Search

OBJECTIVE A recent comparative analysis between neurosurgical and endovascular treatments for craniocervical junction (CCJ) arteriovenous fistulas (AVFs) revealed better treatment outcomes in the neurosurgery group than in the endovascular group. This finding was attributed to the higher than expected rate of ischemic complications in the endovascular group than in the neurosurgery group (26% vs 7.7%, p = 0.037). The aim of the present study was to describe ischemic complications associated with treatments for CCJ AVFs. METHODS This descriptive study was authorized by the Neurospinal Society of Japan. Data from 97 consecutive patients with CCJ AVFs who underwent neurosurgical (n = 78) or endovascular (n = 19) treatment between 2009 and 2019 were collected from 29 centers. The primary endpoints were details on ischemic complications and their risk factors. Secondary endpoints were details on other complications. RESULTS Among all major complications, ischemic complications were the most common (11% of 97 patients), followed by hemorrhagic complications (7.2%), hydrocephalus (2.1%), and CSF leakage (2.1%). Ischemic complications included 8 spinal, 2 brainstem, and 1 cerebellar infarctions. Iatrogenic occlusion of the anterior or posterior spinal artery from the radiculomedullary or radiculopial arteries caused these complications. Ischemic complications resulted in neurological deficits, including motor paresis, sensory disturbances, and brainstem dysfunction. The modified Rankin Scale score was 3 or higher in 36% of patients with ischemic complications at the final follow-up of 23 months. Risk factors associated with ischemic complications were endovascular treatment (OR 4.3, 95% CI 1.1–16) and spinal feeding arteries (OR 3.8, 95% CI 1.03–14). Most of the other complications were addressed by additional treatment without permanent neurological deficits. CONCLUSIONS Among ischemic complications associated with treatments for CCJ AVFs, spinal infarctions were the most common and were mostly attributed to endovascular procedures for CCJ AVFs fed by spinal arteries. These results support the use of neurosurgery as the first-line treatment for CCJ AVFs.

Supplementary Data from HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma

Supplementary Figure from HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma

Supplementary document

Supplementary Table 1 Primers used for PCR amplification and sequencing Supplementary Table 2 Results of Multiplex PCR based MGH SNAPShot assay, Pyrosequencing and Sanger sequencing in YMG6 patient and xenograft cells Supplementary Table 3 Analysis of microsatellite instability in YMG6 parent and xenograft tumors Supplementary Table 4 Quantitative analysis for MGMT methylation status in YMG6 cells Supplementary Table 5 Multiplex PCR based MGH SnaPShot assay for oligodendroglial tumors Supplementary Table 6 Correlation of xenograft lethality and phosphorylation of PI3K pathway protein Supplementary Table 7 Phosphorylation in PI3K pathway in oligodendroglioma xenograft model Supplementary Table 8 Clinical characteristics in oligodendroglial tumor patients

Supplementary Figure S1-S7

Supplementary Figure 1. A, Hematoxylin and eosin, Ki-67, and IDH1R132H staining in each specimen. B, Sanger sequencing, immunohistochemical analysis, pyrosequencing, and FISH to identify YMG6 tumors as oligodendroglial tumors. C, Multiplex Ligation-dependent Probe Amplification assay demonstrating chromosome 1p and 19q co-deletion in YMG6R3F (left) and YMG6R3T (right). Bars, 50 �m. Supplementary Figure 2. A, DNA fingerprinting showing matched DNA identification in YMG6R3F (upper), YMG6R3T (middle), and YMG6R3T xenograft (YMG6R3Tsc1, lower). Supplementary Figure 3. Sanger sequencing indicating MSH6Ala1293Ser (left, arrow) and STK11Pro281Leu (right, arrow) in YMG6I. B, Immunohistochemical analysis demonstrating MSH6 expression in YMG6I (left) and YMG6R4T (right). C, Immunohistochemical analysis demonstrating LKB1/STK11 expression in YMG6I (left) and YMG23 (right, positive control). D, Sanger sequencing indicating MSH6Gly409Glu (arrow) in YMG6R4T. E, F, Upper gastrointestinal endoscopy (E) and colonoscopy (F) demonstrating no abnormal lesion in YMG6 patient. G, FDG-PET indicating no abnormal uptake in YMG6 patient. Bars, 50 �m. Supplementary Figure 4. Microsatellite instability (MSI)-PCR indicating microsatellite stable (MSS) in YMG6R2 and YMG6R3T. MSI-H, microsatellite instability high. MSS, microsatellite stable. Supplementary Figure 5. Immunohistochemical analysis demonstrating ATRX expression and weak expression of p53 in YMG6R3T. Supplementary Figure 6. Pyrosequencing indicating PIK3CAE542K (arrows) in YMG6I and YMG6R3T. B, Immunohistochemical analysis demonstrating phospho-AKT, -4EBP1, and -S6K expression in YMG6I and YMG6R1. Supplementary Figure 7. A, Multiplex Ligation-dependent Probe Amplification assay indicating 1p and 19q co-deletion in YMG6R3Tsc1. B, Sanger sequencing showing mutation in IDH1 (arrow; c.395G>A, left) and TERT (arrow; c.-124C>T, right) of YMG6R4Tsc1. Supplementary Figure 8. A, Overview and microscopic view of hematoxylin and eosin (H&E, upper), Ki-67 (middle) and IDH1R132H (lower) in first (YMG6R3Tsc1, left), second (YMG6R3Tsc2, middle), and third (YMG6R3Tsc3, right) generation YMG6R3T xenograft. B, H&E (upper), Ki-67 (middle), and IDH1R132H (lower) in YMG6R4Tsc1 (left), YMG6R4Tsc2 (middle), and YMG6R4Tsc3 (right). C, Sanger sequencing showing mutation of IDH1 (arrows, c.395G>A, left) and TERT (arrows, c.-124C>T, right), and PIK3CA (arrows, c.1624G>A) in YMG6R3Tsc2 (upper), YMG6R4Tsc2 (middle), and YMG6R4Tsc3 (lower). D, Immunohistochemical analysis demonstrating strong expression of phospho-AKT (Ser473, left), phospho-4EBP1 (middle), and phospho-S6K (right) in YMG6R4Tsc3. Bars, 50 �m. Supplementary Figure 9. A, Upper, Sanger sequencing showing IDH1 mutation (arrow, c.395 G>A), TERT (arrow, c.-124C>T), and PIK3CA (arrow, c.3140A>G) in YMG23. Lower, MLPA demonstrating chromosome 1p/19q co-deletion and CDKN2A (chr.9p.21) loss in YMG23 patient tumor. B, Immunohistochemical analysis demonstrating negative expression of p16INK4a/CDKN2A in YMG23 (upper). YMG5 (CDKN2A intact) served as positive control. C, Sanger sequencing showing mutations of IDH1 (arrow, c.395G>A, R132H, left) and TERT (arrow, c.-124C>T) in YMG5. D, Sanger sequencing showing mutations of IDH1 (arrow, c.395G>A), TERT (arrow, c.-124C>T), and PIK3CA (arrow, c.3140A>G) in YMG23sc1. E, MLPA demonstrating chromosome 1p/19q co-deletion and CDKN2A loss (chr.9p.21) in YMG23sc1. F, immunohistochemical analysis demonstrating negative expression of p16INK4a/CDKN2A in YMG23sc1. Bars, 50 �m. Supplementary Figure 10. A, B, C, Sanger sequencing showing IDH1 mutation (arrows, c.395G>A, R132H, left) and TERT promoter mutation (c.-124C>T, C228T or c.-146C>T, C250T), and in YMG46 (A), YMG28 (B) and YMG53 (C). PIK3CA mutation (c.1406A>G, E542G, arrow, A, right) in YMG46. D, Contrast enhancing MRI showing non-enhanced tumor recurrence at right frontal lobe (left). H&E (upper) and IDH1R132H staining (lower) in YMG53 (AOD, middle). Overview of H&E staining indicating no xenograft formation in YMG53sc1 (right). Bars, 50 �m. Supplementary Figure 11. A, Overview and magnification of hematoxylin and eosin staining of second passaged YMG23 xenograft model (YMG23sc2). B, C, Immunohistochemical analysis demonstrating expression of IDHR132H (B, left), Ki-67 (B, right), phospho-AKT (C, left), phospho-4EBP1 (C, middle), and phospho-S6K (C, right) in YMG23sc2. D, Sanger sequencing showing mutations in IDH1 (arrow, c.395 G>A), TERT (arrow, c.-124C>T), and PIK3CA (arrow, c.3140A>G) in YMG23sc2. Bars, 50 �m. Supplementary Figure 12. (A-D) Contrast enhanced MRI of the indicated patients at pre-treatment (left) and post-chemotherapy with/without radiotherapy (right). Supplementary Figure 13. Kaplan Meier Curve indicating no survival difference (P = 0.9) of overall survival in PIK3CA/PIK3RI- mutant (blue) and -wild-type (red) oligodendroglial tumor patients. Supplementary Figure 14. A, Relative cell viability of YMG28 (left) and YMG46 (right) cells after 3-day treatment with FK866 combined with DMSO control (blue bars) or TMZ (200 �M, purple bars). *, P

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.

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 GSK3β (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.

Supplementary Table from HSP90 Inhibition Overcomes Resistance to Molecular Targeted Therapy in BRAFV600E-mutant High-grade Glioma

Supplementary Table S1-S12

Purpose:Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression.Experimental Design:Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo.Results:A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1R132H and 1p/19q codeletion) and PIK3CAE542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo—evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma.Conclusions:Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

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., 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., 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., 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.

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.

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.

OBJECTIVESpinal arteriovenous shunts are rare vascular lesions and are classified into 4 types (types I–IV). Due to rapid advances in neuroimaging, spinal epidural AVFs (edAVFs), which are similar to type I spinal dural AVFs (dAVFs), have recently been increasingly reported. These 2 entities have several important differences that influence the treatment strategy selected. The purposes of the present study were to compare angiographic and clinical differences between edAVFs and dAVFs and to provide treatment strategies for edAVFs based on a multicenter cohort.METHODSA total of 280 consecutive patients with thoracic and lumbosacral spinal dural arteriovenous fistulas (dAVFs) and edAVFs with intradural venous drainage were collected from 19 centers. After angiographic and clinical comparisons, the treatment failure rate by procedure, risk factors for treatment failure, and neurological outcomes were statistically analyzed in edAVF cases.RESULTSFinal diagnoses after an angiographic review included 199 dAVFs and 81 edAVFs. At individual centers, 29 patients (36%) with edAVFs were misdiagnosed with dAVFs. Spinal edAVFs were commonly fed by multiple feeding arteries (54%) shunted into a single or multiple intradural vein(s) (91% and 9%) through a dilated epidural venous plexus. Preoperative modified Rankin Scale (mRS) and Aminoff-Logue gait and micturition grades were worse in patients with edAVFs than in those with dAVFs. Among the microsurgical (n = 42), endovascular (n = 36), and combined (n = 3) treatment groups of edAVFs, the treatment failure rate was significantly higher in the index endovascular treatment group (7.5%, 31%, and 0%, respectively). Endovascular treatment was found to be associated with significantly higher odds of initial treatment failure (OR 5.72, 95% CI 1.45–22.6). In edAVFs, the independent risk factor for treatment failure after microsurgery was the number of intradural draining veins (OR 17.9, 95% CI 1.56–207), while that for treatment failure after the endovascular treatment was the number of feeders (OR 4.11, 95% CI 1.23–13.8). Postoperatively, mRS score and Aminoff-Logue gait and micturition grades significantly improved in edAVFs with a median follow-up of 31 months.CONCLUSIONSSpinal epidural AVFs with intradural venous drainage are a distinct entity and may be classified as type V spinal vascular malformations. Based on the largest multicenter cohort, this study showed that primary microsurgery was superior to endovascular treatment for initial treatment success in patients with spinal edAVFs.

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.

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.

OBJECTIVE Craniocervical junction (CCJ) arteriovenous fistulas (AVFs) are treated using neurosurgical or endovascular options; however, there is still no consensus on the safest and most effective treatment. The present study compared the treatment results of neurosurgical and endovascular procedures for CCJ AVFs, specifically regarding retreatment, complications, and outcomes. METHODS This was a multicenter cohort study authorized by the Neurospinal Society of Japan. Data on consecutive patients with CCJ AVFs who underwent neurosurgical or endovascular treatment between 2009 and 2019 at 29 centers were analyzed. The primary endpoint was the retreatment rate by procedure. Secondary endpoints were the overall complication rate, the ischemic complication rate, the mortality rate, posttreatment changes in the neurological status, independent risk factors for retreatment, and poor outcomes. RESULTS Ninety-seven patients underwent neurosurgical (78 patients) or endovascular (19 patients) treatment. Retreatment rates were 2.6% (2/78 patients) in the neurosurgery group and 63% (12/19 patients) in the endovascular group (p < 0.001). Overall complication rates were 22% and 42% in the neurosurgery and endovascular groups, respectively (p = 0.084). Ischemic complication rates were 7.7% and 26% in the neurosurgery and endovascular groups, respectively (p = 0.037). Ischemic complications included 8 spinal infarctions, 2 brainstem infarctions, and 1 cerebellar infarction, which resulted in permanent neurological deficits. Mortality rates were 2.6% and 0% in the neurosurgery and endovascular groups, respectively (p > 0.99). Two patients died of systemic complications. The percentages of patients with improved modified Rankin Scale (mRS) scores were 60% and 37% in the neurosurgery and endovascular groups, respectively, with a median follow-up of 23 months (p = 0.043). Multivariate analysis identified endovascular treatment as an independent risk factor associated with retreatment (OR 54, 95% CI 9.9–300; p < 0.001). Independent risk factors associated with poor outcomes (a postoperative mRS score of 3 or greater) were a pretreatment mRS score of 3 or greater (OR 13, 95% CI 2.7–62; p = 0.001) and complications (OR 5.8; 95% CI 1.3–26; p = 0.020). CONCLUSIONS Neurosurgical treatment was more effective and safer than endovascular treatment for patients with CCJ AVFs because of lower retreatment and ischemic complication rates and better outcomes.

Purpose: Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. Experimental Design: Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo. Results: A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1R132H and 1p/19q codeletion) and PIK3CAE542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo—evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma. Conclusions: Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.

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.

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.

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.

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.We reviewed the medical records of 27 patients who underwent GKRS for asymptomatic obstructive hydrocephalus related to posterior fossa metastases.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) (P0.0001) 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 (P0.0001) and single and 2- or 3-fraction GKRS (P0.0001) were significantly correlated with unfavorable outcomes. All but 1 patient avoided surgical procedure for hydrocephalus after GKRS.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.

Aplastic or twig-like middle cerebral artery(Ap/T-MCA)is a rare congenital anomaly, and several cases of ruptured cerebral aneurysm associated with Ap/T-MCA have been reported. Recently, the association of ring finger protein 213(iRNF213/i)mutations with moyamoya disease has been identified, and the involvement of such mutations in intracranial arterial stenosis lesions other than those of moyamoya disease has been suggested. A 53-year-old woman with headache and nausea was admitted to our hospital. Computed tomography showed a diffuse subarachnoid hemorrhage. Cerebral angiography revealed left-sided Ap/T-MCA and two aneurysms in several fine arterioles. We performed trapping of these aneurysms. In the clinical course after surgery, she developed aphasia and mild motor paralysis. The patient was transferred to a rehabilitation hospital. The genetic screening revealed that she carried a heterozygous mutation ofiRNF213/i(c. 14429GA p. R4810K). This is the first report of an association between Ap/T-MCA andiRNF213/imutations. In patients with theiRNF213/imutation, there is also the possibility of a progression of the intracranial arterial stenosis to other sites. Such patients should be carefully observed after the completion of their treatment.

Cerebral bypass surgery, such as the superficial temporal artery-middle cerebral artery bypass, is one of the essential procedures for cerebral revascularization. However, very narrow or thin blood vessels will increase the risk of anastomotic problems, such as occurs in Moyamoya disease. For such vessels, we have devised a "lifting method" in the recipient arteriotomy. In the present study, we have introduced this novel optional technique and evaluated its effects.The lifting method is a procedure of lifting the incision edge of a linear incision on the recipient vessel to widen the ostium. We attempted the lifting method in 23 consecutive patients (41 arteries) and, as a historical control, compared the results with those from the conventional method in 25 consecutive patients (37 arteries) for the previous 3 years. We compared patient age, years of surgical experience, recipient vessel diameter, anastomotic events, and final patency. As a subanalysis, the same evaluations were performed separately for patients with Moyamoya disease. Furthermore, the time required for the lifting procedure was measured retrospectively.The incidence of anastomotic events with the conventional method was 13.5% overall and 19% in those with Moyamoya disease. No adverse events occurred with the lifting method (P0.05). No statistically significant differences were found for the other factors, including final patency between the 2 groups. The time required for the lifting procedure averaged 1 minute, 15 seconds.Use of the lifting method widens and secures the ostium in a recipient vessel and greatly facilitates operability. We have found it to be a foolproof method enabling safe and reliable anastomosis even with narrow or thin vessels.

OBJECTIVEThe 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).METHODSData 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.RESULTSSpinal 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).CONCLUSIONSBased 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.

Central nervous system hemangioblastoma is a benign tumor associated with or without von Hippel-Lindau (VHL) disease which is an autosomal dominant hereditary disease that results from a germline mutation in the VHL gene. A main axis of signaling pathways in central nervous system hemangioblastoma is VHL-HIF signaling pathway. Here, we propose an alternative VHL-JAK-STAT signaling pathway in hemangioblastoma and discuss the role. Using MACS method, Scl+ hemangioblast-like cells were isolated from multipotent nestin-expressing stem cells. Then, ubiquitination of JAK2 in those cells and immunoprecipitation between JAK2 and VHL were examined. Then, expressions of JAK2 and STAT3 in those cells and expressions of VHL-associated hemangioblastoma tissues were examined. In addition, the VHL genes of patients bearing hemangioblastoma were analyzed. JAK2 and STAT3 in Scl+ hemangioblast-like cells were ubiquitinated after VHL- expression vector was transferred to those cells. Expressions of JAK2 and STAT3 in those cells were well recognized before the transfer, but those disappeared after the transfer. Expressions of both JAK2 and STAT3 in hemangioblastoma tissues were well shown. The VHL gene analysis revealed that patients bearing hemangioblastoma carried missense mutations in 5, small deletions in 2, large deletions in 4, and nonsense mutation in 1 VHL-JAK-STAT signaling pathway might play an important role in proliferation, angiogenesis, and maintenance of stem-cell-nature in hemangioblastoma as an alternative signaling pathway to supplement VHL-HIF signaling pathway.

Background Paragangliomas are generally benign, slow-growing tumors. However, approximately 10%–20% are malignant, characterized by distant metastasis. Recently, a germ line mutation in succinate dehydrogenase B subunit (SDHB) has been shown to be associated with malignant behavior in paraganglioma. Here we present a case of SDHB-negative malignant paraganglioma of the jugular foramen with a pseudohypoxic microenvironment and unique imaging features on [18F]-fluoro-2-deoxy- d -glucose positron emission tomography ([18F]-FDG PET), and discuss the significance of SDHB immunohistochemistry and the potential of [18F]-FDG PET for clinical management. Case Description A 55-year-old woman was diagnosed with jugular foramen paraganglioma. Initial surgical resection was performed; however, follow-up [18F]-FDG PET indicated multiple uptake regions throughout the body. Biopsies for multiple recurrent lesions revealed consistent pathological features, suggesting distant metastasis. Immunohistochemical analysis revealed a lack of SDHB immunostaining in all specimens. Pseudohypoxic markers, including hypoxia-inducible factor-1α and downstream glycolysis enzymes, were strongly expressed. [18F]-FDG PET demonstrated increased uptake in the lesions, and the patient died 3 years after initial metastasis. Conclusion In patients with head and neck paraganglioma without SDHB expression, close follow-up should be considered because of the risk for metastasis. In such cases, [18F]-FDG PET might be useful for detecting metastasis due to atypical accumulation from pseudohypoxia-induced glycolysis.

Background Bow hunter's syndrome (BHS) is rare and typically induced by mechanical compression of the dominant vertebral artery (VA) during head rotation. We report a case of BHS induced by nondominant VA compression in which contralateral VA patency was preserved. Definite diagnosis of BHS is not often feasible because of transient symptoms and nonspecific clinical features, such as vertigo or dizziness, especially in nondominant VA compression. We discuss the diagnostic clues of BHS and clinical features of BHS caused by nondominant VA compression through a literature review. Case Description A 65-year-old man suffered repeated bouts of dizziness whenever his head was rotated to the left. This dizziness was consistently accompanied by downbeat nystagmus (DBN). Radiography revealed left VA compression by a lateral osteophyte at the C3-C4 level only during left head rotation. In contrast, patency of the right VA, which was almost equivalent in size to the left VA, was preserved during head rotation. The distinctive clinical finding of head rotation-induced DBN, which is usually associated with lesions involving the caudal midline cerebellum, was observed. Symptoms disappeared immediately after left VA decompression with osteophytectomy and C3-C4 fusion. Conclusions Despite excellent flow through the contralateral VA, occlusion of the nondominant VA occasionally induces BHS. According to a review of the literature, BHS cases do not always depend on the VA on one side for blood supply. Head rotation–induced DBN can be useful for diagnosis of BHS, even in cases of nondominant VA compression.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of extranodal non-Hodgkin lymphoma that carries an unsatisfactory prognosis. Treating refractory PCNSL is challenging because of resistance to conventional cytotoxic and intrathecal chemotherapies. Therefore, novel therapeutic approaches are needed. Here, we report a 12-year-old boy with CD20-positive PCNSL, which was refractory to combination chemotherapy and intravenous rituximab. However, the patient achieved complete remission after repeated intraventricular rituximab administration. The results of this case indicate that intraventricular rituximab is an effective option to treat refractory PCNSL in children.

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.