Interleukin-6 induces nascent protein synthesis in human dorsal root ganglion nociceptors primarily via MNK-eIF4E signaling.

Plasticity of dorsal root ganglion (DRG) nociceptors in the peripheral nervous system requires new protein synthesis. This plasticity is believed to be responsible for the physiological changes seen in DRG nociceptors in animal models of chronic pain. Experiments in human DRG (hDRG) neurons also support this hypothesis, but a direct observation of nascent protein synthesis in response to a pain promoting substance, like interleukin-6 (IL-6), has not been measured in these neurons. To fill this gap in knowledge, we used acutely prepared human DRG explants from organ donors. These explants provide a physiologically relevant microenvironment, closer to in vivo conditions, allowing for the examination of functional alterations in DRG neurons reflective of human neuropathophysiology. Using this newly developed assay, we demonstrate upregulation of the target of the MNK1/2 kinases, phosphorylated eIF4E (p-eIF4E), and nascently synthesized proteins in a substantial subset of hDRG neurons following exposure to IL-6. To pinpoint the specific molecular mechanisms driving this IL-6-driven increase in nascent proteins, we used the specific MNK1/2 inhibitor eFT508. Treatment with eFT508 resulted in the inhibition of IL-6-induced increases in p-eIF4E and nascent proteins. Additionally, using TRPV1 as a marker for nociceptors, we found that these effects occurred in a large number of human nociceptors. Our findings provide clear evidence that IL-6 drives nascent protein synthesis in human TRPV1+ nociceptors primarily via MNK1/2-eIF4E signaling. The work links animal findings to human nociception, creates a framework for additional hDRG signaling experiments, and substantiates the continued development of MNK inhibitors for pain.

Meteorin Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Mice.

Chemotherapy-induced peripheral neuropathy is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 × 4 mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (.5 and 1.8 mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin ( .5 and 1.8 mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), reduced the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin 43 protein expression in the dorsal root ganglion. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for chemotherapy-induced peripheral neuropathy treatment. PERSPECTIVE: Chemotherapy neuropathy is a major clinical problem that decreases quality of life for cancer patients and survivors. Our experiments demonstrate that Meteorin treatment alleviates pain-related behaviors, and signs of neurotoxicity in a mouse model of paclitaxel neuropathy.

Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decreases ISR activation in DRG neurons.

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes mechanical hypersensitivity in mice by inducing the integrated stress response (ISR), which is characterized by phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant proteins that neutralize MGO. We hypothesized that activating Nrf2 using diroximel fumarate (DRF) would alleviate MGO-induced pain hypersensitivity. We pretreated male and female C57BL/6 mice daily with oral DRF prior to intraplantar injection of MGO (20 ng). DRF (100 mg/kg) treated animals were protected from developing MGO-induced mechanical and cold hypersensitivity. Using Nrf2 knockout mice we demonstrate that Nrf2 is necessary for the anti-nociceptive effects of DRF. In cultured mouse and human dorsal root ganglion (DRG) sensory neurons, we found that MGO induced elevated levels of p-eIF2α. Co-treatment of MGO (1 µM) with monomethyl fumarate (MMF, 10, 20, 50 µM), the active metabolite of DRF, reduced p-eIF2α levels and prevented aberrant neurite outgrowth in human DRG neurons. Our data show that targeting the Nrf2 antioxidant system with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.

A Female-Specific Role for Calcitonin Gene-Related Peptide (CGRP) in Rodent Pain Models.

We aimed to investigate a sexually dimorphic role of calcitonin gene-related peptide (CGRP) in rodent models of pain. Based on findings in migraine where CGRP has a preferential pain-promoting effect in female rodents, we hypothesized that CGRP antagonists and antibodies would attenuate pain sensitization more efficaciously in female than male mice and rats. In hyperalgesic priming induced by activation of interleukin 6 signaling, CGRP receptor antagonists olcegepant and CGRP8-37 both given intrathecally, blocked, and reversed hyperalgesic priming only in females. A monoclonal antibody against CGRP, given systemically, blocked priming specifically in female rodents but failed to reverse it. In the spared nerve injury model, there was a transient effect of both CGRP antagonists, given intrathecally, on mechanical hypersensitivity in female mice only. Consistent with these findings, intrathecally applied CGRP caused a long-lasting, dose-dependent mechanical hypersensitivity in female mice but more transient effects in males. This CGRP-induced mechanical hypersensitivity was reversed by olcegepant and the KCC2 enhancer CLP257, suggesting a role for anionic plasticity in the dorsal horn in the pain-promoting effects of CGRP in females. In spinal dorsal horn slices, CGRP shifted GABAA reversal potentials to significantly more positive values, but, again, only in female mice. Therefore, CGRP may regulate KCC2 expression and/or activity downstream of CGRP receptors specifically in females. However, KCC2 hypofunction promotes mechanical pain hypersensitivity in both sexes because CLP257 alleviated hyperalgesic priming in male and female mice. We conclude that CGRP promotes pain plasticity in female rodents but has a limited impact in males.SIGNIFICANCE STATEMENT The majority of patients impacted by chronic pain are women. Mechanistic studies in rodents are creating a clear picture that molecular events promoting chronic pain are different in male and female animals. We sought to build on evidence showing that CGRP is a more potent and efficacious promoter of headache in female than in male rodents. To test this, we used hyperalgesic priming and the spared nerve injury neuropathic pain models in mice. Our findings show a clear sex dimorphism wherein CGRP promotes pain in female but not male mice, likely via a centrally mediated mechanism of action. Our work suggests that CGRP receptor antagonists could be tested for efficacy in women for a broader variety of pain conditions.

Pipeline Embolization Device for Small Intracranial Aneurysms: Evaluation of Safety and Efficacy in a Multicenter Cohort.

BACKGROUND: To date, the use of the flow-diverting Pipeline Embolization Device (PED) for small intracranial aneurysms (≤ 7 mm) has been reported only in single-center series. OBJECTIVE: To evaluate the safety and efficacy of the PED in a multicenter cohort. METHODS: Five major academic institutions in the United States provided data on patient demographics, aneurysm features, and treatment characteristics of consecutive patients with aneurysms ≤ 7 mm treated with a PED between 2009 and 2015. Radiographic outcome was assessed with digital subtraction angiography. Clinical outcome was measured with the modified Rankin Scale. RESULTS: The cumulative number of aneurysms ≤ 7 mm treated with PED at the 5 institutions was 149 in 117 patients (age, 54 years [range, 29-87 years]; male to female, 1-5.9). Aneurysms were most commonly located in the paraophthalmic segment (67.1%) of the internal carotid artery. Radiographic outcome at last follow-up was available for 123 aneurysms (82.6%), with a complete occlusion rate of 87%. Thromboembolic and symptomatic procedural complications occurred in 8.7% and 6% of the aneurysms treated, respectively. There was 1 mortality (0.9%) unrelated to the PED procedure. Multivariable logistic regression identified size < 4 mm, balloon angioplasty to open the device, and simultaneous treatment of multiple aneurysms as predictors of procedural complications. Good clinical outcome was achieved in 96% of electively treated patients. CONCLUSION: In the largest series on PED for small aneurysms to date, data suggest that treatment with the flow-diverting PED is safe and efficacious, with complication rates comparable to those for traditional endovascular techniques.

Dual diagnostic catheter technique in the endovascular management of anterior communicating artery complex aneurysms.

BACKGROUND: The configuration of the anterior communicating artery (AcomA) complex is important in the endovascular treatment of AcomA complex aneurysms. In cases of codominant anterior cerebral arteries (ACA), coil embolization may result in inadvertent occlusion of the contralateral ACA due to poor visualization. A second diagnostic catheter in the contralateral carotid artery may help with visualization of this angiographic blind spot. To our knowledge, the safety and efficacy of this dual diagnostic catheter technique have never been assessed. METHODS: A cohort of consecutive patients that underwent coil embolization of an AcomA complex aneurysm at a major academic institution in the United States between 2007 and 2014 were retrospectively reviewed. RESULTS: Eighty-two patients who had an AcomA complex aneurysm treated with coil embolization were identified. The dual diagnostic catheter technique was used in 17 (20.7%) patients. Aneurysms treated with the dual diagnostic catheter technique were less frequently ruptured and had less favorable dome-to-neck ratios as well as neck width for primary coil embolization. The rate of codominant ACAs was significantly higher and stent-assisted coil embolization was performed more frequently. The rate of thromboembolic complications, angiographic outcome, and retreatment did not differ between both the groups. CONCLUSIONS: The dual diagnostic catheter technique is a safe and effective method during coil embolization of AcomA complex aneurysms and preferred for aneurysms with codominant ACAs, incorporation of either A1 or A2 segments into the aneurysm, and aneurysms with a wide neck and low dome-to-neck ratios.

Lazic Aneurysm Clip System for Microsurgical Clipping of Cerebral Aneurysms: Transition to a New Aneurysm Clip System in an Established Cerebrovascular Practice.

BACKGROUND: In an era of continued advancements in endovascular treatment of cerebral aneurysms, novel developments concerning microsurgical clipping are sparse. The Lazic aneurysm clip system represents such an advancement. The applier has a malleable shaft and is designed to minimally obstruct the view of the surgical field. The purpose of this study was to illustrate the transition to this new aneurysm clip system in an established cerebrovascular practice. METHODS: We retrospectively reviewed all aneurysms treated with microsurgical clipping using the Lazic aneurysm clip system in 1 cerebrovascular practice in the United States from January 2009 to June 2016. RESULTS: Between 2009 and 2016, a total of 973 aneurysms underwent surgical clipping. The Lazic clip system was used in 191 (19.6%) aneurysms (maximum diameter, 5.6 ± 3.8 mm) in 181 patients. The middle cerebral artery was the most frequent location (25.7%) followed by posterior communicating artery (20.9%). There was a continuous increase in the percentage of aneurysms treated with the Lazic clip system from 6% in 2009 to 98% in 2016. The proportion of posterior circulation aneurysms treated with Lazic clips decreased, whereas the middle cerebral artery location increased. There were a total of 11 complications (5.8%), but no instances of clip malfunction. CONCLUSIONS: In the largest series to date, the Lazic clip system proved to be safe and efficacious and presents an interesting alternative to established aneurysm clip systems. This study illustrates the transition of an established cerebrovascular practice to the Lazic clip system.

Surgeon interrater reliability in the endoscopic assessment of cistern scarring and aqueduct patency.

OBJECTIVE The success of endoscopic third ventriculostomy with choroid plexus cauterization may have associations with age, etiology of hydrocephalus, previous shunting, cisternal scarring, and possibly aqueduct patency. This study aimed to measure interrater reliability among surgeons in identifying cisternal scarring and aqueduct patency. METHODS Using published definitions of cistern scarring and aqueduct patency, 7 neuroendoscopists with training from Dr. Warf in Uganda and 7 neuroendoscopists who were not trained by Dr. Warf rated cistern status from 30 operative videos and aqueduct patency from 26 operative videos. Interrater agreement was calculated using Fleiss' kappa coefficient (κ). Fisher's 2-tailed exact test was used to identify differences in the rates of agreement between the Warf-trained and nontrained groups compared with Dr. Warf's reference answer. RESULTS Aqueduct status, among all raters, showed substantial agreement with κ = 0.663 (confidence interval [CI] 0.626-0.701); within the trained group and nontrained groups, there was substantial agreement with κ = 0.677 (CI 0.593-0.761) and κ = 0.631 (CI 0.547-0.715), respectively. The identification of cistern scarring was less reliable, with moderate agreement among all raters with κ = 0.536 (CI 0.501-0.571); within the trained group and nontrained groups, there was moderate agreement with κ = 0.555 (CI 0.477-0.633) and κ = 0.542 (CI 0.464-0.620), respectively. There was no statistically significant difference in the amount of agreement between groups compared with Dr. Warf's reference. CONCLUSIONS Regardless of training with Dr. Warf, all neuroendoscopists could identify scarred cisterns and aqueduct patency with similar reliability, emphasizing the strength of the published definitions. This makes the identification of this risk factor for failure generalizable for surgical decision making and research studies.

Response of silent corticotroph pituitary carcinoma to chemotherapy: case report.

Silent pituitary corticotroph carcinomas are rare, with only six previously described cases in the literature. We report a patient with a silent pituitary corticotroph adenoma treated with multiple trans-sphenoidal resections. Twelve years after her initial presentation, she returned with leptomeningeal metastases to the posterior fossa, foramen magnum, and numerous other subarachnoid locations involving the spine. Histopathology obtained from the metastatic foci was identical to previous trans-sphenoidal specimens - consistent with the diagnosis of corticotroph pituitary carcinoma. A carboplatin and etoposide chemotherapy regimen successfully arrested disease progression and produced regression of multiple radiographically documented leptomeningeal deposits. To the authors' knowledge, this is the first report of a patient with silent pituitary carcinoma treated successfully with chemotherapy.

Middle meningeal artery: Gateway for effective transarterial Onyx embolization of dural arteriovenous fistulas.

Curative transarterial embolization of noncavernous sinus dural arteriovenous fistulas (dAVFs) is challenging. We sought to evaluate the role of the middle meningeal artery (MMA) in endovascular treatment of these lesions. We performed a retrospective cohort study on patients who underwent transarterial Onyx embolization of a noncavernous sinus dAVFs with contribution from the MMA at a major academic institution in the United States from January 2009 to January 2015. Twenty consecutive patients who underwent transarterial Onyx embolization of a noncavernous sinus dAVF were identified. One patient was excluded as there was no MMA contribution to the dAVF. All of the remaining 19 patients (61.3 ± 13.8 years of age) underwent transarterial embolization through the MMA. Six patients (31.6%) presented with intraparenchymal or subarachnoid hemorrhage from the dAVF. The overall angiographic cure rate was 73.7% upon last follow up. In 71.4% of successfully treated patients transarterial embolization of the MMA alone was sufficient to achieve angiographic cure. When robust MMA supply was present, MMA embolization resulted in angiographic cure even after embolization of other arterial feeders had failed in 92.9% of patients. A robust contribution of the MMA to the fistula was the single most important predictor for successful embolization (P = 0.00129). We attribute our findings to the fairly straight, non-tortuous course of the MMA that facilitates microcatheter access, navigation, and Onyx penetration. Noncavernous sinus dAVF can be successfully embolized with transarterial Onyx through the MMA, as long as supply is robust. A transvenous approach is rarely necessary. Clin. Anat. 29:718-728, 2016. © 2016 Wiley Periodicals, Inc.

Pipeline Embolization Device for small paraophthalmic artery aneurysms with an emphasis on the anatomical relationship of ophthalmic artery origin and aneurysm.

OBJECTIVE Contemporary treatment for paraophthalmic artery aneurysms includes flow diversion utilizing the Pipeline Embolization Device (PED). Little is known, however, about the potential implications of the anatomical relationship of the ophthalmic artery (OA) origin and aneurysm, especially in smaller aneurysms. METHODS Four major academic institutions in the United States provided data on small paraophthalmic aneurysms (≤ 7 mm) that were treated with PED between 2009 and 2015. The anatomical relationship of OA origin and aneurysm, radiographic outcomes of aneurysm occlusion, and patency of the OA were assessed using digital subtraction angiography. OA origin was classified as follows: Type 1, OA separate from the aneurysm; Type 2, OA from the aneurysm neck; and Type 3, OA from the aneurysm dome. Clinical outcome was assessed using the modified Rankin Scale, and visual deficits were categorized as transient or permanent. RESULTS The cumulative number of small paraophthalmic aneurysms treated with PED between 2009 and 2015 at the 4 participating institutions was 69 in 52 patients (54.1 ± 13.7 years of age) with a male-to-female ratio of 1:12. The distribution of OA origin was 72.5% for Type 1, 17.4% for Type 2, and 10.1% for Type 3. Radiographic outcome at the last follow-up (median 11.5 months) was available for 54 aneurysms (78.3%) with complete, near-complete, and incomplete occlusion rates of 81.5%, 5.6%, and 12.9%, respectively. Two aneurysms (3%) resulted in transient visual deficits, and no patient experienced a permanent visual deficit. At the last follow-up, the OA was patent in 96.8% of treated aneurysms. Type 3 OA origin was associated with a lower rate of complete aneurysm occlusion (p = 0.0297), demonstrating a trend toward visual deficits (p = 0.0797) and a lower rate of OA patency (p = 0.0783). CONCLUSIONS Pipeline embolization treatment of small paraophthalmic aneurysms is safe and effective. An aneurysm where the OA arises from the aneurysm dome may be associated with lower rates of aneurysm occlusion, OA patency, and higher rates of transient visual deficits.

Documentation of Improved Outcomes for Intracranial Aneurysm Management Over a 15-Year Interval.

BACKGROUND AND PURPOSE: Despite rapid advancements in intracranial aneurysm management, there is no evidence as of yet that this has translated into improvement in overall prognosis. METHODS: We compared 2 periods of aneurysm management, 1998 to 2003 (n=1023 aneurysms) and 2007 to 2013 (n=1499 aneurysms), at a single, high-volume neurovascular center. Our outcome of interest was low or moderate disability (Glasgow Outcome Scale score of 4 or 5) at 6 months or more post treatment. RESULTS: There were significant improvements in outcome for surgical, endovascular, and overall treatment of unruptured (adjusted odds ratio [OR], 2.33; P=0.0091; adjusted OR, 4.40; P=0.0271; and adjusted OR, 2.58; P=0.0008, respectively) and ruptured (adjusted OR, 3.18; P=0.0004; adjusted OR, 3.54; P=0.0001; and adjusted OR, 3.11; P<0.0001, respectively) aneurysms from the first to the second time period. In 2007 to 2013, the proportion of cases with low or moderate disability at 6 months post subarachnoid hemorrhage was 75.6% for surgical clipping and 76.6% for endovascular therapy. CONCLUSIONS: We report significantly improved outcomes over time for overall aneurysm management and for multiple patient subgroups, associated with increased usage of endovascular therapy.

Aberrant cervical vasculature anastomosis as cause of neck pain and successful treatment with embolization technique.

We report a patient with non-dermatomal radiating neck pain without focal neurologic deficit. Traditional workup could not identify an anatomic or biomechanical cause. Imaging showed a deep cervical vessel centered in the region of pain. Angiography later identified an aberrant anastomosis of this vessel with the occipital artery. Subsequent endovascular embolization of this arterial trunk resulted in complete pain relief.

Aberrant cervical vasculature anastomosis as cause of neck pain and successful treatment with embolization technique.

We report a patient with non-dermatomal radiating neck pain without focal neurologic deficit. Traditional workup could not identify an anatomic or biomechanical cause. Imaging showed a deep cervical vessel centered in the region of pain. Angiography later identified an aberrant anastomosis of this vessel with the occipital artery. Subsequent endovascular embolization of this arterial trunk resulted in complete pain relief.

Rule of 5: angiographic diameters of cervicocerebral arteries in children and compatibility with adult neurointerventional devices.

BACKGROUND AND PURPOSE: The safety of using adult-sized neuroendovascular devices in the smaller pediatric vasculature is not known. In this study we measure vessel diameters in the cervical and cranial circulation in children to characterize when adult-approved devices might be compatible in children. METHODS: For 54 children without vasculopathy (mean age 9.5±4.9 years (range 0.02-17.8), 20F/34M) undergoing catheter angiography, the diameters of the large vessels in the cervical and cranial circulation (10 locations, 611 total measurements) were assessed by three radiologists. Mean±SD diameter was calculated for the following age groups: 0-6 months, 1, 2, 3, 4, 5-9, 10-14, and 15-18 years. To compare with adult sizes, each vessel measurement was normalized to the respective region mean diameter in the oldest age group (15-18 years). Normalized measurements were compared with age and fitted to a segmented regression. RESULTS: Vessel diameters increased rapidly from 0 to 5 years of age (slope=0.069/year) but changed minimally beyond that (slope=0.005/year) (R(2)=0.2). The regression model calculated that, at 5 years of age, vessels would be 94% of the diameter of the oldest age group (compared with 59% at birth). In addition, most vessels in children under 5, while smaller, were still potentially large enough to be compatible with many adult devices. CONCLUSIONS: The growth curve of the cervicocerebral vasculature displays rapid growth until age 5, at which point most children's vessels are nearly adult size. By age 5, most neuroendovascular devices are size-compatible, including thrombectomy devices for stroke. Under 5 years of age, some devices might still be compatible.

Minimizing bleeding complications in spinal tumor surgery with preoperative Onyx embolization via dual-lumen balloon catheter.

BACKGROUND: Intraoperative bleeding is a significant risk in surgery for highly vascular spinal tumors, but preoperative embolization can safely decrease intraoperative blood loss in extrinsic spine tumors. Onyx, widely used for cerebrovascular embolization, has been increasingly used as an embolic agent for preoperative spinal tumor embolization. The Scepter catheter, a dual-lumen balloon catheter, may improve tumor parenchymal penetration without the danger and limitations of significant embolic reflux. This may reduce bleeding risk during spinal surgery. METHODS: Eleven consecutive cases of preoperative Onyx embolization of extrinsic spinal tumors were identified, all of whom had subsequent spinal surgery. Demographic data and clinical variables were collected. Patients were divided into Scepter (n=6) and non-Scepter (n=5) groups. The Mann-Whitney U test was used to compare continuous outcome variables and the Fisher exact test was used to compare categorical variables. RESULTS: Estimated blood loss in the Scepter group was significantly lower than in the non-Scepter group (584±124 vs 2400±738 mL, p=0.004). The volume of intraoperative transfusion was also significantly lower (1.2±0.4 vs 5.8±1.7 units, p=0.004). There was no significant difference in the number of vessels embolized, vials of Onyx used, use of coiling adjunct, contrast load, radiation dose, or fluoroscopy time per pedicle (p>0.05). CONCLUSIONS: The addition of the Scepter catheter to preoperative Onyx embolization is safe and feasible. In this small series, the Scepter catheter was associated with a reduction of intraoperative bleeding by 76% and a 79% lower transfusion volume. This was not accompanied by any unwanted increase in vials of Onyx used, contrast load, radiation dose, or fluoroscopy time.

Simultaneous stent expansion/balloon deflation technique to salvage failed balloon remodeling.

Herniation, with possible embolization, of coils into the parent vessel following aneurysm coiling remains a frequent challenge. For this reason, balloon or stent assisted embolization remains an important technique. Despite the use of balloon remodeling, there are occasions where, on deflation of the balloon, some coils, or even the entire coil mass, may migrate. We report the successful use of a simultaneous adjacent stent deployment bailout technique in order to salvage coil prolapse during balloon remodeling in three patients. Case No 1 was a wide neck left internal carotid artery bifurcation aneurysm, measuring 9 mm×7.9 mm×6 mm with a 5 mm neck. Case No 2 was a complex left superior hypophyseal artery aneurysm, measuring 5.3 mm×4 mm×5 mm with a 2.9 mm neck. Case No 3 was a ruptured right posterior communicating artery aneurysm, measuring 4 mm×4 mm×4.5 mm with a 4 mm neck. This technique successfully returned the prolapsed coil mass into the aneurysm sac in all cases without procedural complications. The closed cell design of the Enterprise VRD (Codman and Shurtleff Inc, Raynham, Massachusetts, USA) makes it ideal for this bailout technique, by allowing the use of an 0.021 inch delivery catheter (necessary for simultaneous access) and by avoiding the possibility of an open cell strut getting caught on the deflated balloon. We hope this technique will prove useful to readers who may find themselves in a similar predicament.

Initial experience with dual-lumen balloon catheter injection for preoperative Onyx embolization of skull base paragangliomas.

OBJECT Paragangliomas are highly vascular head and neck tumors for which preoperative embolization is often considered to facilitate resection. The authors evaluated their initial experience using a dual-lumen balloon to facilitate preoperative embolization in 5 consecutive patients who underwent preoperative transarterial Onyx embolization assisted by the Scepter dual-lumen balloon catheter between 2012 and 2014. OBJECT The authors reviewed the demographic and clinical records of 5 patients who underwent Scepter-assisted Onyx embolization of a paraganglioma followed by resection between 2012 and 2014. Descriptive statistics of clinical outcomes were assessed. RESULTS Five patients (4 with a jugular and 1 with a vagal paraganglioma) were identified. Three paragangliomas were embolized in a single session, and each of the other 2 were completed in 3 staged sessions. The mean volume of Onyx used was 14.3 ml (range 6-30 ml). Twenty-seven vessels were selectively catheterized for embolization. All patients required selective embolization via multiple vessels. Two patients required sacrifice of parent vessels (1 petrocavernous internal carotid artery and 1 vertebral artery) after successful balloon test occlusion. One patient underwent embolization with Onyx-18 alone, 2 with Onyx-34 alone, and 1 with Onyx-18 and -34. In each case, migration of Onyx was achieved within the tumor parenchyma. The mean time between embolization and resection was 3.8 days (range 1-8 days). Gross-total resection was achieved in 3 (60%) patients, and the other 2 patients had minimal residual tumor. The mean estimated blood loss during the resections was 556 ml (range 200-850 ml). The mean postoperative hematocrit level change was -17.3%. Two patients required blood transfusions. One patient, who underwent extensive tumor penetration with Onyx, developed a temporary partial cranial nerve VII palsy that resolved to House-Brackmann Grade I (out of VI) at the 6-month follow-up. One patient experienced improvement in existing facial nerve weakness after embolization. CONCLUSIONS Scepter catheter-based Onyx embolization seems to be safe and effective. It was associated with excellent distal tumor vasculature penetration and holds promise as an adjunct to conventional transarterial Onyx embolization of paragangliomas. However, the ease of tumor penetration should encourage caution in practitioners who may be able to effect comparable improvement in blood loss with more conservative proximal Onyx penetration.

Epidural Bovine Pericardium Facilitates Dissection During Cranioplasty: A Technical Note.

BACKGROUND AND OBJECTIVE: Adhesions and scarring of the subcutaneous tissue to the dura mater or dural substitute often complicate cranioplasty. We present our experience with epidural bovine pericardium as a barrier membrane to minimize adhesions and facilitate separation of tissue layers. METHODS: A cohort of patients who underwent decompressive craniectomy and subsequent cranioplasty at a major academic institution in the United States from August 2007 to October 2013 and had epidural bovine pericardium placed as a barrier membrane was retrospectively reviewed. Medical records and imaging studies were reviewed for a number of variables including presence of adhesions, infection, contusions, and operative complications. RESULTS: Twenty-nine patients (male-to-female = 1:1.1; mean age 45 ± 14.7 years) who underwent decompressive craniectomy with placement of epidural bovine pericardium with subsequent cranioplasty were identified. The median interval between craniectomy and cranioplasty was 64 days, and autologous bone was used for cranioplasty in 86.2% of cases. The average size of cranial defect was 71.2 ± 28.5 cm(2). At the time of cranioplasty, no or minimal adhesions were found between the subcutaneous tissue and the epidural bovine pericardium. There were 2 (6.9%) infections, 2 (6.9%) patients had contusion after the cranioplasty, and no patient had a complication after cranioplasty that required reoperation. CONCLUSIONS: Epidural bovine pericardium at the time of decompressive craniectomy facilitates dissection at the time of cranioplasty and is not associated with any additional risks.

TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.

Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.