[Preoperative Simulation for Complication Control in Spinal Surgery].

The craniovertebral junction not only contains anatomically important structures such as the medulla oblongata, upper cervical spinal cord, and vertebral artery, but also controls the dynamic movements of flexion, extension, and rotation of the head and neck. Consequently, instability and spinal deformities can easily occur in the craniovertebral region, and appropriate treatment should be selected based on the specificity of the lesion. Basilar invagination often involves bone and vascular anomalies and fusion surgery is often required. Therefore, careful pre-operative simulations are necessary. The creation and use of three-dimensional bone models, including image navigation, are useful for surgical simulation.

Network Meta-Analysis of C5 Palsy After Anterior Cervical Decompression of Three to Six Levels: Comparing Three Different Procedures.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: Using a network meta-analysis (NMA), this study aimed to compare the risks of C5 palsy after three different procedures of anterior cervical decompression. SUMMARY OF BACKGROUND DATA: C5 palsy is a well-known complication affecting the quality of life after anterior procedures. Due to the limited evidence on the various procedures available, we evaluate the basis for selection to prevent palsy and achieve maximal decompression in cases spanning 3-6 levels. MATERIALS AND METHODS: We conducted a comprehensive search for C5 palsy and complications after 3representative procedures, including anterior cervical discectomy and fusion (ACDF), anterior cervical corpectomy and fusion (ACCF), and their combination (hybrid), involving 3 to 6 intervertebral levels. The incidence of C5 palsy was compared using a NMA. RESULTS: We identified 1655 patients in 11 studies who met inclusion criteria. Sixty-nine patients (4.2%) developed delayed C5 palsies. The incidences among ACDF, ACCF, and hybrid cases were 2.3% (16/684, 95% CI: 1.4% to 3.8%), 6.4% (39/613, 95% CI: 4.7% to 8.6%), and 3.9% (14/358, 95% CI: 2.3% to 6.5%), respectively ( P < 0.01). A NMA was performed for 15 pairwise comparisons across the 3 procedure arms: ACDF versus hybrid, 7/232 (3.0%) versus 11/234 (4.7%); hybrid versus ACCF, 14/301 (4.3%) versus 18/224 (8.0%); ACCF versus ACDF, 38/523 (7.8%) versus 16/619 (2.6%). Compared with ACDF, the risk of C5 palsy was significantly higher in ACCF (odds ratio: 2.72, 95% CI: 1.47 to 5.01), whereas ACDF versus hybrid did not significantly differ in risk (odds ratio: 1.56, 95% CI: 0.68 to 3.60). CONCLUSION: We determined that ACCF was associated with a higher risk of postoperative C5 palsy than ACDF in cases spanning 3 to 6 intervertebral levels. If practicable, ACDF surgery may be an appropriate choice for cases requiring anterior decompression of 3 to 6 levels. LEVEL OF EVIDENCE: Level III.

Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

Epilepsy with Eyelid Myoclonia Complicated by Polycystic Ovary Syndrome: Valproate Withdrawal, Vagus Nerve Stimulation, and Seizure Reduction.

Epilepsy with eyelid myoclonia is a childhood-onset generalized epilepsy, which is more common in women. Over 90% of the patients continue antiseizure medications, especially valproate, and more than 60% of cases are refractory. The efficacy of vagus nerve stimulation in treating eyelid myoclonia is still unknown. Polycystic ovary syndrome is highly prevalent in women with epilepsy receiving valproate; nevertheless, no reports on the complication of polycystic ovary syndrome in women with epilepsy with eyelid myoclonia were found. In this report, a case of a woman with epilepsy with eyelid myoclonia who developed polycystic ovary syndrome while receiving valproate and underwent vagus nerve stimulation is described. A 26-year-old female patient has been administered valproate since the occurrence of generalized seizures at the age of 12 years and then developed polycystic ovary syndrome. When the dose of valproate was reduced as an adult, her epilepsy became intractable. Information from her mother led to a video electroencephalography re-evaluation, and she was finally diagnosed 15 years after onset. The patient underwent vagus nerve stimulation. In a short-term follow-up, she achieved >50% seizure reduction at low output currents of <1.00 mA. Polycystic ovary syndrome was cured 15 months after valproate withdrawal. There are three key points presented in this case: Vagus nerve stimulation therapy was useful for treating epilepsy with eyelid myoclonia with absence. Women with epilepsy with eyelid myoclonia taking valproate must be aware of the risk of polycystic ovary syndrome and monitor their menstrual cycles. Information from the family, such as home videos, helped with the diagnosis.

Clinical Characteristics and Long-term Outcomes of Spinal Pilocytic Astrocytomas: A Multicenter Retrospective Study by the Neurospinal Society of Japan.

OBJECTIVE: The characteristics, imaging features, long-term surgical outcomes, and recurrence rates of primary spinal pilocytic astrocytomas (PAs) have not been clarified owing to their rarity and limited reports. Thus, this study aimed to analyze the clinical presentation, radiological features, pathological findings, and long-term outcomes of spinal PAs. METHODS: Eighteen patients with spinal PAs who were surgically treated between 2009 and 2020 at 58 institutions were included in this retrospective multicenter study. Patient data, including demographics, radiographic features, treatment modalities, and long-term outcomes, were evaluated. RESULTS: Among the 18 consecutive patients identified, 11 were women and 7 were men; the mean age at presentation was 31 years (3-73 years). Most PAs were located eccentrically, were solid or heterogeneous in appearance (cystic and solid), and had unclear margins. Gross total resection (GTR), subtotal resection (STR), partial resection (PR), and biopsy were performed in 28%, 33%, 33%, and 5% of cases, respectively. During a follow-up period of 65 ± 49 months, 4 patients developed a recurrence; however, the recurrence-free survival did not differ significantly between the GTR and non-GTR (STR, PR, and biopsy) groups. CONCLUSION: Primary spinal PAs are rare and present as eccentric and intermixed cystic and solid intramedullary cervical tumors. The imaging features of spinal PAs are nonspecific, and a definitive diagnosis requires pathological support. Surgical resection with prevention of neurological deterioration can serve as the first-line treatment; however, the resection rate does not affect recurrence-free survival. Investigation of relevant molecular biomarkers is required to elucidate the regrowth risk and prognostic factors.

Left Distal Transradial Approach for the Treatment of a Sacral Extradural Arteriovenous Fistula: A Technical Note and Literature Review.

BACKGROUND: Sacral extradural arteriovenous fistula (SEAVF) is relatively rare, and its etiology is unknown. They are mostly fed by the lateral sacral artery (LSA). For endovascular treatment, both the stability of the guiding catheter and accessibility of the microcatheter to the fistula, distal to the LSA are required for sufficient embolization of the fistulous point. Cannulation of these vessels requires either crossover at the aortic bifurcation or retrograde cannulation using the transfemoral approach. However, atherosclerotic femoral and tortuous aortoiliac vessels can make the procedure technically difficult. Although the right transradial approach (TRA) can reduce this difficulty by straightening the access route, a potential risk remains for cerebral embolism because it passes the aortic arch. Herein, we present a case of successful embolization of a SEAVF using a left distal TRA. METHODS: We report a case of a 47-year-old man with SEAVF treated with embolization using a left distal TRA. Lumbar spinal angiography showed a SEAVF with an intradural vein through the epidural venous plexus fed by the left LSA. A 6-French guiding sheath was cannulated into the internal iliac artery via the descending aorta using the left distal TRA. A microcatheter could be advanced into the extradural venous plexus over the fistula point from the intermediate catheter placed at the LSA. Embolization with coils and n-butyl cyanoacrylate was successfully performed. RESULTS: The SEAVF completely disappeared on neuroimaging, and the patient gradually recovered. CONCLUSIONS: Left distal TRA could be a useful, safe, and less invasive option for the embolization of SEAVF, especially for patients with high-risk factors for aortogenic embolism or puncture site complications.

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development.

The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.

SOCS7-Derived BC-Box Motif Peptide Mediated Cholinergic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells (ADMSCs) are a type of pluripotent somatic stem cells that differentiate into various cell types such as osteoblast, chondrocyte, and neuronal cells. ADMSCs as donor cells are used to produce regenerative medicines at hospitals and clinics. However, it has not been reported that ADMSCs were differentiated to a specific type of neuron with a peptide. Here, we report that ADMSCs differentiate to the cholinergic phenotype of neurons by the SOCS7-derived BC-box motif peptide. At operations for patients with neurological disorders, a small amount of subcutaneous fat was obtained. Two weeks later, adipose-derived mesenchymal stem cells (ADMSCs) were isolated and cultured for a further 1 to 2 weeks. Flow cytometry analysis for characterization of ADMSCs was performed with CD73, CD90, and CD105 as positive markers, and CD14, CD31, and CD56 as negative markers. The results showed that cultured cells were compatible with ADMSCs. Immunocytochemical studies showed naïve ADMSCs immunopositive for p75NTR, RET, nestin, keratin, neurofilament-M, and smooth muscle actin. ADMSCs were suggested to be pluripotent stem cells. A peptide corresponding to the amino-acid sequence of BC-box motif derived from SOCS7 protein was added to the medium at a concentration of 2 µM. Three days later, immunocytochemistry analysis, Western blot analysis, ubiquitination assay, and electrophysiological analysis with patch cramp were performed. Immunostaining revealed the expression of neurofilament H (NFH), choline acetyltransferase (ChAT), and tyrosine hydroxylase (TH). In addition, Western blot analysis showed an increase in the expression of NFH, ChAT, and TH, and the expression of ChAT was more distinct than TH. Immunoprecipitation with JAK2 showed an increase in the expression of ubiquitin. Electrophysiological analysis showed a large holding potential at the recorded cells through path electrodes. The BC-box motif peptide derived from SOCS7 promoted the cholinergic differentiation of ADMSCs. This novel method will contribute to research as well as regenerative medicine for cholinergic neuron diseases.

HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma.

PURPOSE: Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E-mutant high-grade gliomas (HGG); however, the therapeutic effect is limited by the emergence of drug resistance. EXPERIMENTAL DESIGN: We established multiple paired BRAFV600E-mutant HGG patient-derived xenograft models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment-resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo. RESULTS: We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the reactivation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E-mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3ß (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular targeted therapy. CONCLUSIONS: The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E-mutant HGG.

Practical Arachnoid Anatomy for the Technical Consideration of Galen Complex Dissection: Cadaveric and Clinical Evaluation.

BACKGROUND: The occipital transtentorial approach (OTA) is a very useful but challenging approach to expose the pineal region because the deep-seated arachnoid membranes usually fold and extend over the great vein of Galen (GVG), leading to dense and poor visibility. In addition, the practical aspects of arachnoid anatomy are not well understood. We aimed to develop a safe surgical procedure for the OTA according to the practical aspects of arachnoid anatomy. METHODS: The procedure is shown through an illustrative video of surgery and cadaver. Five cadavers were analyzed for their arachnoid structures and the surgical procedures via the OTA, in strict compliance with legal and ethical requirements. RESULTS: All cadavers showed a 2-layered arachnoid structure-one belonging to the occipital lobe, and the other to the cerebellum. According to our cadaveric analysis, the arachnoid attachment of the tentorial apex can be peeled bluntly, with an average distance of 10.2 mm. For our clinical presentation, a pineal tumor with hydrocephalus was detected in a 14-year-old boy. While using the OTA and expanding the deep surgical field, we detached the membrane from the tentorial apex and bluntly peeled it to reveal the deep veins. Finally, gross total removal of the tumor was achieved. CONCLUSIONS: A 2-layered arachnoid structure interposes the GVG from above and below the tentorium. The arachnoid membrane below the tentorium can be peeled off bluntly from the GVG to the attachment bundle limited by the penetrating veins. This detachment technique is useful for safe enlargement of the surgical field for the OTA.

IDH-Mutant Astrocytoma With Chromosome 19q13 Deletion Manifesting as an Oligodendroglioma-Like Morphology.

Partial deletions in chromosomes 1p and 19q are found in a subset of astrocytic tumors; however, it remains unclear how these alterations affect their histological features and prognosis. Herein, we present 3 cases of isocitrate dehydrogenase (IDH)-mutant astrocytoma with chromosome 19q13 deletion. In the first case, the primary tumor harbored an IDH1 mutation with chromosome 1p/19q partial deletions, which covered 19q13 and exhibited a durable initial response to radiotherapy and temozolomide (TMZ) treatment. However, the tumor lost the chromosome 1p/19q partial deletions at recurrence and became resistant to TMZ. Histologically, an oligodendroglioma-like feature was found in the primary tumor but not in the recurrent tumor. Capicua transcriptional repressor (CIC), located on 19q13, was less expressed in the primary tumor but was highly expressed in the recurrent tumor. Similar histological findings were observed in 2 other astrocytic tumors with IDH1 or IDH2 mutations. These tumors also had chromosome 19q13 deletion, including the CIC gene, weakly expressed CIC, and oligodendroglioma-like morphology. These tumors recurred at 6 and 32 months, respectively. These findings suggest that IDH-mutant astrocytoma with chromosome 19q13 partial deletion, including the CIC gene, may induce an oligodendroglioma-like phenotype, but the clinical prognosis may not be similar to that of genetically defined oligodendroglioma.

Verbal and memory deficits caused by aphasic status epilepticus after resection of a left temporal lobe glioma.

BACKGROUND: Nonconvulsive status epilepticus (NCSE) is induced by common neurosurgical conditions, for example, trauma, stroke, tumors, and surgical interventions in the brain. The aggressiveness of the treatment for NCSE depends on its neurological prognosis. Aphasic status epilepticus (ASE) is a subtype of focal NCSE without consciousness impairment. The impact of ASE on neurological prognosis is poorly documented. We describe a case of postoperative ASE resulting in verbal and memory deficits. CASE DESCRIPTION: A 54-year-old, right-handed man with focal impaired awareness seizures underwent partial resection for a left temporal lobe tumor. No neurological deficits were observed immediately after surgery. Three days later, however, a focal to bilateral tonic-clonic seizure (FBTCS) occurred, followed by aphasia. Electroencephalography revealed 1.5 Hz left-sided periodic discharges. He was diagnosed with ASE. Multiple anti-seizure drugs were ineffective for the resolution of the patient's verbal disturbance. Nine days after the FBTCS, deep sedation with intravenous anesthetics was performed and the ASE stopped. Thereafter, his symptoms gradually improved. However, the prolonged ASE resulted in verbal and memory deficits. Automated hippocampal volumetry revealed an approximate decrease of 20% on the diseased side on magnetic resonance imaging 3 months after surgery. CONCLUSION: Prolonged ASE can induce verbal and memory deficits. Early intervention with intravenous anesthetics is required to obtain a favorable neurological prognosis.

Superficial siderosis and nonobstructive hydrocephalus due to subependymoma in the ventricle: An illustrative case report.

Background: Intraventricular tumors can generally result in obstructive hydrocephalus as they grow. Rarely, however, some intraventricular tumors develop superficial siderosis (SS) and trigger hydrocephalus, even though the tumor has hardly grown. Here, we present an illustrative case of SS and nonocclusive hydrocephalus caused by subependymoma of the lateral ventricles. Case Description: A 78-year-old man with an intraventricular tumor diagnosed 7 years ago had been suffering from gait disturbance for 2 years. He also developed cognitive impairment. Intraventricular tumors showed little growth on annual magnetic resonance imaging (MRI). MRI T2-star weighted images (T2*WI) captured small intratumoral hemorrhages from the beginning of the follow-up. Three years before, at the same time as the onset of ventricular enlargement, T2*WI revealed low intensity in the whole tumor and cerebral surface. Subsequent follow-up revealed that this hemosiderin deposition had spread to the brain stem and cerebellar surface, and the ventricles had expanded further. Cerebrospinal fluid (CSF) examination revealed xanthochromia. The tumor was completely removed en bloc. Histopathological findings were consistent with those of subependymoma. Although CSF findings improved, SS and hydrocephalus did not improve. Therefore, the patient underwent a lumboperitoneal shunt for CSF diversion after tumor resection. Conclusion: Some intraventricular tumors cause SS and nonobstructive hydrocephalus due to microbleeding, even in the absence of tumor growth. T2*WI and, if necessary, timely CSF examination can allow identification of presymptomatic SS. This follow-up strategy may provide a favorable course by facilitating early intervention in patients with intraventricular lesions, not just subependymomas.

Efficacy of Supraclavicular Scalenotomy Followed by External Neurolysis without Rib Resection for Post-traumatic Neurogenic Thoracic Outlet Syndrome.

MINI: Most patients with neurogenic thoracic outlet syndrome (NTOS) have a history of trauma. Scar tissue formation within the scalene muscle and around the nerves after injury cause arm and hand symptoms. We report that supraclavicular scalenotomy followed by external neurolysis without rib resection is very effective as the surgical treatment.

Consecutive case series. Our aim was to evaluate the outcomes of patients who underwent supraclavicular scalenotomy followed by external neurolysis without rib resection for post-traumatic NTOS. Neurogenic thoracic outlet syndrome (NTOS) comprises over 95% of all TOS patients, and most patients with NTOS have a history of trauma before the onset of their symptoms. Patients treated with supraclavicular scalenotomy and neurolysis without rib resection from September 2014 to December 2019 were retrospectively reviewed by using the medical records and operative notes. Patient's characteristics, clinical symptoms before treatment, operative findings, and short- and long-term outcomes were assessed. To assess clinical outcomes at 2 months after surgery (short-term outcomes) and 12 months later (long-term outcomes), we used a 4-grade categorization (Excellent, Good, Fair, and Poor) of patients' subjective evaluations after surgery on the basis of modified Odom's criteria. Excellent and Good were defined as a successful outcome. Ninety-six supraclavicular scalenotomies without rib resection were performed on patients with post-traumatic NTOS. The most common intraoperative observation was the fibrous bands within the anterior scalene muscle in 86 cases (89.6%). The short-term outcome with patients' subjective evaluation in 96 operations at 2 months after surgery showed a 96.9% success rate (Excellent + Good). In 85 cases followed for more than 12 months after surgery, the success rate based on patients' subjective evaluation at the last clinic follow-up appointment as a long-term outcome was 74.1%. In post-traumatic NTOS, it has been reported the arm and hand symptoms are due to pressure on the brachial plexus, which can stem from the swollen muscle following injuries and later from tightness of the scarred muscle. Considering this mechanism and our results, we concluded that supraclavicular scalenotomy and external neurolysis without rib resection made sense, as they were very effective and adequate to improve symptoms of NTOS. Level of Evidence: 5.

Neurosurgical versus endovascular treatment of spinal dural arteriovenous fistulas: a multicenter study of 195 patients.

OBJECTIVE: The purpose of the present study was to compare the treatment success rates of primary neurosurgical and endovascular treatments in patients with spinal dural arteriovenous fistulas (dAVFs). METHODS: Data from 199 consecutive patients with thoracic and lumbosacral spinal dAVFs were collected from 18 centers. Angiographic and clinical findings, the rate of initial treatment failure or recurrence by procedures, risk factors for treatment failure, complications, and neurological outcomes were statistically analyzed. RESULTS: Spinal dAVFs were frequently detected in the thoracic region (81%), fed by a single feeder (86%), and shunted into an intradural vein via the dura mater. The fistulous connection between the feeder(s) and intradural vein was located at a single spinal level in 195 patients (98%) and at 2 independent levels in 4 patients (2%). Among the neurosurgical (n = 145), and endovascular (n = 50) treatment groups of single dAVFs (n = 195), the rate of initial treatment failure or recurrence was significantly higher in the index endovascular treatment group (0.68% and 36%). A multivariate analysis identified endovascular treatment as an independent risk factor with significantly higher odds of initial treatment failure or recurrence (OR 69; 95% CI 8.7-546). The rate of complications did not significantly differ between the two treatment groups (4.1% for neurosurgical vs 4.0% for endovascular treatment). With a median follow-up of 26 months, improvements of ≥ 1 point in the modified Rankin Scale (mRS) score and Aminoff-Logue gait and Aminoff-Logue micturition grades were observed in 111 (56%), 121 (61%), and 79 (40%) patients, respectively. Independent risk factors for lack of improvement in the Aminoff-Logue gait grades were multiple treatments due to initial treatment failure or recurrence (OR 3.1) and symptom duration (OR 1.02). CONCLUSIONS: Based on data obtained from the largest and most recently assessed multicenter cohort, the present study shows that primary neurosurgery is superior to endovascular treatment for the complete obliteration of spinal dAVFs by a single procedure.

A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein-Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease. SIGNIFICANCE: A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5330/F1.large.jpg.

Acute Management of Gamma Knife Radiosurgery for Asymptomatic Obstructive Hydrocephalus Associated with Posterior Fossa Metastases.

OBJECTIVE: We retrospectively assessed the effectiveness and safety of Gamma Knife radiosurgery (GKRS) for asymptomatic obstructive hydrocephalus associated with posterior fossa metastases, which was known empirically but not well discussed. METHODS: We reviewed the medical records of 27 patients who underwent GKRS for asymptomatic obstructive hydrocephalus related to posterior fossa metastases. RESULTS: Cumulative control rates of hydrocephalus were 11.1%, 51.9%, 70.4%, and 74.6% at 1, 2, 3, and 6 months after GKRS. Primary gastrointestinal tract cancer (P = 0.001) was significantly correlated with unfavorable management. Evans ratio at GKRS (median 0.31) improved significantly compared with that at 1-3 months after GKRS (median 0.26) (P < 0.0001) and maintained at 6 to 12 months. Cumulative local tumor control rates were 91.7%, 70.8%, and 64.4% at 3, 6, and 12 months after GKRS. Primary gastrointestinal tract cancer (P = 0.018) and no conventional systemic agents (P = 0.027) were significantly correlated with unfavorable control. Cumulative incidence rates of adverse radiation effects were 0.0%, 16.7%, and 24.2% at 6, 9, and 12 months after GKRS. Primary gastrointestinal tract cancer (P < 0.0001) and single and 2- or 3-fraction GKRS (P < 0.0001) were significantly correlated with unfavorable outcomes. All but 1 patient avoided surgical procedure for hydrocephalus after GKRS. CONCLUSIONS: The present findings suggest that GKRS is an effective and safe treatment for asymptomatic obstructive hydrocephalus caused by posterior fossa metastases, and all but 1 could avoid invasive surgical procedures for hydrocephalus. Posterior fossa metastases from gastrointestinal tract cancer resulted in unsatisfactory outcomes for control of hydrocephalus, tumor progression, and adverse radiation effects.

Anterior Cervical Decompression and C5 Palsy: A Systematic Review and Meta-analysis of Three Reconstructive Surgeries.

STUDY DESIGN: A systematic review and meta-analysis were performed with the literature including the case of C5 palsy following anterior cervical decompression surgery. OBJECTIVE: The aim of this study was to compare three reconstructive procedures of anterior cervical decompression, the incidences of delayed C5 palsy and other complications were assessed. SUMMARY OF BACKGROUND DATA: Delayed C5 palsy is now a well-known complication after cervical decompression surgery. The etiology of C5 palsy has been studied, especially after posterior surgery. However, in anterior surgery there has been a lack of investigation due to procedure variation. Additionally, limited evidence exists regarding the risk of C5 palsy in surgical procedures. METHODS: We performed an extensive literature search for C5 palsy and other complications with ACDF, ACCF, and their combination (Hybrid). Gross incidences of C5 palsy after these three procedures were compared, and specific superiorities (or inferiorities) were investigated via comparison of binary outcomes between two of three groups using odds ratios (OR). RESULTS: Twenty-six studies met the inclusion criteria. A total of 3098 patients were included and 5.8% of those developed C5 palsy. Meta-analyses demonstrated that ACDF had a lower risk of palsy than ACCF (OR 0.36, 95% confidence interval [CI] 0.16-0.78), whereas ACDF versus Hybrid (OR 0.60, 95% CI 0.24-1.51) and Hybrid versus ACCF (OR 1.11, 95% CI 0.29-4.32) were not significantly different. Although these differences were not observed in shorter lesion subgroups, there were significant differences between the three procedures in longer lesion subgroups (P = 0.0005). Meta-analyses revealed that in longer lesions, ACDF had a significantly lower incidence than ACCF (OR 0.42, 95% CI 0.22-0.82). Additionally, Hybrid surgery was noninferior for palsy occurrence compared to ACCF, and suggested a trend for reduced rates of other complications compared to ACCF. CONCLUSION: ACDF may yield better outcomes than Hybrid and ACCF. Furthermore, Hybrid may have advantages over ACCF in terms of surgical complications. LEVEL OF EVIDENCE: 3.

BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young.

We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11C-methionine uptake and a region with homogenous low 18F-fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1), a major transporter of methionine; c-Myc; and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and c-Myc. Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF V600E-mutated PLNTY and glioblastoma cells. The BRAF inhibitor dabrafenib moderately suppressed cell viability in PLNTY. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling and downstream c-Myc induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.

BC-Box Motif in SOCS6 Induces Differentiation of Epidermal Stem Cells into GABAnergic Neurons.

The BC-box motif in suppressor of cytokine signaling 6 (SOCS6) promotes the neuronal differentiation of somatic stem cells, including epidermal stem cells. SOCS6 protein belongs to the group of SOCS proteins and inhibits cytokine signaling. Here we showed that epidermal stem cells were induced to differentiate into GABAnergic neurons by the intracellular delivery of a peptide composed of the amino-acid sequences encoded by the BC-box motif in SOCS6 protein. The BC-box motif (SLQYLCRFVI) in SOCS6 corresponded to the binding site of elongin BC. GABAnergic differentiation mediated by the BC-box motif in SOCS6 protein was caused by ubiquitination of JAK2 and inhibition of the JAK2-STAT3 pathway. Furthermore, GABAnergic neuron-like cells generated from epidermal stem cells were transplanted into the brain of a rodent ischemic model. Then, we demonstrated that these transplanted cells were GAD positive and that the cognitive function of the ischemic model rodents with the transplanted cells was improved. This study could contribute to not only elucidating the mechanism of GABAnergic neuronal differentiation but also to neuronal regenerative medicine utilizing GABAnergic neurons.