Clinical outcomes of stereotactic biopsy on children with pontine diffuse midline glioma.

INTRODUCTION: Diffuse midline glioma (DMG) of the pons occurs in pediatric patients and carries a dismal prognosis. Biopsy is not necessary for diagnosis but provides information, particularly H3K27M status, with prognostic implications. Additionally, biopsy information may open therapeutic options such as clinical trials that require mutation status. Therefore, we sought to assess the safety of surgical biopsy in DMG patients as well as its potential impact on clinical course. METHODS: Retrospective analysis of patients who were radiographically and clinically diagnosed with pontine DMG in the last 5 years was performed. We assessed demographic, clinical, radiographic, surgical, and follow-up data. RESULTS: 25 patients were included; 18 (72%) underwent biopsy while 7 (28%) declined. 12 biopsies (67%) were performed with robotic arm and 5 (27%) with frameless stereotaxy. Three biopsied patients (17%) experienced new post-operative neurologic deficits (1 facial palsy, 1 VI nerve palsy and 1 ataxia) that all resolved at 2-week follow-up. All biopsies yielded diagnostic tissue. Fourteen patients (78%) had H3K27M mutation. Median OS for H3K27M patients was 10 months compared to 11 months in the wild-type patients (p = 0.30, log-rank test). Median OS for patients enrolled in clinical trials was 12 months compared to 8 months for non-trial patients (p = 0.076). CONCLUSION: In our series, stereotactic pontine DMG biopsies did not carry any permanent deficit or complication and yielded diagnostic tissue in all patients. Similar post-operative course was observed in both robot-assisted and frameless stereotactic approaches. There was no significant difference in survival based on mutation status or clinical trial enrollment.

Seizure outcomes after resection of primary brain tumors in pediatric patients: a systematic review and meta-analysis.

PURPOSE: Primary brain neoplasms are the most common solid tumors in pediatric patients and seizures are a common presenting symptom. Surgical intervention improves oncologic outcomes and seizure burden. A better understanding of factors that influence seizure outcomes in the surgical management of primary brain tumors of childhood can guide treatment approach thereby improving patient quality of life. METHODS: We performed a systematic analysis using articles queried from PubMed, EMBASE, and Cochrane published from January 1990 to August 2022 to determine predictors of seizure outcomes in pediatric patients undergoing resection of primary brain tumors. RESULTS: We identified 24 retrospective cohort studies, one prospective cohort study, and one mixed retrospective and prospective study for the systematic analysis. A total of 831 pediatric patients were available for analysis. 668 (80.4%) patients achieved seizure freedom after surgery. Complete tumor resection increased the likelihood of a seizure-free (Engel I) outcome compared to subtotal resection (OR 7.1, 95% CI 2.3-21.9). Rates of Engel I seizure outcomes did not significantly differ based on factors such as age at seizure onset, duration of epilepsy, gender, tumor laterality, or age at surgery, but trended towards significance for improved outcomes in temporal lobe tumors. CONCLUSION: Primary brain tumors in the pediatric population are commonly associated with seizures. Resection of these lesions reduces seizure burden and is associated with high rates of seizure freedom. Complete resection, compared to subtotal resection, significantly increases the likelihood of seizure-free outcomes.

Integrated clinical genomic analysis reveals xenobiotic metabolic genes are downregulated in meningiomas of current smokers.

INTRODUCTION: Meningiomas are the most common primary intracranial tumor. Recently, various genetic classification systems for meningioma have been described. We sought to identify clinical drivers of different molecular changes in meningioma. As such, clinical and genomic consequences of smoking in patients with meningiomas remain unexplored. METHODS: 88 tumor samples were analyzed in this study. Whole exome sequencing (WES) was used to assess somatic mutation burden. RNA sequencing data was used to identify differentially expressed genes (DEG) and genes sets (GSEA). RESULTS: Fifty-seven patients had no history of smoking, twenty-two were past smokers, and nine were current smokers. The clinical data showed no major differences in natural history across smoking status. WES revealed absence of AKT1 mutation rate in current or past smokers compared to non-smokers (p = 0.046). Current smokers had increased mutation rate in NOTCH2 compared to past and never smokers (p < 0.05). Mutational signature from current and past smokers showed disrupted DNA mismatch repair (cosine-similarity = 0.759 and 0.783). DEG analysis revealed the xenobiotic metabolic genes UGT2A1 and UGT2A2 were both significantly downregulated in current smokers compared to past (Log2FC = - 3.97, padj = 0.0347 and Log2FC = - 4.18, padj = 0.0304) and never smokers (Log2FC = - 3.86, padj = 0.0235 and Log2FC = - 4.20, padj = 0.0149). GSEA analysis of current smokers showed downregulation of xenobiotic metabolism and enrichment for G2M checkpoint, E2F targets, and mitotic spindle compared to past and never smokers (FDR < 25% each). CONCLUSION: In this study, we conducted a comparative analysis of meningioma patients based on their smoking history, examining both their clinical trajectories and molecular changes. Meningiomas from current smokers were more likely to harbor NOTCH2 mutations, and AKT1 mutations were absent in current or past smokers. Moreover, both current and past smokers exhibited a mutational signature associated with DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Furthermore, current smokers exhibited downregulation xenobiotic metabolic gene sets, as well as enrichment in gene sets related to mitotic spindle, E2F targets, and G2M checkpoint, which are hallmark pathways involved in cell division and DNA replication control. In aggregate, our results demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.

Thoracolumbar Scoliosis in Pediatric Patients With Loeys-Dietz Syndrome: A Case Series.

Background Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder that predominantly affects cardiovascular, skeletal, and craniofacial structures. Associated thoracolumbar scoliosis in LDS can be challenging to manage, though other etiologies of pediatric scoliosis have better-defined management guidelines. We examined our institutional experience regarding the treatment of pediatric patients with LDS and scoliosis. Methodology In this retrospective study, all patients seen at our pediatric tertiary care center from 2004 through 2018 with a diagnosis of LDS were reviewed, and those with radiographic diagnoses of scoliosis (full-length scoliosis X-rays) were included. Demographic, clinical, and radiographic parameters were collected, and management strategies were reported. Results A total of 39 LDS patients whose ages ranged between seven and 13 years were identified. A total of nine patients were radiographically diagnosed with scoliosis, but three patients were excluded due to incomplete medical records, leaving six patients. The median age at scoliosis diagnosis was 11.5 years, with a median follow-up of 51 months. Two patients were successfully managed with observation (average initial Cobb angle (CA): 14°, average final CA: 20.5°). Two were braced, one successfully (initial CA: 15°, final CA: 30°) and one with a progressive disease requiring surgery (initial CA: 40°, final CA: 58°). Of the two who were offered surgical correction, one underwent surgery with a durable correction of spinal deformity (CA: 33° to 19°). One patient underwent a recent correction of aortic root dilatation and was not a candidate for scoliosis surgery. Conclusions Principles of adolescent idiopathic scoliosis management such as bracing for CA of 20-50° and surgery for CA of >50° can be applied to LDS patients with good outcomes. This augments our understanding of the treatment algorithm for pediatric patients with LDS.

CXCR4 expression is associated with proneural-to-mesenchymal transition in glioblastoma.

Glioblastoma (GBM) is the most common primary intracranial malignant tumor and consists of three molecular subtypes: proneural (PN), mesenchymal (MES) and classical (CL). Transition between PN to MES subtypes (PMT) is the glioma analog of the epithelial-mesenchymal transition (EMT) in carcinomas and is associated with resistance to therapy. CXCR4 signaling increases the expression of MES genes in glioma cell lines and promotes EMT in other cancers. RNA sequencing (RNAseq) data of PN GBMs in The Cancer Genome Atlas (TCGA) and secondary high-grade gliomas (HGGs) from an internal cohort were examined for correlation between CXCR4 expression and survival as well as expression of MES markers. Publicly available single-cell RNA sequencing (scRNAseq) data was analyzed for cell type specific CXCR4 expression. These results were validated in a genetic mouse model of PN GBM. Higher CXCR4 expression was associated with significantly reduced survival and increased expression of MES markers in TCGA and internal cohorts. CXCR4 was expressed in immune and tumor cells based on scRNAseq analysis. Higher CXCR4 expression within tumor cells on scRNAseq was associated with increased MES phenotype, suggesting a cell-autonomous effect. In a genetically engineered mouse model, tumors induced with CXCR4 exhibited a mesenchymal phenotype and shortened survival. These results suggest that CXCR4 signaling promotes PMT and shortens survival in GBM and highlights its inhibition as a potential therapeutic strategy.

PulseRider-assisted embolization of a distal anterior cerebral artery bifurcation aneurysm: illustrative case.

BACKGROUND: PulseRider is an endovascular device that can be a useful adjunctive device for wide-necked bifurcation aneurysms. However, its use in distal vessels such as the anterior cerebral artery (ACA) has not been widely reported. OBSERVATIONS: The authors reported the case of a 75-year-old woman who underwent coiling of a 6.9-mm distal ACA aneurysm with PulseRider assistance. Using a partially intraaneurysmal deployment technique, the wide-necked aneurysm was successfully embolized, resulting in Raymond-Roy class II occlusion without intra- or periprocedural complications. LESSONS: This case illustrates a novel approach to treatment for wide-necked distal ACA aneurysms, which can be challenging to treat via traditional endovascular means. PulseRider can be safely used to treat distal ACA aneurysms with minimal residual aneurysm.

Myeloid sarcoma of the skull base: A case report and systematic literature review.

Background: Myeloid sarcoma (MS), or chloroma, is a rare extramedullary malignant tumor that consists of undifferentiated granulocytic cells, and it is most commonly associated with acute myeloid leukemia (AML). Intracranial MS accounts for 0.4% of MS cases, and involvement of the skull base and visual dysfunction is rarely reported. However, the optimal treatment and response to treatment of skull base MS in the presence of visual symptoms is unknown. Case Description: A 30-year-old male with a history of AML presented with rapidly progressive vision loss and a sellar and parasellar mass with bilateral cavernous sinus and optic nerve encasement. The patient underwent endoscopic endonasal transsphenoidal biopsy revealing intracranial MS. He was treated postoperatively with high-dose intravenous and intrathecal cytarabine and had complete restoration of his vision by postoperative day 11. A systematic review of the literature identified six cases of skull base MS, five of whom presenting with visual symptoms. All patients underwent systemic chemotherapy with cytarabine and/or cyclophosphamide, with infrequent use of intrathecal chemotherapy or radiation. Those with reported visual outcomes were diagnosed 4 months or longer after symptom onset and demonstrated no visual improvement with treatment. Conclusion: Skull base MS is a rare disease entity with a high prevalence of visual dysfunction. Our patient's complete disappearance of intracranial disease and resolution of visual symptoms with systemic and intrathecal chemotherapy highlight the importance of timely diagnosis and appropriate treatment without a need for direct surgical decompression.

3-Dimensional Modeling in Virtual Reality for Resection of a Pineal Region Falcotentorial Meningioma.

We present a parietal interhemispheric approach to resect a pineal region falcotentorial meningioma. Three-dimensional (3D) modeling was used to visualize and plan the surgical approach in virtual reality (Video 1). A 78-year-old woman was incidentally found to have a slow-growing falcotentorial meningioma. The tumor was first treated with stereotactic radiosurgery, but the patient had progressive confusion, memory issues, and bilateral temporal field cuts with interval expansion of the tumor and significantly increased peritumoral vasogenic edema on magnetic resonance imaging. After recommending tumor resection, the patient consented to surgery and underwent resection via a posterior interhemispheric subsplenial approach. Using a 3D model in virtual reality, we discuss the advantages and disadvantages of various classical approaches to the pineal region for resection of this tumor.1-3 Falcotentorial meningiomas often displace the deep veins inferiorly, making an interhemispheric approach more favorable.4-6 Preoperative visualization of critical deep venous structures with the 3D model was a valuable adjunct to magnetic resonance imaging for achieving safe resection. We depict key steps of the surgical planning process using virtual reality and demonstrate how simulation can be used to evaluate risks and benefits of different surgical corridors. A small rim of residual tumor adherent to the deep cerebral veins was intentionally left behind in order to minimize risk of morbidity to the patient.7 At 1-month follow-up, the patient's cognition had returned to baseline and her vision had significantly improved. Ultimately, surgical planning using virtual reality promotes both neurosurgical education and patient safety through clear visualization and understanding of different surgical approaches.

Racial and Socioeconomic Disparities in Patients With Meningioma: A Retrospective Cohort Study.

BACKGROUND: Meningiomas are the most common intracranial neoplasms. Although genomic analysis has helped elucidate differences in survival, there is evidence that racial disparities may influence outcomes. African Americans have a higher incidence of meningiomas and poorer survival outcomes. The etiology of these disparities remains unclear, but may include a combination of pathophysiology and other factors. OBJECTIVE: To determine factors that contribute to different clinical outcomes in racial populations. METHODS: We retrospectively reviewed 305 patients who underwent resection for meningiomas at a single tertiary care facility. We used descriptive statistics and univariate, multivariable, and Kaplan-Meier analyses to study clinical, radiographical, and histopathological differences. RESULTS: Minority patients were more likely to present through the emergency department than an outpatient clinic (P < .0001). They were more likely to present with more advanced clinical symptoms with lower Karnofsky Performance scores, more frequently had peritumoral edema (P = .0031), and experienced longer postoperative stays in the hospital (P = .0053), and African-American patients had higher hospitalization costs (P = .046) and were more likely to be publicly insured. Extent of resection was an independent predictor of recurrence freedom (P = .039). Presentation in clinic setting trended toward an association with recurrence-free survival (P = .055). We observed no significant difference in gross total resection rates, postoperative recurrence, or recurrence-free survival. CONCLUSION: Minority patients are more likely to present with severe symptoms, require longer perioperative hospitalization, and generate higher hospitalization costs. This may be due to socioeconomic factors that affect access to health care. Targeting barriers to access, especially to subspecialty care, may facilitate more appropriate and timely diagnosis, thereby improving patient care and outcomes.

Prolonged survival after laser interstitial thermal therapy in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Management includes surgical resection followed by chemoradiation, and prognosis remains poor. Surgical resection is not possible for some deep-seated or eloquent tumors. Laser interstitial thermal therapy (LITT) has emerged as a new, minimally invasive surgical option for deep-seated GBM. CASE DESCRIPTION: We report a case of newly diagnosed thalamic GBM managed with LITT followed by radiation and chemotherapy. CONCLUSION: The patient remains well at 50-month post-LITT, indicating a potentially unique durability of LITT treatment in GBM.

Predictors of postoperative seizure outcome in supratentorial meningioma.

OBJECTIVE: Meningiomas are the most common primary intracranial tumor. Seizures are common sequelae of meningioma development. Meningioma patients with seizures can be effectively treated with resection, with reports of seizure freedom of 60%-90%. Still, many patients manifest persistent epilepsy. Determining factors associated with worsened seizure outcomes remains critical in improving the quality of life for these patients. The authors sought to identify clinical, radiological, and histological factors associated with worse seizure outcomes in patients with supratentorial meningioma and preoperative seizures. METHODS: The authors retrospectively reviewed the charts of 384 patients who underwent meningioma resection from 2008 to 2020. The charts of patients with a documented history of preoperative seizures were further reviewed for clinical, radiological, operative, perioperative, histological, and postoperative factors associated with seizures. Engel class at last follow-up was retrospectively assigned by the authors and further grouped into favorable (class I) and worse (class II-IV) outcomes. Factors were subsequently compared by group using comparative statistics. Univariable and multivariable regression models were utilized to identify independent predictors of worse seizure outcome. RESULTS: Fifty-nine patients (15.4%) were found to have preoperative seizures, of whom 57 had sufficient postoperative data to determine Engel class outcome. Forty-two patients (74%) had Engel class I outcomes. The median follow-up was 17 months. Distinct margins on preoperative imaging (p = 0.012), Simpson grade I resection (p = 0.004), postresection ischemia (p = 0.019), WHO grade (p = 0.019), and recurrent disease (p = 0.015) were found to be the strongest predictors of Engel class outcome in univariable logistic regression. MIB-1 index (p = 0.001) and residual volume (p = 0.014) at last follow-up were found to be the strongest predictors of Engel class outcome in univariable generalized linear regression. Postresection ischemia (p = 0.012), WHO grade (p = 0.022), recurrent disease (p = 0.038), and MIB-1 index (p = 0.002) were found to be the strongest independent predictors of Engel class outcomes in multivariable analysis. CONCLUSIONS: Postresection ischemia, higher WHO grade, elevated MIB-1 index, and disease recurrence independently predict postresection seizure persistence in patients with supratentorial meningioma. Further understanding of the etiology of these markers may aid in elucidation of this complex disease process and guide management to prevent worse outcomes.

Identification of novel fusion transcripts in meningioma.

INTRODUCTION: Meningiomas are the most common primary intracranial tumor. Recent next generation sequencing analyses have elaborated the molecular drivers of this disease. We aimed to identify and characterize novel fusion genes in meningiomas. METHODS: We performed a secondary analysis of our RNA sequencing data of 145 primary meningioma from 140 patients to detect fusion genes. Semi-quantitative rt-PCR was performed to confirm transcription of the fusion genes in the original tumors. Whole exome sequencing was performed to identify copy number variations within each tumor sample. Comparative RNA seq analysis was performed to assess the clonality of the fusion constructs within the tumor. RESULTS: We detected six fusion events (NOTCH3-SETBP1, NF2-SPATA13, SLC6A3-AGBL3, PHF19-FOXP2 in two patients, and ITPK1-FBP2) in five out of 145 tumor samples. All but one event (NF2-SPATA13) led to extremely short reading frames, making these events de facto null alleles. Three of the five patients had a history of childhood radiation. Four out of six fusion events were detected in expression type C tumors, which represent the most aggressive meningioma. We validated the presence of the RNA transcripts in the tumor tissue by semi-quantitative RT PCR. All but the two PHF19-FOXP2 fusions demonstrated high degrees of clonality. CONCLUSIONS: Fusion genes occur infrequently in meningiomas and are more likely to be found in tumors with greater degree of genomic instability (expression type C) or in patients with history of cranial irradiation.

Accuracy and Workflow Improvements for Responsive Neurostimulation Hippocampal Depth Electrode Placement Using Robotic Stereotaxy.

Background: Robotic stereotaxy is increasingly common in epilepsy surgery for the implantation of stereo-electroencephalography (sEEG) electrodes for intracranial seizure monitoring. The use of robots is also gaining popularity for permanent stereotactic lead implantation applications such as in deep brain stimulation and responsive neurostimulation (RNS) procedures. Objective: We describe the evolution of our robotic stereotactic implantation technique for placement of occipital-approach hippocampal RNS depth leads. Methods: We performed a retrospective review of 10 consecutive patients who underwent robotic RNS hippocampal depth electrode implantation. Accuracy of depth lead implantation was measured by registering intraoperative post-implantation fluoroscopic CT images and post-operative CT scans with the stereotactic plan to measure implantation accuracy. Seizure data were also collected from the RNS devices and analyzed to obtain initial seizure control outcome estimates. Results: Ten patients underwent occipital-approach hippocampal RNS depth electrode placement for medically refractory epilepsy. A total of 18 depth electrodes were included in the analysis. Six patients (10 electrodes) were implanted in the supine position, with mean target radial error of 1.9 ± 0.9 mm (mean ± SD). Four patients (8 electrodes) were implanted in the prone position, with mean radial error of 0.8 ± 0.3 mm. The radial error was significantly smaller when electrodes were implanted in the prone position compared to the supine position (p = 0.002). Early results (median follow-up time 7.4 months) demonstrate mean seizure frequency reduction of 26% (n = 8), with 37.5% achieving ≥50% reduction in seizure frequency as measured by RNS long episode counts. Conclusion: Prone positioning for robotic implantation of occipital-approach hippocampal RNS depth electrodes led to lower radial target error compared to supine positioning. The robotic platform offers a number of workflow advantages over traditional frame-based approaches, including parallel rather than serial operation in a bilateral case, decreased concern regarding human error in setting frame coordinates, and surgeon comfort.

The Role of Merlin/NF2 Loss in Meningioma Biology.

Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of NF2 mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin's many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated NF2-deletion-based in vitro and in vivo models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor.

Infundibular Epidermoid Cyst: Case Report and Systematic Review.

BACKGROUND: Intracranial epidermoid cysts are benign, congenital, keratinizing, squamous epithelial-lined cysts filled with keratin. They are uncommon and often pose a surgical challenge owing to the adherence to surrounding structures. They are typically found at the cerebellopontine angle or in the parasellar region, where they are associated with abnormal development of the Rathke pouch; involvement of the pituitary stalk is rare. CASE DESCRIPTION: The patient's electronic health record was queried for relevant data. A systematic review of the literature using dedicated search terms for cases of infundibular epidermoid cysts was conducted. We present a unique case of a 55-year-old male who presented with vision changes and was found to have a parasellar epidermoid cyst confined to the pituitary stalk. The patient underwent endoscopic transsphenoidal resection, and gross total resection was achieved. The patient's postoperative course was significant for possible chemical meningitis and the development of panhypopituitarism. The patient's vision subjectively improved after surgery. CONCLUSIONS: Although 3 other cases of epidermoid cysts involving the pituitary stalk were identified, our patient's tumor was unique in that it was confined to the stalk. Our patient's case highlights a surgical approach to parasellar epidermoid cysts and the possible complications associated therewith.

Endovascular "Boost": External Carotid Angioplasty to Augment Flow Before Superficial Temporal-Middle Cerebral Artery Bypass.

BACKGROUND: Superficial temporal artery-middle cerebral artery (STA-MCA) bypass may be used to augment cerebral blood flow in patients with select cerebrovascular pathologies or after failed attempts at revascularization. In this article we describe the use of balloon angioplasty to boost the flow of the external carotid artery (ECA) including the STA to be later used as a donor artery for a STA-MCA bypass procedure. CASE DESCRIPTION: A 67-year-old male with bilateral carotid artery stenosis presented 2 days after a right middle cerebral artery (MCA) stroke and was admitted for medical management. Over the next 4 days his examination worsened; magnetic resonance imaging and computed tomography perfusion confirmed a right MCA stroke with penumbra and angiography revealed complete occlusion of the right internal carotid artery within a prior carotid stent. There was also a right ECA stenosis at its origin, thus limiting options for traditional extracranial-intracranial bypass. Therefore the patient underwent balloon angioplasty of the right ECA by traversing the carotid stent followed by right STA-MCA bypass, resulting in increased flow, clinical stability, and improved cerebral perfusion. CONCLUSIONS: This case highlights a unique strategy for the management of internal carotid artery occlusion in combination with an ipsilateral ECA stenosis. We also demonstrate the utility of endovascular adjuncts to open vascular surgery when complex patterns of stenosis or occlusion exist.

Back Muscle Morphometry: Effects on Outcomes of Spine Surgery.

BACKGROUND: This review seeks to synthesize emerging literature on the effects of back muscle size on outcomes in spine surgery. Risk factors that contribute to poor surgical outcomes continue to be an area of interest in spine surgery because proper risk stratification can result in reduction in morbidity and enhanced patient care. However, the impact of muscle size on spine surgical outcomes is an understudied avenue with paucity of data evaluating the relationship among back muscles and surgical outcomes, patient's quality of life, and functional improvement postoperatively. METHODS: This review was centered around identifying studies that assessed the impact of back muscle size on spine surgery outcomes. RESULTS: Five retrospective studies were selected for review. All studies set out to see if differences in muscle size existed in patients with disparate post-operative outcomes as a primary objective. The studies support the association between larger back muscles and improved outcomes. The size and relative cross sectional area of paraspinal muscles and the size of the psoas muscle were associated with functional outcomes, incidence of complications and also fusion rates. CONCLUSION: With reduction in surgical complications and improvement in postoperative functional outcomes, back muscle morphometry ought to be included in the preoperative surgical planning as a predictor of outcomes.

Inositol Hexakisphosphate Kinase-3 Regulates the Morphology and Synapse Formation of Cerebellar Purkinje Cells via Spectrin/Adducin.

The inositol hexakisphosphate kinases (IP6Ks) are the principal enzymes that generate inositol pyrophosphates. There are three IP6Ks (IP6K1, 2, and 3). Functions of IP6K1 and IP6K2 have been substantially delineated, but little is known of IP6K3's role in normal physiology, especially in the brain. To elucidate functions of IP6K3, we generated mice with targeted deletion of IP6K3. We demonstrate that IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells. IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. Consequently, IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. Thus, IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells. SIGNIFICANCE STATEMENT: We identified and cloned a family of three inositol hexakisphosphate kinases (IP6Ks) that generate the inositol pyrophosphates, most notably 5-diphosphoinositol pentakisphosphate (IP7). Of these, IP6K3 has been least characterized. In the present study we generated IP6K3 knock-out mice and show that IP6K3 is highly expressed in cerebellar Purkinje cells. IP6K3-deleted mice display defects of motor learning and coordination. IP6K3-null mice manifest aberrations of Purkinje cells with a diminished number of synapses. IP6K3 interacts with the cytoskeletal proteins spectrin and adducin whose altered disposition in IP6K3 knock-out mice may mediate phenotypic features of the mutant mice. These findings afford molecular/cytoskeletal mechanisms by which the inositol polyphosphate system impacts brain function.

Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNA repair and cell death.

Inositol polyphosphates containing an energetic pyrophosphate bond are formed primarily by a family of three inositol hexakisphosphate (IP6) kinases (IP6K1-3). The Cullin-RING ubiquitin ligases (CRLs) regulate diverse biological processes through substrate ubiquitylation. CRL4, comprising the scaffold Cullin 4A/B, the E2-interacting Roc1/2, and the adaptor protein damage-specific DNA-binding protein 1, is activated by DNA damage. Basal CRL4 activity is inhibited by binding to the COP9 signalosome (CSN). UV radiation and other stressors dissociate the complex, leading to E3 ligase activation, but signaling events that trigger signalosome dissociation from CRL4 have been unclear. In the present study, we show that, under basal conditions, IP6K1 forms a ternary complex with CSN and CRL4 in which IP6K1 and CRL4 are inactive. UV dissociates IP6K1 to generate IP7, which then dissociates CSN-CRL4 to activate CRL4. Thus, IP6K1 is a novel CRL4 subunit that transduces UV signals to mediate disassembly of the CRL4-CSN complex, thereby regulating nucleotide excision repair and cell death.