aβ throughout the life of J20 mice and highlight the difficulty in attributing synaptotoxicity to a single Aβ species. [Copyright &y& Elsevier]

Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-β protein (Aβ) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Aβ from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Aβ dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Aβ N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Aβ dimers, suggesting that plaque cores are largely inactive but sequester Aβ dimers that are synaptotoxic. We conclude that soluble Aβ oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by decreased synapse density in hippocampus and neocortex, and synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-β protein (Aβ) in AD, a direct link between a specific form of Aβ and synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Aβ dimers and trimers, but not monomers, induce progressive loss of hippocampal synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Aβ-specific antibodies or a small-molecule modulator of Aβ aggregation. Mechanistically, Aβ-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Aβ oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low-n oligomers of human Aβ trigger synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Aβ-induced neuronal dysfunction. [ABSTRACT FROM AUTHOR]

The accumulation of amyloid β-protein (Aβ) in brain regions serving memory and cognition is a central pathogenic feature of Alzheimer's disease (AD). We have shown that small soluble oligomers of human Aβ that are naturally secreted by cultured cells inhibit hippocampal long-term potentiation (LTP) in vitro and in vivo and transiently impair the recall of a complex learned behaviour in rats. These results support the hypothesis that diffusible oligomers of Aβ initiate a synaptic dysfunction that may be an early event in AD. We now report detailed electrophysiological analyses that define conditions under which acute application of soluble Aβ inhibits hippocampal synaptic plasticity in wild-type mice. To ascertain which Aβ assemblies contribute to the impairment of LTP, we fractionated oligomers by size-exclusion chromatography and found that Aβ trimers fully inhibit LTP, whereas dimers and tetramers have an intermediate potency. Natural Aβ oligomers are sensitive to heat denaturation, primarily inhibit the induction phase of LTP, and cause a sustained impairment of LTP even after extensive washout. We observed no effects of Aβ oligomers on presynaptic vesicle release. LTP in juvenile mice is resistant to the effects of Aβ oligomers, as is brain-derived-neurotrophic-factor-induced LTP in adult hippocampus. We conclude that specific assemblies, particularly timers, of naturally secreted Aβ oligomers are potent and selective inhibitors of certain forms of hippocampal LTP. [ABSTRACT FROM AUTHOR]

BACKGROUND CONTEXT Pedicle screw fixation can be a major challenge in patients with spinal metastases. The osteopenic nature of the vertebrae along with factors like previous radiation, immunosuppression, and marrow replacement by cancer affect the bone quality for fixation. Complications related to cement augmentation are known. We share our initial experience with the fenestrated screws. PURPOSE To demonstrate the efficacy and safety of this new screw technology in challenged fixation environements, specifically vertebral column metastases. STUDY DESIGN/SETTING Retropsective analysis from a prospective spine oncology database at a major cancer center. PATIENT SAMPLE We identified 38 consecutive patients who underwent posterior thoracic, lumbar, or sacral decompression and stabilization for pathologic fracture or cord compression (T1-sacrum) related to metastatic cancer over a 1 year period. OUTCOME MEASURES Preoperative SINS (spine instability neoplastic score), ASIA grade, cancer histology, radiation history, ECOG, and patient demographics were recorded and analyzed in a multivariable regression analysis. Postoperative CT was performed in all cases. CT was reviewed and cement extravasation was recorded at each level of pedicle screw placement in (1) the epidural space, (2) neural foramen, (3) paravertebral space, (4) lung, and (5) nearby vasculature including the segmental vessels and aorta. Complications and instrumentation or implant failure were recorded. Patient reported outcomes measures were recorded prospectively including EQ-5D, PROMIS-pain, PROMIS-disability, PROMIS-depression, Spine Oncology Study Group Questionnaire. METHODS IRB approval was obtained and a retrospective analysis was performed on a prospective spine oncology outcomes database. Fenestrated screws became available at our institution in November 2016. We identified 38 consecutive patients who underwent posterior thoracic, lumbar, or sacral decompression and stabilization for pathologic fracture or cord compression (T1-sacrum). In each case, postoperative CT imaging was performed within 24 hours of surgery. The investigators independently reviewed the studies evaluating for the extent of cement fill and extravasation. Chart review was performed for analysis of implant or construct failure and complications. RESULTS Thirty eight patients were identified and a total of 292 fenestrated screws were placed with an mean 7.21 screws implanted percase. The most common construct was two levels above and two levels below the site of worst vertebral fracture or cord compression. Cement extravasated into the (1) epidural space at six levels (2.97%), (2) neural foramen at three levels (1.49%), (3) paravertebral space at 37 levels (18.3%), (4) lung – 0, (5) nearby vasculature at 15 levels (7.42%). There was no cement spread to the aorta or vena cava. No patients developed a symptomatic radiculopathy from foraminal extent. No patient required reexploration, cement removal, or hardware revision. Follow-up ranged from 1 month to 15 months with no significant change invertebral body height at the instrumented levels by CT and x-ray. CONCLUSIONS Fenestrated screws with cement provide a safe and effective method for stabilization in the cancer patient. [ABSTRACT FROM AUTHOR]

BACKGROUND CONTEXT Spinal metastases are a major cause of morbidity in patients with cancer. Molecular profiling strategies to characterize lung cancer have identified several genetic biomarkers that may lead to more effective prognostication. PURPOSE The aim of this study was to ascertain whether gene expression signatures in patients with advanced metastatic disease are associated with survival, when the disease has progressed to the spine. PATIENT SAMPLE We identified every consecutive patient at our institution with metastatic lung cancer who underwent surgery for spinal metastases from 2011 to 2017. Inclusion criteria were the availability of genetic mutational data through chart review, and the existence of any known metastatic lesion in the body and spine at the time of presentation. OUTCOME MEASURES Median overall survival (OS) was recorded following both diagnosis and surgical treatment. METHODS Genetic mutations in ALK, MET, ROS1, EGFR, and KRAS were chosen a priori for study based on availability by standard SNaPshot Lung Tumor Genotyping Analysis. Survival time was the duration between treatment for spinal metastases and death. Kaplan-Meier methods and the log-rank test were applied to characterize survival data. RESULTS Twenty-six patients met criteria for inclusion. Median survival following surgery was 0.67 years. Median overall survival (OS) following diagnosis was 2.7 years. The presence of molecular abnormalities in patients with spinal metastases was significantly associated with increased OS(HR 0.38, 95% CI 0.12-1.22, P=.03). CONCLUSIONS Molecular phenotyping may provide prognostic insight in patients undergoing surgery for spinal metastases. This is the first study to demonstrate an association between genetic mutational data and OS in this patient population. It also represents the largest published series of such patients (n=26) for which genetic mutational data are reported. Future models estimating survival for patients with spinal metastases may be enhanced by incorporation of molecular criteria. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

BACKGROUND CONTEXT The decision for surgical intervention of metastatic lesions of the spine integrates the etiology of pain and neurologic deficits, oncologic history, mechanical instability and systemic disease status. For instance, given the lack of sensitivity to radiation therapy, patients with symptomatic metastatic renal cell cancer (RCC) to the spine are treated with surgical decompression, radiosurgery and medical adjuvant therapies. Modern medical management of metastatic RCC includes therapies targeting growth pathways (PDGFR, mTOR), angiogenesis, and immunotherapy. PURPOSE We hypothesized that patients with spinal RCC metastases would continue to benefit from postoperative initiation of these therapeutics despite presenting with advanced stages of disease. STUDY DESIGN/SETTING Retrospective cohort study. PATIENT SAMPLE We included patients with metastatic renal cell carcinoma involving the spine treated with surgery between 2010 and 2017. The study was approved by the IRB at Massachusetts General Hospital. OUTCOME MEASURES Baseline characteristics were recorded for patients, including ASIA and performance scores, Fuhrman grade, adjuvant therapies, progression free (PFS) and overall survival (OS) following the respective procedures. Preprocedural imaging was reviewed to assign spinal instability neoplastic score (SINS) and epidural spinal cord compression (ESCC) classification. METHODS Kaplan-Meier survival analysis was performed using R statistical software. RESULTS We identified 32 patients with metastatic RCC to the spine treated at MGH between 2010 and 2017 by surgical resection with 72% also receiving postoperative radiosurgery. Instrumented stabilization was performed in 81% of patients for ESCC 2-3 and median preoperative SINS 12. Preoperative embolization was performed in 62% of patients with lower intraoperative blood loss (500±310cc vs. 1000±510cc). Increased progression free (160±91 days vs. 112±50days) and overall survival (913±317 days vs. 466±255 days) following surgery was noted in patients who received postoperative targeted therapies, including inhibitors of PDGFR (100%), VEGF (50%), mTOR (33%) and PD-L1 (11%) initiated at a median of 63 days (28-1254 days) postoperatively. All patients noted postoperative improvement in pain and neurologic function. Postoperative complications included one wound infection and one pulmonary embolus requiring anticoagulation. CONCLUSIONS Postoperative outcomes for metastatic RCC without targeted therapies in this cohort are similar to those reported in earlier series prior to the adoption of these adjuvants. However, we observe a significant increase in survival when modern targeted therapies are administered postoperatively. This has implications on optimizing postoperative multimodal management and also the preoperative evaluation of patients with systemic disease who may have previously been deemed poor surgical candidates. Future analyses of the molecular alterations in metastatic RCC of the spine may further resolve the natural history and predicted treatment response. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

Papillary meningioma (PM) is a World Health Organization (WHO) grade III tumor defined histologically by a perivascular pseudopapillary growth pattern across most of the tumor (> 50%) [[10]]. Our findings suggest that I BAP1 i mutations tend to occur in rhabdoid meningiomas whereas I PBRM1 i mutations tend to occur in papillary meningiomas, although genetic and histologic overlap is noted. Although our findings suggest that I PBRM1 i mutation is uncommon in meningioma, the inclusion of patients with this defined genetic subtype of meningioma in similar trials may reveal new therapeutic approaches. In conclusion, we identify the tumor suppressor gene I PBRM1 i as a recurrently altered gene in meningiomas with papillary histomorphology. [Extracted from the article]

Interbody spacers have been successfully used in spinal fusion procedures with the aim to restore disc height, provide stability, and promote bone fusion. The authors evaluated the efficacy of structural body allograft versus polyetheretherketone (PEEK) implants in patients undergoing spinal fusion surgery. A systematic review of electronic databases was conducted using different Medical Subject Headings terms from January 1970 to August 2019. Pooled and subgroup analyses were performed using random-effects and fixed-effects models based on I 2 heterogeneity. The analysis included 6640 patients (structural allograft 64% and PEEK cage 36%) from 7 comparative studies. There were no statistically significant differences in age (P = 0.27), sex (P = 0.31), body mass index (P = 0.82), and smoking status (P = 0.27) between the 2 groups. Overall, the mean follow-up was 12.9 ± 1.5 months. Pooled meta-analysis revealed that patients with structural allograft had 2.59-fold higher likelihood of fusion compared with patients with PEEK cages (odds ratio [OR] 2.59, 95% confidence interval [CI] 1.02–6.57, P = 0.05) at last follow-up evaluation. Patients with structural allograft had 61% less likelihood of pseudarthrosis (OR 0.39, 95% CI 0.15–0.98, P = 0.05) and 74% lower incidence of reoperation compared with patients with PEEK implants (OR 0.26, 95% CI 0.09–0.79, P = 0.02). Our results suggest that patients with structural allografts had a higher subsidence rate compared with patients with PEEK implants, but this was statistically insignificant (OR 1.07, 95% CI 0.45–2.53, P = 0.89). Our results corroborate that structural allografts are highly effective in promoting bony fusion compared with PEEK implants in patients undergoing spinal fusion surgery. [ABSTRACT FROM AUTHOR]

Group patients who required open surgery for metastatic breast cancer to the spine by functional level and metastatic disease characteristics to identify factors that predispose to poor outcomes. A retrospective analysis included patients managed at 2 tertiary referral centers from 2008 to 2020. The primary outcome was a 90-day adverse event. A 2-step unsupervised cluster analysis stratified patients into cohorts using function at presentation, preoperative spine radiation, structural instability, epidural spinal cord compression (ESCC), neural deficits, and tumor location/hormone status. Comparisons were performed using χ2 test and one-way analysis of variance. Five patient "clusters" were identified. High function (HIGH) had thoracic metastases and an Eastern Cooperative Oncology Group (ECOG) score of 1.0 ± 0.8. Low function/irradiated (LOW + RADS) had preoperative radiation and the lowest Karnofsky scores (56.0 ± 10.6). Estrogen receptor or progesterone receptor (ER/PR) positive patients had >90% estrogen/progesterone positivity and moderate Karnofsky scores (74.0 ± 11.5). Lumbar/noncompressive (NON-COMP) had the fewest patients with ESCC grade 2 or 3 epidural disease (42.1%, P < 0.001). Low function/neurologic deficits (LOW + NEURO) had ESCC grade 2 or 3 disease and neurologic deficits. Adverse event rates were 25.0% in the HIGH group, 73.3% in LOW + RADS, 24.0% in ER/PR, 31.6% in NON-COMP, and 60.0% in LOW + NEURO (P = 0.003). Function at presentation, tumor hormone signature, radiation history, and epidural compression delineated postoperative trajectory. We believe our results can aid in expectation management and the identification of at-risk patients who may merit closer surveillance following surgical intervention. [ABSTRACT FROM AUTHOR]

Low fusion rates and cage subsidence have been reported as the main drawbacks of lumbar fixation with static interbody cages. Although several clinical and biomechanical studies have evaluated the efficacy of 360 interbody fixation constructs (anterior cage plus posterior fixation), no study has reported the biomechanical comparison between such constructs and more novel techniques which use standalone fixation implants. A cadaver validated computational model of lumbar spine was used to compare the biomechanics of spine instrumented with 360 fixations vs standalone cage and screw and cage with lateral plate systems. To compare the mechanical stability of different interbody fixation techniques in lumbar spinal segments with standalone interbody vs static cage with posterior fixation or lateral plate system. Finite element modeling. Range of motion across instrument segments and load sharing on vertebral endplate. An experimentally validated finite element (FE) model of L1-pelvic segment was used to simulate ALIF and LIF lumbar fixation techniques including: ALIF cage at L5-S1 plus posterior screw-rod fixation (360 construct) vs ALIF standalone (screw through the cage). LIF cage at L4-L5 vs LIF cage with integrated two-hole lateral plate system. 4WEB Medical's Truss ALIF (27mm x 25mm), Lateral Truss (22mm X 5mm) cages and 2-hole integrated plate systems were used for simulation of the surgical procedure. For 360 constructs, a generic posterior rod and screw system was used. All models were subjected to a 400N compressive pre-load followed by an 8Nm moment to simulation flexion-extension, left and right bending and axial rotation motions. The segmental kinematics and the load sharing at the inferior endplate were compared among cases. The segmental motion in standalone ALIF construct was 1.1°(Flex-Ext), 0.9° (LB) and 0.4° vs 0.8°, 0.8° and 0.6° in 360 ALIF in the same planes of motion. When comparing lateral cases, the motions were 1.2° (Flex-Ext), 1.4° (LB) and 0.5° (AR) in lateral cage with plate vs 0.9°, 1.0° and 0.8° in the 360 lateral construct for the same loads. The peak stresses in extension for the LIF stand-alone cage were somewhat higher than the posterior instrumented cases, but not significant. When comparing the mechanical stress on the inferior endplate of the index segment, the standalone ALIF had almost 20% higher peak stress compared to the 360 ALIF. In the lateral construct, the cage-plate segment experienced 15% lower stresses on the endplate compared to the 360 lateral construct. Our data suggest that standalone ALIF cage with screw through the cage is able to provide kinematic stability in the fixation construct comparable to the cage plus posterior fixation, although the 360 construct is able to provide slightly more stability in the sagittal plane. Also, the standalone cage results in higher stresses applied to the endplate compared the cage in 360 constructs. The lateral cage with integrated plate had superior stability in axial rotation compared to the 360 lateral construct. The loads on the endplate were also slightly lower compared to the 360-fixation case. Standalone ALIF and LIF with lateral plate are biomechanically effecient alternatives to 360-fixation constructs at least under the controlled conditions analyzed in the present study. Clinical data are required to support the findings and define the further role and application of standalone cages. 4WEB ALIF Truss System (Approved for this indication), 4WEB Lateral Plate System (Approved for this indication), 4WEB Lateral Truss System (Approved for this indication) [ABSTRACT FROM AUTHOR]

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer's disease (AD) has led to advanced human trials of Aβ-lowering agents. The "amyloid hypothesis" of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site. [ABSTRACT FROM AUTHOR]

Combining our data with these prior reports, focusing on WHO grade 1 meningiomas only, Clark et al. found I TRAF7 i co-mutations in 50/68 I AKT1 i -mutant intracranial meningiomas (15 were I AKT1 i "isolated", and 3 were co-mutant for I AKT1/NF2 i ), while we observed only 1 of 15 co-mutant tumors. In contrast to I AKT1 i -mutant intracranial meningiomas, where I TRAF7 i mutations are found to co-occur very frequently [[5]], we observed only a single I AKT1 i -mutant SM case with a I TRAF7 i co-mutation. Subsequently, Sahm et al. screened 1437 tumors for I AKT1 i mutations and found 65 mutant cases, including 6 I AKT1 i -mutant cases in 57 SMs [[10]], and described a strong association between I AKT1 i SP I E17K i sp mutations and spinal tumor localization. [Extracted from the article]

Developing effective treatments for neurodegenerative diseases is one of the greatest medical challenges of the 21st century. Although many of these clinical entities have been recognized for more than a hundred years, it is only during the past twenty years that the molecular events that precipitate disease have begun to be understood. Protein aggregation is a common feature of many neurodegenerative diseases, and it is assumed that the aggregation process plays a central role in pathogenesis. In this process, one molecule (monomer) of a soluble protein interacts with other monomers of the same protein to form dimers, oligomers, and polymers. Conformation changes in three-dimensional structure of the protein, especially the formation of β-strands, often accompany the process. Eventually, as the size of the aggregates increases, they may precipitate as insoluble amyloid fibrils, in which the structure is stabilized by the β-strands interacting within a β-sheet. In this review, we discuss this theme as it relates to the two most common neurodegenerative conditions—Alzheimer's and Parkinson's diseases. [ABSTRACT FROM AUTHOR]

Treatment of osteoporosis with medications like teriparatide, a parathyroid hormone, is known to improve bone density and reduce the risk of osteoporotic vertebral fractures. Anecdotal and limited surgical series have described the utility of this treatment for osteoporotic patients prior to spinal fusion surgery, but there is variability in adoption of this strategy as well as consensus regarding optimal treatment duration before and after surgery. In this study, the clinical results of the use of teriparatide for this application are reviewed and critically examined. We conducted a systematic review of electronic databases using different MeSH terms from 1980 to 2020. Pooled and subgroup analyses were performed using fixed and random effect models based upon the heterogeneity (I2). The results were reported as either mean difference (MD) or odds ratio (OR) with 95% confidence interval (CI). A total of 771 patients from 12 studies were identified. Three hundred seventy-seven patients (90.8% females) were treated with teriparatide. Lumbar spinal fusion rates were significantly higher among patients who received teriparatide compared to the non-teriparatide group (OR 2.15, 95%CI 1.56–2.97, p < 0.00001). Subgroup analysis revealed that patients receiving teriparatide demonstrated 2.12-fold and 2.23-fold higher likelihood of fusion compared to those in the bisphosphonate (OR 2.12, 95%CI 1.45–3.11, p = 0.0001) and placebo (OR 2.23, 95%CI 1.22–4.08, p = 0.009) cohorts, respectively. The treatment effect of teriparatide was associated with significantly reduced subsequent vertebral fractures (OR 0.16, 95%CI 0.06–0.41, p = 0.0002), sagittal malalignment (MD − 3.85, 95%CI: −6.49 to − 1.21, p = 0.004), limb visual analogue score (VAS) (MD − 0.36, 95%CI − 0.64 to − 0.09, p = 0.008), and spinal VAS (MD − 0.24, 95%CI − 0.44 to − 0.04, p = 0.02) compared to the non-teriparatide group. Patients using teriparatide had 30% less likelihood of screw loosening at last follow-up compared to the non-teriparatide group; however, this was not statistically significant (OR 0.70, 95%CI 0.43–1.14, p = 0.15). There did not exist any statistically significant difference between the two comparative groups in terms of pseudoarthrosis (OR 0.54, 95%CI 0.24–1.21, p = 0.13), cage subsidence (OR 1.30, 95%CI 0.38–4.52, p = 0.68), and bone mineral density (MD 0.04, 95%CI − 0.19–0.29, p = 0.74) at last follow-up examination. This meta-analysis corroborates the effectiveness of teriparatide resulting in higher fusion rates. Further study is required to determine the optimal duration of treatment and timing of surgery. [ABSTRACT FROM AUTHOR]

Tumors are complex materials whose physical properties dictate growth and treatment outcomes. Recent evidence suggests time-dependent physical properties, such as viscoelasticity, are crucial, distinct mechanical regulators of cancer progression and malignancy, yet the genesis and consequences of tumor viscoelasticity are poorly understood. Here, using Wide-bandwidth AFM-based ViscoElastic Spectroscopy (WAVES) coupled with mathematical modeling, we probe the origins of tumor viscoelasticity. From single carcinoma cells to increasingly sized carcinoma spheroids to established tumors, we describe a stepwise evolution of dynamic mechanical properties that create a nanorheological signature of established tumors: increased stiffness, decreased rate-dependent stiffening, and reduced energy dissipation. We dissect this evolution of viscoelasticity by scale, and show established tumors use fluid-solid interactions as the dominant mechanism of mechanical energy dissipation as opposed to fluid-independent intrinsic viscoelasticity. Additionally, we demonstrate the energy dissipation mechanism in spheroids and established tumors is negatively correlated with the cellular density, and this relationship strongly depends on an intact actin cytoskeleton. These findings define an emergent and targetable signature of the physical tumor microenvironment, with potential for deeper understanding of tumor pathophysiology and treatment strategies. [ABSTRACT FROM AUTHOR]

Tranexamic acid (TXA) is an effective and commonly used hemostatic agent for perioperative blood loss in various surgical specialties. It is being increasingly used in spinal deformity surgery. We aimed to evaluate the safety and efficacy of topical TXA (tTXA) compared to both placebo and/or intravenous (IV) TXA in patients undergoing spinal deformity surgery. We conducted a systematic review of the electronic databases using different MeSH terms from January 1970 to August 2019. Pooled and subgroup analysis was performed using fixed and random-effect model based upon the heterogeneity (I2). A total of 609 patients (tTXA: n = 258, 42.4%) from 8 studies were included. We found that there was a statistically significant difference in terms of (i) postoperative blood loss [mean difference (MD) − 147.1, 95% CI − 189.5 to − 104.8, p < 0.00001], (ii) postoperative hemoglobin level (MD 1.09, 95% CI 0.45 to 1.72, p = 0.0008), (iii) operative time (MD 7.47, 95% CI 2.94 to 12.00, p < 0.00001), (iv) postoperative transfusion rate [odds ratio (OR) 0.39, 95% CI 0.20 to 0.78, p = 0.007], postoperative drain output (MD, − 184.0, 95% CI − 222.03 to − 146.04, p < 0.00001), and (v) duration of hospital stay (MD − 1.14, 95% CI − 1.44 to − 0.85, p < 0.00001) in patients treated with tTXA compared to the control group. However, there was no significant difference in terms of intraoperative blood loss (p = 0.13) and complications (p = 0.23) between the two comparative groups. Furthermore, low-dose (250–500 mg) tTXA (p < 0.00001) reduced postoperative blood loss more effectively compared to high-dose tTXA (1–3 g) (p = 0.001). Our meta-analysis corroborates the effectiveness and safety of tTXA in spinal deformity surgery. [ABSTRACT FROM AUTHOR]

Background Context: The introduction and integration of robot technology into modern spine surgery provides surgeons with millimeter accuracy for pedicle screw placement. Coupled with computer-based navigation platforms, robot-assisted spine surgery utilizes augmented reality to potentially improve the safety profile of instrumentation.Purpose: In this study, the authors seek to determine the safety and efficacy of robotic-assisted pedicle screw placement compared to conventional free-hand (FH) technique.Study Design/setting: We conducted a systematic review of the electronic databases using different MeSH terms from 1980 to 2020.Outcome Measures: The present study measures pedicle screw accuracy, complication rates, proximal-facet joint violation, intraoperative radiation time, radiation dosage, and length of surgery.Results: A total of 1,525 patients (7,379 pedicle screws) from 19 studies with 777 patients (51.0% with 3,684 pedicle screws) in the robotic-assisted group were included. Perfect pedicle screw accuracy, as categorized by Gerztbein-Robbin Grade A, was significantly superior with robotic-assisted surgery compared to FH-technique (Odds ratio [OR]: 1.68, 95% confidence interval [CI]: 1.20-2.35; p=.003). Similarly, clinically acceptable pedicle screw accuracy (Grade A+B) was significantly higher with robotic-assisted surgery versus FH-technique (OR: 1.54, 95% CI: 1.01-2.37; p=.05). Furthermore, the complication rates and proximal-facet joint violation were 69% (OR: 0.31, 95% CI: 0.20-0.48; p<.00001) and 92% less likely (OR: 0.08, 95% CI: 0.03-0.20; p<.00001) with robotic-assisted surgery versus FH-group. Robotic-assisted pedicle screw implantation significantly reduced intraoperative radiation time (MD: -5.30, 95% CI: -6.83-3.76; p<.00001) and radiation dosage (MD: -3.70, 95% CI: -4.80-2.60; p<.00001) compared to the conventional FH-group. However, the length of surgery was significantly higher with robotic-assisted surgery (MD: 22.70, 95% CI: 6.57-38.83; p=.006) compared to the FH-group.Conclusion: This meta-analysis corroborates the accuracy of robot-assisted pedicle screw placement. [ABSTRACT FROM AUTHOR]

With the increasing prevalence of obesity, there is a need to understand the impact of body mass index (BMI) on spine surgery outcomes. Previous literature has reported the influence of obesity in thoracolumbar surgery; however, the impact of obesity on postoperative complications after posterior cervical fusion (PCF) is unknown. Consecutive patients who underwent cervical laminectomy and multi-level instrumented fusion for degenerative spinal conditions at an academic tertiary care hospital between 2012 and 2019 were evaluated. Patients were categorized into groups with a BMI ≥30.0 kg/m2. The modified Japanese Orthopedic Association (mJOA) score, Nurick grading, complications, and postoperative radiographic factors were analyzed. Correlations between postoperative outcomes and obesity were calculated at baseline and 1 year. A total of 275 patients were included, with 80 obese (29.1%) and 195 nonobese (70.9%) patients. At baseline, obesity was associated with worse myelopathy (mJOA score: 10.2 vs. 13.1, P = 0.04 and Nurick grading: 3.2 vs. 1.1, P = 0.05) and abnormal cervical radiographic alignment (C2-7 sagittal vertical axis: 43.9 vs. 38.1 mm, P = 0.04). The intraoperative estimated blood loss was higher among obese patients (561.1 vs. 391.2 mL, P < 0.001). There was no significant difference in absolute scores for neurologic outcomes and radiographic alignment at 12 months after surgery. However, obese patients had significantly more complications than nonobese patients in terms of mechanical failure (6.3% vs. 0.5%, P = 0.05) and wound infection (8.7% vs. 0.0%, P = 0.04). Our results corroborate that PCF surgery provides significant improvement in neurologic and radiographic outcomes at 12 months after surgery for degenerative cervical spinal disorders. Obesity is a factor to consider in the pre-operative risk assessment. [ABSTRACT FROM AUTHOR]

Objective: Conventional techniques for atlantoaxial fixation and fusion typically pass cables or wires underneath C1 lamina to secure the bone graft between the posterior elements of C1-2, which leads to complications such as cerebrospinal fluid (CSF) leak and neurological injury. With the evolution of fixation hardware, we propose a novel C1-2 fixation technique that avoids the morbidity and complications associated with sublaminar cables and wires. Methods: This technique entails wedging and anchoring a structural iliac crest graft between C1 and C2 for interlaminar arthrodesis and securing it using a 0-Prolene suture at the time of C1 lateral mass and C2 pars interarticularis screw fixation. Results: We identified 32 patients who underwent surgery for atlantoaxial with our technique. A 60% improvement in pain-related disability from preoperative baseline was demonstrated by Neck Disability Index (p < 0.001). There were no neurologic deficits. Complications included 2 patients CSF leaks related to presenting trauma, 1 patient with surgical site infection, and 1 patient with transient dysphagia. The rate of radiographic atlantoaxial fusion was 96.8% at 6 months, with no evidence of instrumentation failure, graft dislodgement, or graft related complications. Conclusion: We demonstrate a novel technique for C1-2 arthrodesis that is a safe and effective option for atlantoaxial fusion. [ABSTRACT FROM AUTHOR]

Preoperative prognostication of adverse events (AEs) for patients undergoing surgery for lumbar degenerative spondylolisthesis (LDS) can improve risk stratification and help guide the surgical decision-making process. The aim of this study was to develop and validate a set of predictive variables for 30-day AEs after surgery for LDS. The American College of Surgeons National Surgical Quality Improvement Program was used for this study (2005–2016). Logistic regression (enter, stepwise, and forward) and LASSO (least absolute shrinkage and selection operator) methods were performed to identify and select variables for analyses, which resulted in 26 potential models. The final model was selected based on clinical criteria and numeric results. The overall 30-day rate of AEs for 80,610 patients who underwent surgery for LDS in this database was 4.9% (n = 3965). The median age of the cohort was 58.0 years (range, 18–89 years). The model with the following 10-predictive factors (age, gender, American Society of Anesthesiologists grade, autogenous iliac bone graft, instrumented fusion, levels of surgery, surgical approach, functional status, preoperative serum albumin [g/dL] and serum alkaline phosphatase [IU/L]) performed well on the discrimination, calibration, Brier score, and decision analyses to develop machine learning algorithms. Logistic regression showed higher areas under the curve than did LASSO methods across the different models. The predictive probability derived from the best model is uploaded on an open-access Web application, which can be found at: https://spine.massgeneral.org/drupal/Lumbar-Degenerative-AdverseEvents. It is feasible to develop machine learning algorithms from large datasets to provide useful tools for patient counseling and surgical risk assessment. [ABSTRACT FROM AUTHOR]

Objective: Lumbar fusion with implantation of interbody cage is a common procedure for treatment of lumbar degenerative disease. This study aims to compare the fusion and subsidence rates of titanium (Ti) versus polyetheretherketone (PEEK) interbody cages after posterior lumbar interbody fusion and investigate the effect of clinical and radiological outcomes following fusion on patient-reported outcomes. Methods: A systematic search strategy of 4 electronic databases (MEDLINE, Embase, Web of Science, and Cochrane) was conducted using different MeSH (medical subject headings) terms until January 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated using fixed and random-effect models based upon the heterogeneity (I2) to estimate the association between interbody cages and the measured outcomes. Results: A total of 1,094 patients from 11 studies were reviewed. The final analysis included 421 patients (38.5%) who had lumbar surgery using a Ti and/or a Ti-coated interbody cage and 673 patient (61.5%) who had lumbar surgery using a PEEK cage. Overall, PEEK interbody devices were associated with a significantly lower fusion rate compared with Ti interbody devices (OR, 0.62; 95% CI, 0.41–0.93; p = 0.02). There was no difference in subsidence rates between Ti and PEEK groups (OR, 0.91; 95% CI, 0.54–1.52; p = 0.71). Also, there were no statistically significant differences in visual analogue scale (VAS)-low back pain (p = 0.14) and Japanese Orthopedic Association scale (p = 0.86) between the 2 groups. However, the PEEK group had lower odds of leg pain after surgery compared to the Ti group (OR [VAS-leg], 0.61; 95% CI, 0.28–0.94; p = 0.003). Conclusion: Ti and Ti-coated PEEK cages used for posterior lumbar interbody fusion are associated with similar rates of subsidence, but a higher rate of fusion compared to PEEK interbody cages. Randomized controlled trials are needed to better assess the effect of cage materials and potential factors that could influence the outcomes of interbody lumbar fusion. [ABSTRACT FROM AUTHOR]

The potential of big data analytics to improve the quality of care for patients with spine tumors is significant. At this moment, the application of big data analytics to oncology and spine surgery is at a nascent stage. As such, efforts are underway to advance data-driven oncologic care, improve patient outcomes, and guide clinical decision making. This is both relevant and critical in the practice of spine oncology as clinical decision making is often made in isolation looking at select variables deemed relevant by the physician. With rapidly evolving therapeutics in surgery, radiation, interventional radiology, and oncology, there is a need to better develop decision-making algorithms utilizing the vast data available for each patient. The challenges and limitations inherent to big data analyses are presented with an eye towards future directions. [ABSTRACT FROM AUTHOR]

Background: Carotid artery injury and stroke secondary to prolonged retraction remains an extremely rare complication in anterior cervical discectomy and fusion (ACDF). However, multiple studies have demonstrated that carotid artery retraction during the surgical approach may alter the normal blood flow, leading to a significant reduction in the cross-sectional area of the vessel. Others have suggested that dislodgment of atherosclerotic plaques following manipulation of the carotid artery can be a potential risk for intracranial embolus and stroke.Purpose: We aimed to evaluate: (1) the incidence of postoperative stroke following ACDF and (2) incidence of other postoperative complications in a cohort of patients who had a diagnosis of carotid artery stenosis (CAS) versus those who did not.Patient Sample: This study utilized the Statewide Planning and Research Cooperative System database from January 1, 2009 to December 31, 2013. All patients who underwent (ACDF) and had a preoperative diagnosis of CAS were identified using the International Classification of Disease, ninth revision codes. Those who had a previous history of stroke were excluded. Patients who had CAS were propensity score matched to patients without history of CAS for demographics and Charlson/Deyo comorbidity scores.Outcome Measures: Incidence of postoperative stroke and other complications were compared between the cohorts. The threshold for statistical significance was set at a p<.05. This study received no funding. The authors report no conflict of interests relevant to this study.Results: There were 34,975 patients who underwent an ACDF in the study time period. After excluding those under the age of 18 and with history of previous stroke, there were 61 patients who had CAS that were compared with a propensity-matched cohort. The CAS cohort had a significantly higher incidence of postoperative stroke during their hospitalization (6.6% vs 0%, p<.042). The CAS cohort also had higher rates of acute renal failure (27.9% vs 4.9%, p = .01) and sepsis (18% vs 4.9%, p = .023). There were no stroke related deaths.Conclusions: Patients with CAS who underwent ACDF had a statistically significant greater incidence of developing a postoperative stroke. To the best of our knowledge, no previous study has evaluated the development of postoperative stroke in patients with CAS undergoing ACDF. Larger, multicenter studies are needed to estimate the true incidence of stroke in this specific patient population. However, our results may illustrate the importance of preoperative optimization, approach-selection, and postoperative stroke surveillance in patients with a history of CAS who undergoes ACDF. [ABSTRACT FROM AUTHOR]

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes. [ABSTRACT FROM AUTHOR]

H1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that PARP activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of temozolomide on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to temozolomide, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis. The acute time period (<3 hours) after temozolomide treatment displayed a burst of NAD+ consumption driven by PARP activation. In IDH1-mutant-expressing cells, this consumption reduced further the abnormally lowered basal steady-state levels of NAD+, introducing a window of hypervulnerability to NAD+ biosynthesis inhibitors. This effect was selective for IDH1-mutant cells and independent of methylguanine methyltransferase or mismatch repair status, which are known rate-limiting mediators of adjuvant temozolomide genotoxic sensitivity. Combined temozolomide and NAMPT inhibition in an in vivo IDH1-mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find IDH1-mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD+ pathways yield potent anticancer efficacy in vivo. Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy. [ABSTRACT FROM AUTHOR]

A photograph of the CT scan of a patient explaining transient aqueductal occlusion in intracerebral haemorrhage is presented.

The effectiveness of starting systemic therapies after surgery for spinal metastases from renal cell carcinoma (RCC) has not been evaluated in randomized clinical trials. Agents that target tyrosine kinases, mammalian target of rapamycin signaling, and immune checkpoints are now commonly used. Variables like sarcopenia, nutritional status, and frailty may impact recovery from spine surgery and are considered when evaluating a patient's candidacy for such treatments. Better understanding the significance of these variables may help improve patient selection for available treatment options after surgery. Study the treatment effect of postoperative systemic therapies on survival. Observational study using comparative effectiveness methods. Adult patients who underwent spine surgery for metastatic renal cell carcinoma (RCC) between 2010-2019 at Massachusetts General Hospital. The primary outcome of this study is overall survival. Univariable and multivariable Cox regression analyses were performed to determine factors associated with overall survival (OS) in a retrospective cohort of adult patients who underwent spine surgery for metastatic RCC between 2010-2019. Propensity score matched (PSM) analysis and inversive probability weighting (IPW) were performed to determine the treatment effect of postoperative systemic therapy on OS. To address confounding and minimize bias in estimations, PSM and IPW were adjusted for covariates including age, gender, frailty, sarcopenia, nutrition, visceral metastases, IMDC (International Metastatic RCC Database Consortium) risk score, and performance status. Eighty-eight patients (73.9% male; median age, 62 [29-84] years) were identified. Forty-nine of 88 (55.7%) had intermediate IMDC risk and 29 of 88 (33.0%) had poor IMDC risk. Median follow-up was 17 months (1-104 months) during which 57 (64.7%) died. Poor IMDC risk (HR, 3.2, [1.08-9.3]), baseline performance status (ECOG 3-4; HR, 2.7 [1.5-4.7]), and nutrition (prognostic nutritional index 1st tertile; PNI <40.74; HR=2.69, [1.42-5.1]) were associated with worse OS. Sarcopenia and frailty were not significantly associated with poor survival. Postoperative systemic therapy was associated with prolonged OS, demonstrated by similar effects from multivariable Cox analysis (HR, 0.55 [0.30-1.00]), PSM (HR, 0.53 [0.29-0.93]), and IPW (HR, 0.47 [0.24-0.94]) and comparable confidence intervals. Median survival for those receiving postoperative systemic therapy was 28 (CI 95%, 19-43) months versus 12 (CI 95%, 4-37) months for those who only had surgery (log-rank P =.027). This comparative analysis demonstrates that postoperative systemic therapy is associated with improved survival in specific cohorts with metastatic spinal RCC after adjusting for frailty, sarcopenia, and malnutrition. The marked differences in survival should be taken into consideration when planning for surgery. This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal long-term potentiation (LTP) can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field EPSPs and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Aβ oligomers from three distinct sources (cultured cells,ADcortex, or synthetic peptide) inhibited LTP, and this was prevented by the selectiveNR2Binhibitors ifenprodil andRo25-6981. Soluble Aβ enhanced NR2B-mediatedNMDAcurrents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor DL-threo-β-benzyloxyaspartic acid. Downstream, an Aβ-mediated rise in p38 mitogen-activated protein kinase (MAPK) activation was followed by downregulation of cAMP response element-binding protein, andLTPimpairment was prevented by inhibitors of p38MAPK or calpain. Thus, soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity. [ABSTRACT FROM AUTHOR]

The molecular pathways leading to Alzheimer-type dementia are not well understood, but the amyloid beta-protein is believed to be centrally involved. The quantity of amyloid beta-protein containing plaques does not correlate well with clinical status, suggesting that if amyloid beta-protein is pathogenic it involves soluble non-plaque material. Using 43 brains from the Newcastle cohort of the population-representative Medical Research Council Cognitive Function and Ageing Study, we examined the relationship between biochemically distinct forms of amyloid beta-protein and the presence of Alzheimer-type dementia. Cortical samples were serially extracted with Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and with 88% formic acid and extracts analysed for amyloid beta-protein by immunoprecipitation/western blotting. The cohort was divisible into those with dementia at death with (n = 14) or without (n = 10) significant Alzheimer-type pathology, and those who were not demented (n = 19). Amyloid beta-protein monomer in extracts produced using Tris-buffered saline and Tris-buffered saline containing 1% TX-100 were strongly associated with Alzheimer type dementia (P < 0.001) and sodium dodecyl sulphate-stable amyloid beta-protein dimer was detected specifically and sensitively in Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and formic acid extracts of Alzheimer brain. Amyloid beta-protein monomer in the formic acid fraction closely correlated with diffuse and neuritic plaque burden, but was not specific for dementia. These findings support the hypothesis that soluble amyloid beta-protein is a major correlate of dementia associated with Alzheimer-type pathology and is likely to be intimately involved in the pathogenesis of cognitive failure. [ABSTRACT FROM AUTHOR]

The molecular pathways leading to Alzheimer-type dementia are not well understood, but the amyloid β-protein is believed to be centrally involved. The quantity of amyloid β-protein containing plaques does not correlate well with clinical status, suggesting that if amyloid β-protein is pathogenic it involves soluble non-plaque material. Using 43 brains from the Newcastle cohort of the population-representative Medical Research Council Cognitive Function and Ageing Study, we examined the relationship between biochemically distinct forms of amyloid β-protein and the presence of Alzheimer-type dementia. Cortical samples were serially extracted with Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and with 88% formic acid and extracts analysed for amyloid β-protein by immunoprecipitation/western blotting. The cohort was divisible into those with dementia at death with (n= 14) or without (n= 10) significant Alzheimer-type pathology, and those who were not demented (n= 19). Amyloid b-protein monomer in extracts produced using Tris-buffered saline and Tris-buffered saline containing 1% TX-100 were strongly associated with Alzheimer type dementia (P<0.001) and sodium dodecyl sulphate-stable amyloid β-protein dimer was detected specifically and sensitively in Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and formic acid extracts of Alzheimer brain. Amyloid β-protein monomer in the formic acid fraction closely correlated with diffuse and neuritic plaque burden, but was not specific for dementia. These findings support the hypothesis that soluble amyloid β-protein is a major correlate of dementia associated with Alzheimer-type pathology and is likely to be intimately involved in the pathogenesis of cognitive failure. [ABSTRACT FROM AUTHOR]

Summary: In Alzheimer''s disease (AD), the impairment of declarative memory coincides with the accumulation of extracellular amyloid-β protein (Aβ) and intraneuronal tau aggregates. Dementia severity correlates with decreased synapse density in hippocampus and cortex. Although numerous studies show that soluble Aβ oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble Aβ oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically evoked LTD in the CA1 region. Aβ-enhanced LTD was mediated by mGluR or NMDAR activity. Both forms of LTD were prevented by an extracellular glutamate scavenger system. Aβ-facilitated LTD was mimicked by the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased by soluble Aβ. We conclude that soluble Aβ oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression. [Copyright &y& Elsevier]

One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloidßprotein (Aß), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Aßcould exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Aßspecies in the brain. Intracerebroventricular injection of naturally secreted human Aßinhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Aßcompletely prevented the inhibition of LTP when injected after Aß. Size fractionation showed that Aßoligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Aßantibody again prevented such inhibition. Active immunization against Aßwas partially effective, and the effects correlated positively with levels of antibodies to Aßoligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Aßoligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease. [ABSTRACT FROM AUTHOR]

Recent studies support the hypothesis that soluble oligomers of amyloid β-peptide (Aβ) rather than mature amyloid fibrils are the earliest effectors of synaptic compromise in Alzheimer's disease. We took advantage of an amyloid precursor protein-overexpressing cell line that secretes SDS-stable Aβ oligomers to search for inhibitors of the pathobiological effects of natural human Aβ oligomers. Here, we identify small molecules that inhibit formation of soluble Aβ oligomers and thus abrogate their block of long-term potentiation (LTP). Furthermore, we show that cell derived Aβ oligomers can be separated from monomers by size exclusion chromatography under nondenaturing conditions and that the isolated, soluble oligomers, but not monomers, block LTP. The identification of small molecules that inhibit early Aβ oligomer formation and rescue LTP inhibition offers a rational approach for therapeutic intervention in Alzheimer's disease and highlights the utility of our cell-culture paradigm as a useful secondary screen for compounds designed to inhibit early steps in Aβ oligomerization under biologically relevant conditions. [ABSTRACT FROM AUTHOR]

A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-ßprotein interferes with cognitive function. Soluble oligomeric forms of amyloid-ß, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Althoughß-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-ßmoieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Several surgical techniques for atlantoaxial fixation and arthrodesis have been proposed over the years to treat patients with atlantoaxial instability with the goal of achieving C1-2 fusion. We report a novel C1-2 fixation technique for treating patients with atlantoaxial instability using a loop-suture technique without the use of cables or wires. We propose a safer alternative to securing structural bone graft between C1-2. A retrospective review of a prospective database was performed using this technique from 2013-2018 for patients with atlantoaxial instability related to trauma, degeneration, and inflammatory arthropathy. Primary bone and metastatic cancer were excluded. The technique entails anchoring a structural iliac crest autograft or allograft between C1 and C2 for interlaminar arthrodesis in addition to C1 lateral mass and C2 pars/pedicle screw placement. The bone graft is secured using a 0-Prolene suture which is looped under the C1 lamina with the blunt end of the needle first. The needle is then passed through the graft, through the C2-3 interspinous ligaments, and then tied over the graft. We report the utility, safety, durability, and effectiveness of this approach in 32 consecutive patients A retrospective review of a prospective database was performed using this technique from 2013-2018 for patients with atlantoaxial instability related to trauma, degeneration, and inflammatory arthropathy. Primary bone and metastatic cancer were excluded. The technique entails anchoring a structural iliac crest autograft or allograft between C1 and C2 for interlaminar arthrodesis in addition to C1 lateral mass and C2 pars/pedicle screw placement. The bone graft is secured using a 0-Prolene suture which is looped under the C1 lamina with the blunt end of the needle first. The needle is then passed through the graft, through the C2-3 interspinous ligaments, and then tied over the graft. We report the utility, safety, durability, and effectiveness of this approach in 32 consecutive patients. A total of 32 patients were identified who met criteria for atlantoaxial instability due to traumatic dislocation or ligamentous injury (60.0%), cervical spine degeneration (34.5%), deformity (5.25%) or combination of trauma and degeneration (5.25%). The follow-up period ranged from 6 to 24 months (mean 7.8 months). All patients had improvement in their pain by VAS and NDI (85% and 60% improvement respectively, p<0.001) and there were no implant failures or need for revision surgery. Radiographic evaluation was performed using CT and x-rays at 6 months. There was no evidence of bone graft movement or displacement. CT demonstrated incorporation of the graft in 100% of the cases. There were no neurologic complications. The rate of readmission within 30 days after surgery was 3%. Two patients had CSF leak unrelated to the technique, 1 patient had a surgical site infection, and 1 patient developed transient dysphagia. We demonstrate a novel approach for C1-2 arthrodesis that utilizes a safe technique for securing bone graft without the use of wires or cables, allowing for less sublaminar dissection and potential dural and neurologic injury as well as improved clinical outcomes. This abstract does not discuss or include any applicable devices or drugs. [ABSTRACT FROM AUTHOR]

Background: Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. Methods: 850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed. Results: Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n = 426, 50%), was associated with male sex (64.4% %, p = 0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n = 56) or TP53 mutations (n = 25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p = 0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases—with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n = 22) or PBRM1 (n = 16). A second subgroup contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. Conclusions: Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade/progressive meningiomas and can guide the design of clinical trials. IRB approval status: Reviewed and approved by Western IRB; Protocol No. 20152817. [ABSTRACT FROM AUTHOR]