Inhibition of DUX4 expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD), characterized by progressive muscle weakness and deterioration, is genetically linked to aberrant expression of DUX4 in muscle. DUX4, in its full-length form, is cytotoxic in nongermline tissues. Here, we designed locked nucleic acid (LNA) gapmer antisense oligonucleotides (AOs) to knock down DUX4 in immortalized FSHD myoblasts and the FLExDUX4 FSHD mouse model. Using a screening method capable of reliably evaluating the knockdown efficiency of LNA gapmers against endogenous DUX4 messenger RNA in vitro, we demonstrate that several designed LNA gapmers selectively and effectively reduced DUX4 expression with nearly complete knockdown. We also found potential functional benefits of AOs on muscle fusion and structure in vitro. Finally, we show that one of the LNA gapmers was taken up and induced effective silencing of DUX4 upon local treatment in vivo. The LNA gapmers developed here will help facilitate the development of FSHD therapies.

Reconstructive Approaches Following Sphenoorbital Meningioma Resection.

Sphenoorbital meningiomas are a challenge to access and reconstruct. Although there is much neurosurgical literature on resection of such tumors, there is little discussion on the best methods for the reconstruction of consequent defects, which are often extensive due to large areas of hyperostosis requiring resection. We performed a retrospective analysis of patients who underwent resection and reconstruction of a sphenoorbital meningioma by the senior authors (C.S. and D.A.S.) between 2010 and 2020. Surgical access in all cases included an orbitozygomatic osteotomy. The study cohort consisted of 23 patients (20 female, 3 male) with an average age of 50 (range: 37-72) years at the time of surgery. Most patients had progressive proptosis before the ablative operation. Orbital reconstruction was with a combined titanium-Medpor implant in 18 patients, split calvarial bone graft in 3 patients, and a Medpor implant in 2 patients. Calvarial reconstruction was performed with titanium mesh in 21 patients, split calvarial bone graft and titanium mesh in 1 patient, and craniotomy bone and titanium plate in 1 patient. Reoperation was required in 7 patients due to hypoglobus or enophthalmos (N=2), orbital implant malposition (N=1), abscess (N=1), pain (N=1), intracranial fat graft modification (N=1), and soft tissue deformities (N=2). Our experience demonstrates that sphenoorbital meningiomas can require broad areas of resection of the skull base and calvarium and necessitate comprehensive reconstruction of the anterior cranial fossa, orbital walls, and cranium. Collaboration between craniofacial surgeons and neurosurgeons can achieve optimal results.

Membrane Repair Deficit in Facioscapulohumeral Muscular Dystrophy.

Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. Therefore, we exposed immortalized human FSHD myoblasts, immortalized myoblasts from unaffected siblings, and myofibers from a murine model of FSHD (FLExDUX4) to focal, pulsed laser ablation of the sarcolemma. Repair kinetics and success were determined from the accumulation of intracellular FM1-43 dye post-injury. We subsequently treated FSHD myoblasts with a DUX4-targeting antisense oligonucleotide (AON) to reduce DUX4 expression, and with the antioxidant Trolox to determine the role of DUX4 expression and oxidative stress in membrane repair. Compared to unaffected myoblasts, FSHD myoblasts demonstrate poor repair and a greater percentage of cells that failed to repair, which was mitigated by AON and Trolox treatments. Similar repair deficits were identified in FLExDUX4 myofibers. This is the first study to identify plasma membrane repair deficits in myoblasts from individuals with FSHD, and in myofibers from a murine model of FSHD. Our results suggest that DUX4 expression and oxidative stress may be important targets for future membrane-repair therapies.

Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit.

Mutations of the DYSF gene leading to reduced dysferlin protein level causes limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin facilitates sarcolemmal membrane repair in healthy myofibers, thus its deficit compromises myofiber repair and leads to chronic muscle inflammation. An experimental therapeutic approach for LGMD2B is to protect damage or improve repair of myofiber sarcolemma. Here, we compared the effects of prednisolone and vamorolone (a dissociative steroid; VBP15) on dysferlin-deficient myofiber repair. Vamorolone, but not prednisolone, stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse (B6A/J) myofibers injured by focal sarcolemmal damage, eccentric contraction-induced injury or injury due to spontaneous in vivo activity. Vamorolone decreased sarcolemmal lipid mobility, increased muscle strength, and decreased late-stage myofiber loss due to adipogenic infiltration. In contrast, the conventional glucocorticoid prednisolone failed to stabilize dysferlin deficient muscle cell membrane or improve repair of dysferlinopathic patient myoblasts and mouse myofibers. Instead, prednisolone treatment increased muscle weakness and myofiber atrophy in B6A/J mice-findings that correlate with reports of prednisolone worsening symptoms of LGMD2B patients. Our findings showing improved cellular and pre-clinical efficacy of vamorolone compared to prednisolone and better safety profile of vamorolone indicates the suitability of vamorolone for clinical trials in LGMD2B.

Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence.

Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II.

Amino acid propensities for secondary structures and its variation across protein structures using exhaustive PDB data.

Amino acid propensities for protein secondary structures are vital for protein structure prediction, understanding folding, and design, and have been studied using various theoretical and experimental methods. Traditional assessments of average propensities using statistical methods have been done on relatively smaller dataset for only a few secondary structures. They also involve averaging out the environmental factors and lack insights into consistency of preferences across diverse protein structures. While a few studies have explored variations in propensities across protein structural classes and folds, exploration of such variations across protein structures remains to be carried out. In this work, we have revised the average propensities for all six different secondary structures, namely α-helix, ß-strand, 310-helix, π-helix, turn and coil, analyzing the most exhaustive dataset available till date using two robust secondary structure assignment algorithms, DSSP and STRIDE. The propensities evaluated here can serve as a standard reference. Moreover, we present here, for the first time, the propensities within individual protein structures and investigated how the preferences of residues and more interestingly, of their groups formed based on their structural features, vary across different unique structures. We devised a novel approach- the minimal set analysis, based on the propensity distribution of residues, which along with the group propensities led us to the conclusion that a residue's preference for a specific secondary structure is primarily dictated by its side chain's structural features. The findings in this study provide a more insightful picture of residues propensities and can be useful in protein folding and design studies.

Extreme Lateral Approach to the Craniocervical Junction, Operative Technique and Approach Essentials: 2-Dimensional Operative Video.

INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE: The extreme lateral approach is useful for both extradural and intradural anterior and anterolateral lesions at the lower clivus down to the level of C2. ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT: The patient is evaluated with MRI, computed tomography (CT), and an angiogram. Special attention is given to vascular (vertebral artery course, dominance, tumor feeders) and bony (occipital condyle, jugular tubercle, foramen magnum and extent of bony involvement) anatomy. ESSENTIALS STEPS OF THE PROCEDURE: The patient is positioned lateral with the head flexed and tilted down without axial rotation. A hockey-stick incision is performed, and the myocutaneous flap is raised. A retrocondylar craniectomy is performed. The extradural vertebral artery is exposed for proximal control. A C1 hemilaminectomy is performed. Cephalad/caudal exposure and drilling of the occipital condyle are determined per case. The dura is opened, and the vertebral artery is released at the dural entry point to facilitate the tumor removal. The tumor is debulked and delivered inferoventrally away from the neuroaxis and cranial nerves. After removing the tumor, the dura is closed using an allograft.The patients consented to the procedure and to the publication of their images. PITFALLS/AVOIDANCE OF COMPLICATIONS: • Cranial nerve deficits• Craniocervical instability• Postoperative hydrocephalus• Postoperative pseudomeningocele. VARIANTS AND INDICATIONS FOR THEIR USE: A transmastoid extension of the craniectomy allows access further rostrally in the clivus. For C1-2 chordomas, the approach is extended inferiorly, and the vertebral artery is mobilized out of the C1-2 transverse foramina. For tumors involving the joints, an occipitocervical stabilization is required.Images in video reused with permission as follows: image at 00:16 from Revuelta Barbero et al, Endoscopic endonasal transclival-medial condylectomy approach for resection of a foramen magnum meningioma: 2-dimensional operative video, Oper Neurosurg , 16(2), 2018, by permission from the Congress of Neurological Surgery; images at 00:30, and top image at 00:52 reused from Wen et al, Microsurgical anatomy of the transcondylar, supracondylar, and paracondylar extensions of the far-lateral approach, J Neurosurg , 87(4), 1997, with permission from JNSPG; bottom images at 00:52 from Muthukumar et al, A morphometric analysis of the foramen magnum region as it relates to the transcondylar approach, Acta Neurochir , 147(8), 2005, by permission from Springer Nature.

Superior hypophyseal arteries: angiographic re-discovery, comprehensive assessment, and embryologic implications.

The superior hypophyseal arteries (SHAs) are well known in anatomical and surgical literature, with a well-established role in supply of the anterior hypophysis and superjacent optic apparatus. However, due to small size and overlap with other vessels, in vivo imaging by any modality has been essentially non-existent. Advances in high resolution cone beam CT angiography (CBCTA) now enables this deficiency to be addressed. This paper presents, to the best of our knowledge, the first comprehensive in vivo imaging evaluation of the SHAs. METHODS: Twenty-five CBCTA studies of common or internal carotid arteries were obtained for a variety of clinical reasons. Dedicated secondary reconstructions of the siphon were performed, recording the presence, number, and supply territory of SHAs. A spectrum approach, emphasizing balance with adjacent territories (inferior hypophyseal, ophthalmic, posterior and communicating region arteries) was investigated. RESULTS: The SHAs were present in all cases. Supply of the anterior pituitary was nearly universal (96%) and almost half (44%) originated from the 'cave' region, in excellent agreement with surgical literature. Optic apparatus supply was more difficult to adjudicate, but appeared present in most cases. The relationship with superior hypophyseal aneurysms was consistent. Patency following flow diverter placement was typical, despite a presumably rich collateral network. Embryologic implications with respect to the ophthalmic artery and infraoptic course of the anterior cerebral artery are intriguing. CONCLUSIONS: SHAs are consistently seen with CBCTA, allowing for correlation with existing anatomical and surgical literature, laying the groundwork for future in vivo investigation.

Discontinuation of Postoperative Prophylactic Antibiotics for Endoscopic Endonasal Skull Base Surgery.

Background Postoperative prophylactic antibiotic usage for endoscopic skull base surgery varies based on the institution as evidence-based guidelines are lacking. The purpose of this study is to determine whether discontinuing postoperative prophylactic antibiotics in endoscopic endonasal cases led to a difference in central nervous system (CNS) infections, multi-drug resistant organism (MDRO) infections, or other postoperative infections. Methods This quality improvement study compared outcomes between a retrospective cohort (from September 2013 to March 2019) and a prospective cohort (April 2019 to June 2019) after adopting a protocol to discontinue prophylactic postoperative antibiotics in patients who underwent endoscopic endonasal approaches (EEAs). Our primary end points of the study included the presence of postoperative CNS infection, Clostridium difficile ( C. diff ), and MDRO infections. Results A total of 388 patients were analyzed, 313 in the pre-protocol group and 75 in the post-protocol group. There were similar rates of intraoperative cerebrospinal fluid leak (56.9 vs. 61.3%, p = 0.946). There was a statistically significant decrease in the proportion of patients receiving IV antibiotics during their postoperative course ( p = 0.001) and those discharged on antibiotics ( p = 0.001). There was no significant increase in the rate of CNS infections in the post-protocol group despite the discontinuation of postoperative antibiotics (3.5 vs. 2.7%, p = 0.714). There was no statistically significant difference in postoperative C. diff (0 vs. 0%, p = 0.488) or development of MDRO infections (0.3 vs 0%, p = 0.624). Conclusion Discontinuation of postoperative antibiotics after EEA at our institution did not change the frequency of CNS infections. It appears that discontinuation of antibiotics after EEA is safe.

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

The Cost Effectiveness of Implementation of a Postoperative Endocrinopathy Management Protocol after Resection of Pituitary Adenomas.

Purpose After developing a protocol for evaluating, diagnosing, and treating postoperative endocrinopathy both during the hospitalization and during the immediate discharge period following resection of pituitary adenomas, we sought to assess the impact of this protocol on quality outcomes. Methods An IRB-exempt, quality improvement initiated, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective comparison of a pre-and-post-protocol cohort of all patients undergoing endoscopic endonasal resection of pituitary adenomas at NYU Langone Medical Center from January 2013 to December 2018. Demographic characteristics of the patients and their tumors with their postoperative outcomes were recorded. Quality outcomes regarding number of laboratory studies sent, rate of diabetes insipidus, length of stay, and readmission rate were also recorded. Statistical analysis was performed between the pre- and post-protocol groups. Results There was a significant reduction in laboratory studies sent per patient (55.66 vs. 18.82, p <0.001). This corresponded with an overall cost reduction in laboratory studies of $255.95 per patient. There was a decrease in the overall number of patients treated with DDAVP (21.4% in the pre-protocol group vs. 8.9% in the post-protocol group, p = 0.04). All post-protocol patients requiring DDAVP at discharge were identified by 48 hours. There was no significant change in length of stay or need for hydrocortisone supplementation postoperatively between the two groups. Length of stay was driven mostly by need for reoperation during initial hospitalization. There was no significant change in the rate of 30-day readmission. Conclusion Implementation of a postoperative management protocol results in a more efficient diagnosis and management of endocrinopathy after pituitary adenoma surgery which translates to decreased cost.

Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B.

Efficient sarcolemmal repair is required for muscle cell survival, with deficits in this process leading to muscle degeneration. Lack of the sarcolemmal protein dysferlin impairs sarcolemmal repair by reducing secretion of the enzyme acid sphingomyelinase (ASM), and causes limb girdle muscular dystrophy 2B (LGMD2B). The large size of the dysferlin gene poses a challenge for LGMD2B gene therapy efforts aimed at restoring dysferlin expression in skeletal muscle fibers. Here, we present an alternative gene therapy approach targeting reduced ASM secretion, the consequence of dysferlin deficit. We showed that the bulk endocytic ability is compromised in LGMD2B patient cells, which was addressed by extracellularly treating cells with ASM. Expression of secreted human ASM (hASM) using a liver-specific adeno-associated virus (AAV) vector restored membrane repair capacity of patient cells to healthy levels. A single in vivo dose of hASM-AAV in the LGMD2B mouse model restored myofiber repair capacity, enabling efficient recovery of myofibers from focal or lengthening contraction-induced injury. hASM-AAV treatment was safe, attenuated fibro-fatty muscle degeneration, increased myofiber size, and restored muscle strength, similar to dysferlin gene therapy. These findings elucidate the role of ASM in dysferlin-mediated plasma membrane repair and to our knowledge offer the first non-muscle-targeted gene therapy for LGMD2B.

Growth hormone secreting pituitary carcinomas: Case report and review of literature.

OBJECTIVE: Pituitary carcinoma is a rare tumor, defined as a tumor of adenohypophyseal cells with systemic or craniospinal metastasis. We present a case of a growth hormone (GH)-secreting pituitary carcinoma with a review of literature to better characterize this disease. DESIGN: Case report and literature review of 25 cases of GH-secreting pituitary carcinomas RESULTS: The age of diagnosis of GH-secreting carcinomas ranged 24-69 years old with a mean age of 44.4 with 52% of cases present in females. Mean latency period between diagnosis of acromegaly and transition to pituitary carcinoma was 11.4 years with mean survival being 3.4 years. CONCLUSION: Growth hormone (GH)-secreting pituitary carcinomas are rare and hard to distinguish from aggressive pituitary adenomas. From review of literature, treatment options include debulking surgery, radiotherapy, or chemotherapy with dismal outcomes. There are no diagnostic markers or features which can predict metastatic progression of these tumors. Future studies with genomic landscapes and relevant tumor markers are needed to identify pituitary tumors most likely to metastasize.

Endoplasmic reticulum maintains ion homeostasis required for plasma membrane repair.

Of the many crucial functions of the ER, homeostasis of physiological calcium increase is critical for signaling. Plasma membrane (PM) injury causes a pathological calcium influx. Here, we show that the ER helps clear this surge in cytoplasmic calcium through an ER-resident calcium pump, SERCA, and a calcium-activated ion channel, Anoctamin 5 (ANO5). SERCA imports calcium into the ER, and ANO5 supports this by maintaining electroneutrality of the ER lumen through anion import. Preventing either of these transporter activities causes cytosolic calcium overload and disrupts PM repair (PMR). ANO5 deficit in limb girdle muscular dystrophy 2L (LGMD2L) patient cells compromises their cytosolic and ER calcium homeostasis. By generating a mouse model of LGMD2L, we find that PM injury causes cytosolic calcium overload and compromises the ability of ANO5-deficient myofibers to repair. Addressing calcium overload in ANO5-deficient myofibers enables them to repair, supporting the requirement of the ER in calcium homeostasis in injured cells and facilitating PMR.

Anoctamin 5 Knockout Mouse Model Recapitulates LGMD2L Muscle Pathology and Offers Insight Into in vivo Functional Deficits.

Mutations in the Anoctamin 5 (Ano5) gene that result in the lack of expression or function of ANO5 protein, cause Limb Girdle Muscular Dystrophy (LGMD) 2L/R12, and Miyoshi Muscular Dystrophy (MMD3). However, the dystrophic phenotype observed in patient muscles is not uniformly recapitulated by ANO5 knockout in animal models of LGMD2L. Here we describe the generation of a mouse model of LGMD2L generated by targeted out-of-frame deletion of the Ano5 gene. This model shows progressive muscle loss, increased muscle weakness, and persistent bouts of myofiber regeneration without chronic muscle inflammation, which recapitulates the mild to moderate skeletal muscle dystrophy reported in the LGMD2L patients. We show that these features of ANO5 deficient muscle are not associated with a change in the calcium-activated sarcolemmal chloride channel activity or compromised in vivo regenerative myogenesis. Use of this mouse model allows conducting in vivo investigations into the functional role of ANO5 in muscle health and for preclinical therapeutic development for LGMD2L.

Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated.

PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.

Cavernous sinus lesions.

The cavernous sinus is a complex structure susceptible to a wide variety of vascular, neoplastic and inflammatory pathologies. Vascular pathologies include ICA aneurysms, carotid-cavernous fistulas, cavernous sinus thrombosis, and cavernous hemangioma. Neoplasms that involve the cavernous sinus include pituitary adenoma, meningioma, schwannoma, lymphoma, perineural tumor spread, metastases, and direct tumor invasion. Infectious and inflammatory diseases include Tolosa-Hunt syndrome, sarcoidosis, granulomatosis with polyangiitis, IgG-4 related disease and invasive fungal infections. In this article, we review the clinical and imaging findings of a number of pathologies involving the cavernous sinus, focusing on key features that can narrow the differential diagnosis and, in some cases, support a particular diagnosis.

Intraspinal Dissemination and Local Recurrence of an Intracranial Hemangiopericytoma.

BACKGROUND: Hemangiopericytomas (HPCs) are rare vascular tumors that resemble meningiomas on imaging and have a high rate of local recurrence and metastases. There remains a paucity of data to guide management decisions of intraspinal dissemination of HPCs in the literature, and none specifically related to anaplastic HPCs. CASE DESCRIPTION: We report a case of a 34-year-old woman with locally and distantly recurrent anaplastic HPC (World Health Organization grade III). She initially presented with tinnitus in her right ear. A well-circumscribed, contrast-enhancing lesion was identified in the right cerebellopontine angle. Treatment consisted of subtotal resection and postoperative radiation therapy (RT) to a dose of 60 Gy in 30 fractions. After a 3-year disease-free interval, 7 lesions recurred intra- and extracranially. The extracranial lesions were drop metastases of the original HPC through the cerebrospinal fluid into the spinal canal. Of note, fluorodeoxyglucose positron emission tomography (PET)/computed tomography scan was not sensitive enough to detect these new lesions. The intracranial recurrence was on the edge of the prior radiotherapy field, representing a marginal failure having received less than 50 Gy. The intracranial recurrences were treated with salvage gamma knife stereotactic radiosurgery (SRS) with local control. She underwent intradural extramedullary hemilaminectomy of a thoracic spine metastasis followed by fractionated proton beam therapy (PBT) with a boost to unresected lesions. Within a few months of PBT, she became pregnant. Pregnancy did not affect recurrence or ameliorate tumor growth. CONCLUSIONS: This case report discusses the role genetics, adjuvant RT, SRS, magnetic resonance imaging, and PET scan played in this unique clinical scenario of anaplastic HPC.

Postoperative cerebral venous sinus thrombosis in the setting of surgery adjacent to the major dural venous sinuses.

OBJECTIVECerebral venous sinus thrombosis (CVST) is a known complication of surgeries near the major dural venous sinuses. While the majority of CVSTs are asymptomatic, severe sinus thromboses can have devastating consequences. The objective of this study was to prospectively evaluate the true incidence and risk factors associated with postoperative CVST and comment on management strategies.METHODSA prospective study of 74 patients who underwent a retrosigmoid, translabyrinthine, or suboccipital approach for posterior fossa tumors, or a supratentorial craniotomy for parasagittal/falcine tumors, was performed. All patients underwent pre- and postoperative imaging to evaluate sinus patency. Demographic, clinical, and operative data were collected. Statistical analysis was performed to identify incidence and risk factors.RESULTSTwenty-four (32.4%) of 74 patients had postoperative MR venograms confirming CVST, and all were asymptomatic. No risk factors, including age (p = 0.352), BMI (p = 0.454), sex (p = 0.955), surgical approach (p = 0.909), length of surgery (p = 0.785), fluid balance (p = 0.943), mannitol use (p = 0.136), tumor type (p = 0.46, p = 0.321), or extent of resection (p = 0.253), were statistically correlated with thrombosis. All patients were treated conservatively, with only 1 patient receiving intravenous fluids. There were no instances of venous infarctions, hemorrhages, or neurological deficits. The rate of CSF leakage was significantly higher in the thrombosis group than in the nonthrombosis group (p = 0.01).CONCLUSIONSThis prospective study shows that the radiographic incidence of postoperative CVST is higher than that previously reported in retrospective studies. In the absence of symptoms, these thromboses can be treated conservatively. While no risk factors were identified, there may be an association between postoperative CVST and CSF leak.

Mitochondrial redox signaling enables repair of injured skeletal muscle cells.

Strain and physical trauma to mechanically active cells, such as skeletal muscle myofibers, injures their plasma membranes, and mitochondrial function is required for their repair. We found that mitochondrial function was also needed for plasma membrane repair in myoblasts as well as nonmuscle cells, which depended on mitochondrial uptake of calcium through the mitochondrial calcium uniporter (MCU). Calcium uptake transiently increased the mitochondrial production of reactive oxygen species (ROS), which locally activated the guanosine triphosphatase (GTPase) RhoA, triggering F-actin accumulation at the site of injury and facilitating membrane repair. Blocking mitochondrial calcium uptake or ROS production prevented injury-triggered RhoA activation, actin polymerization, and plasma membrane repair. This repair mechanism was shared between myoblasts, nonmuscle cells, and mature skeletal myofibers. Quenching mitochondrial ROS in myofibers during eccentric exercise ex vivo caused increased damage to myofibers, resulting in a greater loss of muscle force. These results suggest a physiological role for mitochondria in plasma membrane repair in injured cells, a role that highlights a beneficial effect of ROS.