A comparison of endoscopic endonasal versus open approaches for skull base chordoma: a comprehensive National Cancer Database analysis.

OBJECTIVE: The authors of this study aimed to investigate independent prognostic factors of survival with a particular focus on comparing the safety and efficacy of endoscopic endonasal versus open approaches in the surgical management of skull base chordoma. METHODS: A retrospective National Cancer Database review of skull base chordoma patients was performed to capture resection cases from 2010 to 2020, evaluating overall survival (OS), early postoperative mortality, readmission rates, and hospital length of stay (LOS) between surgical approaches and the independent prognostication of death utilizing Cox multivariate regression analysis. RESULTS: Among the 736 patients included in the cohort, 456 patients (62.0%) and 280 patients (38.0%) underwent endoscopic endonasal and open resection, respectively. These values represent a rate of change over the study period of +4.1 versus -0.14 cases per year, respectively. Gross-total resection was achieved in 32.5% of cases. A positive margin status was found in 51.8% of cases. There was no association between extent of resection and surgical approach (p = 0.257). There was no difference in OS (p = 0.562), 30- and 90-day mortality (p = 0.209 and 0.126, respectively), and 30-day readmission (p = 0.438) between the two surgical groups. The mean LOS was reduced by 2.1 days in the endoscopic cohort (p = 0.013) compared with the open approach cohort. Finally, multivariate analysis revealed a tumor size ≥ 4 cm (HR 4.03, p = 0.005) and public insurance (HR 2.76, p = 0.004) as negative predictors of survival and treatment at an academic center (HR 0.36, p = 0.043) as a positive prognosticator of survival. CONCLUSIONS: The endoscopic endonasal approach has been increasingly utilized over time and touts noninferiority with respect to safety and efficacy with a marked improvement in LOS, which carries substantial implications for both healthcare costs and enhanced patient recovery. Future prospective studies are necessary to further delineate trends and surgical outcomes for skull base chordoma.

Pathologic features of brain hemorrhage after radiation treatment: case series with somatic mutation analysis.

BACKGROUND: Radiation treatment for diseases of the brain can result in hemorrhagic adverse radiation effects. The underlying pathologic substrate of brain bleeding after irradiation has not been elucidated, nor potential associations with induced somatic mutations. METHODS: We retrospectively reviewed our department's pathology database over 5 years and identified 5 biopsy specimens (4 patients) for hemorrhagic lesions after brain irradiation. Tissues with active malignancy were excluded. Samples were characterized using H&E, Perl's Prussian Blue, and Masson's Trichrome; immunostaining for B-cells (anti-CD20), T-cells (anti-CD3), endothelium (anti-CD31), macrophages (anti-CD163), α-smooth muscle actin, and TUNEL. DNA analysis was done by two panels of next-generation sequencing for somatic mutations associated with known cerebrovascular anomalies. RESULTS: One lesion involved hemorrhagic expansion among multifocal microbleeds that had developed after craniospinal irradiation for distant medulloblastoma treatment. Three bleeds arose in the bed of focally irradiated arteriovenous malformations (AVM) after confirmed obliteration. A fifth specimen involved the radiation field distinct from an irradiated AVM bed. From these, 2 patterns of hemorrhagic vascular pathology were identified: encapsulated hematomas and cavernous-like malformations. All lesions included telangiectasias with dysmorphic endothelium, consistent with primordial cavernous malformations with an associated inflammatory response. DNA analysis demonstrated genetic variants in PIK3CA and/or PTEN genes but excluded mutations in CCM genes. CONCLUSIONS: Despite pathologic heterogeneity, brain bleeding after irradiation is uniformly associated with primordial cavernous-like telangiectasias and disruption of genes implicated in dysangiogenesis but not genes implicated as causative of cerebral cavernous malformations. This may implicate a novel signaling axis as an area for future study.

Cerebrovascular Complications in Early Survivors of Civilian Penetrating Brain Injury.

BACKGROUND: This study investigates the presence of cerebrovascular injuries in a large sample of civilian penetrating brain injury (PBI) patients, determining the prevalence, radiographic characteristics, and impact on short-term outcome. METHODS: We retrospectively reviewed patients with PBI admitted to our institution over a 2-year period. Computed tomography head scans, computer tomography angiograms and venograms of the intracranial vessels were evaluated to determine the wound trajectory, intracranial injury characteristics, and presence of arterial (AI) and venous sinus (VSI) injuries. Demographics, clinical presentation, and treatment were also reviewed. Discharge disposition was used as surrogate of short-term outcome. RESULTS: Seventy-two patients were included in the study. The mechanism of injury was gunshot wounds in 71 patients and stab wound in one. Forty-one of the 72 patients (60%) had at least one vascular injury. Twenty-six out of 72 patients suffered an AI (36%), mostly pseudoaneurysms and occlusions, involving the anterior and middle cerebral arteries. Of the 72 patients included, 45 had dedicated computed tomography venograms, and of those 22 had VSI (49%), mainly manifesting as superior sagittal sinus occlusion. In a multivariable regression model, intraventricular hemorrhage at presentation was associated with AI (OR 9.9, p = 0.004). The same was not true for VSI. CONCLUSION: Acute traumatic cerebrovascular injury is a prevalent complication in civilian PBI, frequently involving both the arterial and venous sinus systems. Although some radiographic features might be associated with presence of vascular injury, assessment of the intracranial vasculature in the acute phase of all PBI is essential for early diagnosis. Treatment of vascular injury remains variable depending on local practice.

Phantom validation of quantitative susceptibility and dynamic contrast-enhanced permeability MR sequences across instruments and sites.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative permeability (DCEQP) on magnetic resonance (MR) have been shown to correlate with neurovascular disease progression as markers of vascular leakage and hemosiderin deposition. Applying these techniques as monitoring biomarkers in clinical trials will be necessary; however, their validation across multiple MR platforms and institutions has not been rigorously verified. PURPOSE: To validate quantitative measurement of MR biomarkers on multiple instruments at different institutions. STUDY TYPE: Phantom validation between platforms and institutions. PHANTOM MODEL: T1 /susceptibility phantom, two-compartment dynamic flow phantom. FIELD STRENGTH/SEQUENCE: 3T/QSM, T1 mapping, dynamic 2D SPGR. ASSESSMENT: Philips Ingenia, Siemens Prisma, and Siemens Skyra at three different institutions were assessed. A QSM phantom with concentrations of gadolinium, corresponding to magnetic susceptibilities of 0, 0.1, 0.2, 0.4, and 0.8 ppm was assayed. DCEQP was assessed by measuring a MultiHance bolus as the consistency of the width ratio of the curves at the input and outputs over a range of flow ratios between outputs. STATISTICAL TESTS: Each biomarker was assessed by measures of accuracy (Pearson correlation), precision (paired t-test between repeated measurements), and reproducibility (analysis of covariance [ANCOVA] between instruments). RESULTS: QSM accuracy of r2 > 0.997 on all three platforms was measured. Precision (P = 0.66 Achieva, P = 0.76 Prisma, P = 0.69 Skyra) and reproducibility (P = 0.89) were good. T1 mapping of accuracy was r2 > 0.98. No significant difference between width ratio regression slopes at site 2 (P = 0.669) or site 3 (P = 0.305), and no significant difference between width ratio regression slopes between sites was detected by ANCOVA (P = 0.48). DATA CONCLUSION: The phantom performed as expected and determined that MR measures of QSM and DCEQP are accurate and consistent across repeated measurements and between platforms. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1192-1199.

The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation.

Epithelial barrier maintenance and regulation requires an intact perijunctional actomyosin ring underneath the cell-cell junctions. By searching for known factors affecting the actin cytoskeleton, we identified Krev interaction trapped protein 1 (KRIT1) as a major regulator for epithelial barrier function through multiple mechanisms. KRIT1 is expressed in both small intestinal and colonic epithelium, and KRIT1 knockdown in differentiated Caco-2 intestinal epithelium decreases epithelial barrier function and increases cation selectivity. KRIT1 knockdown abolished Rho-associated protein kinase-induced and myosin II motor inhibitor-induced barrier loss by limiting both small and large molecule permeability but did not affect myosin light chain kinase-induced increases in epithelial barrier function. These data suggest that KRIT1 participates in Rho-associated protein kinase- and myosin II motor-dependent (but not myosin light chain kinase-dependent) epithelial barrier regulation. KRIT1 knockdown exacerbated low-dose TNF-induced barrier loss, along with increased cleaved caspase-3 production. Both events are blocked by pan-caspase inhibition, indicating that KRIT1 regulates TNF-induced barrier loss through limiting epithelial apoptosis. These data indicate that KRIT1 controls epithelial barrier maintenance and regulation through multiple pathways, suggesting that KRIT1 mutation in cerebral cavernous malformation disease may alter epithelial function and affect human health.-Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.-C., Weber, C. R., Awad, I. A., Shen, L. The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation.

Cerebral Cavernous Malformation Proteins in Barrier Maintenance and Regulation.

Cerebral cavernous malformation (CCM) is a disease characterized by mulberry shaped clusters of dilated microvessels, primarily in the central nervous system. Such lesions can cause seizures, headaches, and stroke from brain bleeding. Loss-of-function germline and somatic mutations of a group of genes, called CCM genes, have been attributed to disease pathogenesis. In this review, we discuss the impact of CCM gene encoded proteins on cellular signaling, barrier function of endothelium and epithelium, and their contribution to CCM and potentially other diseases.

Rho Kinase Inhibition Blunts Lesion Development and Hemorrhage in Murine Models of Aggressive Pdcd10/Ccm3 Disease.

Background and Purpose- Previously, murine models Krit1 +/- Msh2 -/- and Ccm2 +/- Trp53 -/- showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods- The murine models, Pdcd10 +/- Trp53 -/- and Pdcd10 +/- Msh2 -/-, were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results- The Pdcd10 +/- Trp53 -/- /Msh2 -/- models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P=0.027) by fasudil, and to 0.0047 ( P=0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions- These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.

Phenotypic characterization of murine models of cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that affect around 0.5% of the population. CCMs exist in two forms, sporadic and familial. Mutations in three documented genes, KRIT1(CCM1), CCM2, and PDCD10(CCM3), cause the autosomal dominant form of the disease, and somatic mutations in these same genes underlie lesion development in the brain. Murine models with constitutive or induced loss of respective genes have been applied to study disease pathobiology and therapeutic manipulations. We aimed to analyze the phenotypic characteristic of two main groups of models, the chronic heterozygous models with sensitizers promoting genetic instability, and the acute neonatal induced homozygous knockout model. Acute model mice harbored a higher lesion burden than chronic models, more localized in the hindbrain, and largely lacking iron deposition and inflammatory cell infiltrate. The chronic model mice showed a lower lesion burden localized throughout the brain, with significantly greater perilesional iron deposition, immune B- and T-cell infiltration, and less frequent junctional protein immunopositive endothelial cells. Lesional endothelial cells in both models expressed similar phosphorylated myosin light chain immunopositivity indicating Rho-associated protein kinase activity. These data suggest that acute models are better suited to study the initial formation of the lesion, while the chronic models better reflect lesion maturation, hemorrhage, and inflammatory response, relevant pathobiologic features of the human disease.

The Time Burden of Office Visits in Contemporary Pituitary Care, 2016 to 2019.

BACKGROUND: The concept of "time toxicity" has emerged to address the impact of time spent in the healthcare system; however, little work has examined the phenomenon in the field of otolaryngology. OBJECTIVE: To validate the use of Evaluation and Management (E/M) current procedural terminology codes as a method to assess time burden and to pilot this tool to characterize the time toxicity of office visits associated with a diagnosis of pituitary adenoma between 2016 and 2019. METHODS: A retrospective cohort study of outpatient office visits quantified differences between timestamps documenting visit length and their associated E/M code visit length. The IBM MarketScan database was queried to identify patients with a diagnosis of pituitary adenoma in 2016 and to analyze their new and return claims between 2016 and 2019. One-way ANOVA and two-sample t-tests were used to examine claim quantity, time in office, and yearly visit time. RESULTS: In the validation study, estimated visit time via E/M codes and actual visit time were statistically different (P < 0.01), with E/M codes underestimating actual time spent in 79.0% of visits. In the MarketScan analysis, in 2016, 2099 patients received a primary diagnosis of pituitary adenoma. There were 8490 additional-related claims for this cohort from 2016 to 2019. The plurality of new office visits were with endocrinologists (n = 857; 29.3%). Total time spent in office decreased yearly, from a mean of 113 min (2016) to 69 min (2019) (P < 0.001). CONCLUSIONS: E/M codes underestimate the length of outpatient visits; therefore, time toxicity experienced by pituitary patients may be greater than reported. Further studies are needed to develop additional assessment tools for time toxicity and promote increased efficiency of care for patients with pituitary adenomas.

Special Considerations in Pediatric Endoscopic Skull Base Surgery.

Originally pioneered in adults, endoscopic endonasal approaches for skull base pathology are being increasingly applied as a minimally invasive alternative for young children. Intrinsic anatomic differences between these patient populations have sparked discussions on the feasibility, safety, and efficacy of these techniques in pediatric patients. This work aims to serve as a primer for clinicians engaged in the rapidly evolving field of pediatric endoscopic skull base surgery. A succinct overview of relevant embryology, sinonasal anatomy, and diagnostic workup is presented to emphasize key differences and unique technical considerations. Additional discussions regarding select skull base lesions, reconstructive paradigms, potential surgical complications, and postoperative care are also highlighted in the setting of multidisciplinary teams.

The Zoom RDL radial access system for neurointervention: An early single-center experience.

BACKGROUND: The transradial approach (TRA) for neurointerventional procedures is increasingly being used given its technical feasibility and safety. However, catheter trackability and device deliverability are reported barriers to TRA adoption. METHODS: This is the first report describing the technical feasibility and performance of using the Zoom RDL Radial Access System (Imperative Care, Inc., Campbell, CA) in 29 patients who underwent neurointerventional procedures from October 2022 to January 2023 in a single-center institution. RESULTS: Mean age of the study population was 61.9±17.2 years, 79.3% were male (23/29), and 62.1% were black (18/29). The most common procedures were stroke thrombectomy (31.0%, 9/29) and aneurysm embolization (27.6%, 8/29). All the stroke thrombectomy procedures were successfully performed; first-pass effect rate (mTICI≥2 c in one pass) was achieved in 66.7% (6/9) of cases. We used TRA in 86.2% of cases (25/29), including distal radial/snuffbox access in 31.0% (9/29) of cases. The radial diameter was >2 mm for all cases. An intermediate/aspiration catheter was used in 89.7% (26/29) of cases. Access success was achieved in 89.7% of cases (26/29); two cases required conversion from TRA to transfemoral approach (6.9%) and one case required conversion to a different guide catheter (3.4%). There were no access site complications or other Zoom RDL-related complications. One intracerebral hemorrhage, and one procedure-related thrombus were observed. CONCLUSIONS: The use of Zoom RDL Radial Access System is technically feasible and effective for complex neurointerventional procedures with low complication rates.

Early single-center experience with middle meningeal artery embolization using Zoom™ 45 Catheter.

BACKGROUND: Middle meningeal artery (MMA) embolization for subdural hematomas (SDH) and dural arteriovenous fistulas (dAVFs) has gained momentum in the neuroendovascular space. However, there is variability in the technique for safe and effective embolization. The aim of this report is to describe the technical feasibility and clinical performance of using Zoom™ 45 catheter for MMA access to facilitate embolization. METHODS: We analyzed all cases of MMA embolization in which the Zoom™ 45 catheter was used and performed in our institution from February 2021 to March 2023 for SDH and dAVFs. RESULTS: A total of 32 patients were included. Mean age was 64.0 ± 18.0 years, 75.0% (4/32) were male, and 56.7% (17/30), were black. The technical success was achieved in 93.8% (30/32) of cases, with selective embolization utilizing microcatheter directly into frontal and parietal branches for most patients (96.9%, 31/32). Identification of dangerous collaterals, such as lacrimal and petrous branches, prior to embolization, was achieved in most patients (96.9%, 31/32). Bilateral MMA embolization was done in 50.0% (16/32) of patients. The transradial approach and transfemoral approach were used in 53.1% (17/32) and 46.9% (15/32) of patients, respectively. The most common embolization material was n-butyl cyanoacrylate (84.4%, 27/32). There were no access site complications or complications related to the MMA embolization procedures and used devices. CONCLUSIONS: The use of Zoom™ 45 Catheter seems to be technically feasible, safe, and effective for facilitating MMA access for embolization in the context of SDH and dAVFs.

The Transcaruncular Corridor of the Medial Transorbital Approach to the Frontal Lobe: Technical Nuances and Applications.

BACKGROUND AND IMPORTANCE: Medial orbital access through a transcaruncular corridor has yet to be fully characterized as a potential approach to intradural lesions within the skull base. Transorbital approaches present unique potential in the management of complex neurological pathologies and require subspecialty collaboration across multiple disciplines. CLINICAL PRESENTATION: A 62-year-old man presented with progressive confusion and mild left-sided weakness. He was found to have a right frontal lobe mass with significant vasogenic edema. A comprehensive systemic workup was otherwise unremarkable. A multidisciplinary skull base tumor board conference recommended a medial transorbital approach through transcaruncular corridor, which was performed by neurosurgery and oculoplastics services. Postoperative imaging demonstrated gross total resection of the right frontal lobe mass. Histopathologic evaluation was consistent with amelanotic melanoma with BRAF (V600E) mutation. At his last follow-up visit, 3 months after surgery, the patient did not experience any visual symptoms and had an excellent cosmetic outcome after surgery. CONCLUSION: The transcaruncular corridor through a medial transorbital approach provides a safe and reliable access to the anterior cranial fossa.

Chordoma: A Comprehensive Systematic Review of Clinical Trials.

This systematic review aims to characterize ongoing clinical trials and therapeutic treatment options for chordoma, a rare notochordal remnant tumor that primarily affects the cranial base, mobile spine, and sacrum. While radical surgical resection remains the cornerstone for chordoma management, unique technical challenges posed by its proximity to critical neurovascular structures confer a tendency towards disease recurrence which often requires additional treatment modalities. In an attempt to better understand the current treatment landscape, a systematic review was designed to identify clinical trials directed at chordoma. A total of 108 chordoma trials were identified from four clinical trial databases; fifty-one trials were included in the final analysis, of which only 14 were designated as completed (27.5%). Aggregate data suggests most chordoma interventions are repurposed from other neoplasms that share common molecular pathways, with a recent emphasis on combination therapeutics within and across drug classes. Naturally, the publication and dissemination of clinical trial results remain a concern (n = 4, 28.6%), highlighting the need for enhanced reporting and transparency measures. Active clinical trial efforts are quite promising, with a renewed focus on novel biotherapeutic targets and deciphering the natural history, as well as survivorship of this complex disease.

Trigeminal Schwannoma: A Retrospective Analysis of Endoscopic Endonasal Management, Treatment Outcomes, and Neuropathic Sequelae.

Introduction Trigeminal schwannomas (TS) are rare skull base tumors that have been associated with significant neuropathic sequalae for patients. The authors aim to evaluate the clinical features, treatment outcomes, and neuropathic sequelae following endoscopic endonasal approach (EEA) for TS. Methods The study involves a retrospective review of patients who underwent EEA for resection of TS at a single academic institution between 2004 and 2020. Radiographic and clinical data were recorded and analyzed. Results A total of 16 patients were abstracted, with a mean age at the time of surgery of 44 years with a slight female (1.83:1) predominance. Primary preoperative symptomatology included facial pain/neuralgia ( n = 5, 31.3%), facial hypoesthesia ( n = 4, 25.0%), and headache ( n = 4, 25.0%). Following TS resection, patients were found to have facial hypoesthesia ( n = 11, 68.8%), neuropathic keratopathy ( n = 4, 25.0%), and mastication musculature atrophy ( n = 3, 18.8%). Patients with preoperative facial pain/neuralgia ( n = 5, 31.3%) were significantly more likely to try adjunctive pain therapies ( p = 0.018) as well as seek pain consultation ( p = 0.018). Patients with preoperative migraines ( n = 2, 12.5%) were significantly more likely to trial adjunctive pain therapies ( p = 0.025) and undergo evaluation with pain specialists ( p = 0.025). Finally, patients with preoperative pharmacologic agent utilization were significantly more likely to trial adjunctive pain therapies ( p = 0.036) and pursue pain consultation ( p = 0.036). Conclusion Some degree of trigeminal dysfunction may be more common than previously reported following EEA for TS resection. Factors that appear to play a role in the development of trigeminal dysfunction include pre-existing pain syndromes such as facial pain/neuralgia or headache and preoperative medication utilization.

Headache Diagnosis in Children and Adolescents.

Pediatric headache is a common medical complaint managed across multiple subspecialties with a myriad of unique factors (clinical presentation and disease phenotype) that make accurate diagnosis particularly elusive. A thorough understanding of the stepwise approach to headache disorders in children is essential to ensure appropriate evaluation, timely diagnosis, and efficacious treatment. This work aims to review key components of a comprehensive headache assessment as well as discuss primary and secondary headache disorders observed in children, with a particular focus on clinical pearls and "red flag" symptoms necessitating ancillary diagnostic testing.

Supratentorial lymphocytic inflammation with parenchymal perivascular enhancement responsive to steroids: A case report and literature review.

BACKGROUND: Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids is a rare disorder that presents with subacute brainstem symptoms such as ataxia, facial paresthesias, and episodic diplopia, thought to be due to a T-cell medicated perivascular inflammatory process. A supratentorial variant, Supratentorial Lymphocytic Inflammation with Parenchymal Perivascular Enhancement Responsive to Steroids (SLIPPERS), has been described in only three patients. CASE DESCRIPTION: A 71-year-old male presented with word-finding difficulties, confusion, and left leg weakness. Radiographic workup demonstrated multiple supratentorial ring-enhancing lesions. PET/CT demonstrated hypermetabolism and susceptibility-weighted imaging demonstrated a hemorrhagic component. Frozen pathology revealed a predominately T-cell and monocyte inflammatory infiltrate. He demonstrated interval improvement to dexamethasone therapy, but then demonstrated worsening of his symptoms following discontinuation. CONCLUSION: Given his dramatic response to corticosteroids, he was diagnosed with SLIPPERS. SLIPPERS is an underrecognized diagnostic entity to consider in patients with ring-enhancing lesions and can present with hypermetabolic lesions on PET/CT.

Intracerebral Hemorrhage Volume Reduction and Timing of Intervention Versus Functional Benefit and Survival in the MISTIE III and STICH Trials.

BACKGROUND: The extent of intracerebral hemorrhage (ICH) removal conferred survival and functional benefits in the minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation (MISTIE) III trial. It is unclear whether this similarly impacts outcome with craniotomy (open surgery) or whether timing from ictus to intervention influences outcome with either procedure. OBJECTIVE: To compare volume evacuation and timing of surgery in relation to outcomes in the MISTIE III and STICH (Surgical Trial in Intracerebral Hemorrhage) trials. METHODS: Postoperative scans were performed in STICH II, but not in STICH I; therefore, surgical MISTIE III cases with lobar hemorrhages (n = 84) were compared to STICH II all lobar cases (n = 259) for volumetric analyses. All MISTIE III surgical patients (n = 240) were compared to both STICH I and II (n = 722) surgical patients for timing analyses. These were investigated using cubic spline modeling and multivariate risk adjustment. RESULTS: End-of-treatment ICH volume ≤28.8 mL in MISTIE III and ≤30.0 mL in STICH II had increased probability of modified Rankin Scale (mRS) 0 to 3 at 180 d (P = .01 and P = .003, respectively). The effect in the MISTIE cohort remained significant after multivariate risk adjustments. Earlier surgery within 62 h of ictus had a lower probability of achieving an mRS 0 to 3 at 180 d with STICH I and II (P = .0004), but not with MISTIE III. This remained significant with multivariate risk adjustments. There was no impact of timing until intervention on mortality up to 47 h with either procedure. CONCLUSION: Thresholds of ICH removal influenced outcome with both procedures to a similar extent. There was a similar likelihood of achieving a good outcome with both procedures within a broad therapeutic time window.

Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27.

Sprouty1 (Spry1) is a conserved antagonist of FGF signaling. The goal of this study was to further explore the downstream mechanisms governing Spry1 inhibition of endothelial cell proliferation. Up-regulation of Spry1 in HUVECs inhibited tube formation on Matrigel (n = 6, P < 0.001). This was associated with decreased proliferation as measured by BrdU incorporation (n = 6, P < 0.001) and increased protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A), p21 and cyclin-dependent kinase inhibitor 1B (CDKN1B), p27. A transcriptional analysis using a targeted human angiogenesis array following up-regulation of Spry1 demonstrated a >2-fold increase in an anti-angiogenic factor, serpin peptidase inhibitor, clad F (Serpinf1), and a >2-fold decrease in pro-angiogenic factors fms-related tyrosine kinase 1 (FLT1), angiopoietin2 (Ang-2), and placental growth factor (PGF) (n = 2). To define upstream mechanisms that may regulate endogenous Spry1, we performed a search for responsive elements upstream of the promoter region. This search resulted in the identification of multiple degenerate hypoxia responsive elements. Exposure to hypoxia resulted in a significant increase in Spry1 expression (n = 8, P < 0.01). These findings shed new light on downstream signaling pathways associated with Spry1 anti-proliferative responses, and provide new evidence that hypoxia stimulates Spry1 expression.

Case Demonstrating the Nuances of Acute Cortical Venous Thrombosis Anticoagulation Guidelines.

BACKGROUND: The American Stroke Association and the European Stroke Organization have established guidelines on cerebral venous thrombosis (CVT); however, questions remain when an individual case does not fall within the inclusion criteria on which these guidelines are based. This is relevant when considering the use of anticoagulation in cases of CVT regarding whether or not associated hemorrhage is present and whether the hemorrhage is currently expanding. CASE DESCRIPTION: A 16-year-old right-handed female G2P2 (gravidity 2 [2 pregnancies] and parity 2 [2 live births after at least 24 weeks) presented 8 days postpartum with complaints of slurred speech, right facial droop, and right upper extremity numbness that had progressed over the course of 4 hours before presentation. On imaging the patient had a CVT with associated hemorrhage progressing in size at serial 6-hour stability computed tomography scans for 24 hours post arrival. At 24 hours the patient went into disseminated intravascular coagulation and demonstrated signs of herniation. The patient underwent an emergency hemicraniectomy along with a right frontal external ventricular drain for intracranial pressure monitoring. Most recently, the patient had a Glasgow Coma Scale score of 15 and had a modified Rankin Scale score of 4 and was ultimately discovered to have antiphospholipid syndrome. CONCLUSIONS: This case of CVT demonstrates the need for critically reading guidelines, as in this case the time to anticoagulation treatment was shorter than in cases included in guideline construction and repeated computed tomography examination demonstrated expansion suggesting it is unsuitable for immediate anticoagulation. Certain cases may fall outside of the study parameters on which guidelines are constructed, and clinicians should be aware of these exceptions.