Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. ...Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The authors tested the feasibility of magnetic resonance-guided focused ultrasound (MRgFUS) ablation of mesial temporal lobe epilepsy (MTLE) seizure circuits. Up to one-third of patients with mesial ...temporal sclerosis (MTS) suffer from medically refractory epilepsy requiring surgery. Because current options such as open resection, laser ablation, and Gamma Knife radiosurgery pose potential risks, such as infection, hemorrhage, and ionizing radiation, and because they often produce visual or neuropsychological deficits, the authors developed a noninvasive MRgFUS ablation strategy for mesial temporal disconnection to mitigate these risks.
The authors retrospectively reviewed 3-T MRI scans obtained with diffusion tensor imaging (DTI). The study group included 10 patients with essential tremor (ET) who underwent pretreatment CT and MRI prior to MRgFUS, and 2 patients with MTS who underwent MRI. Fiber tracking of the fornix-fimbria pathway and inferior optic radiations was performed, ablation sites mimicking targets of open posterior hippocampal disconnection were modeled, and theoretical MRgFUS surgical plans were devised. Distances between the targets and optic radiations were measured, helmet angulations were prescribed, and the numbers of available MRgFUS array elements were calculated.
Tractograms of fornix-fimbria and optic radiations were generated in all ET and MTS patients successfully. Of the 10 patients with both the CT and MRI data necessary for the analysis, 8 patients had adequate elements available to target the ablation site. A margin (mean 8.5 mm, range 6.5-9.8 mm) of separation was maintained between the target lesion and optic radiations.
MRgFUS offers a noninvasive option for seizure tract disruption. DTI identifies fornix-fimbria and optic radiations to localize optimal ablation targets and critical surrounding structures, minimizing risk of postoperative visual field deficits. This theoretical modeling study provides the necessary groundwork for future clinical trials to apply this novel neurosurgical technique to patients with refractory MTLE and surgical contraindications, multiple prior surgeries, or other factors favoring noninvasive treatment.
Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains ...poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC
(CTSK
CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2
CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans
, solely in CTSK
CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK
CSCs and a corresponding expansion of DDR2
CSCs, with DDR2
CSC expansion being a direct maladaptive response to CTSK
CSC depletion. DDR2
CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2
CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2
CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK
CSCs. Finally, the human counterparts of DDR2
CSCs and CTSK
CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.
Intracranial arachnoid cysts are commonly characterized as congenital. Evidence to support a congenital origin is scant and documented evolution during infancy also calls into question the genesis of ...these lesions. To improve our understanding of the natural history and the clinical significance of arachnoid cysts on prenatal ultrasound, we conducted a study to describe the fate of these cysts after initial diagnosis.
We conducted a retrospective descriptive review of all prenatal ultrasounds with reported intracranial arachnoid cysts at a tertiary care center from 2010 to 2016 and cohort study comparing patients with additional ultrasound abnormalities to those with an isolated finding of arachnoid cyst. Data collected included gestational age at cyst diagnosis, cyst evolution on follow-up imaging, cyst size and cyst location, postnatal imaging and neurosurgical consultation and intervention. Statistical analysis including Chi-square and Fisher's exact tests and univariate logistic regressions were performed using Stata v. 13 (StataCorp 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). Confidence intervals were reported at 95% and a p-value < .05 was considered significant.
A total of 33,621 anatomical ultrasound scans were performed from 2010 to 2016. Seventy patients (0.2%) had prenatal findings of arachnoid cyst, of which the mean gestational age was 21.46 weeks. Ventriculomegaly was observed in one patient (1.4%) at the time of diagnosis and other abnormalities were found in twelve patients (17%). Complete sonographic follow-up prior to delivery was obtained in 53 (75.7%) patients with 5(9.4%) progression, 5(9.4%) regression, and 43(81.1%) no longer visualized. Forty-three cysts (81.1%) were no longer visualized on follow-up imaging, all of which were interhemispheric in location. All of the cysts that progressed in size on prenatal ultrasounds were > 2 cm in size on initial diagnosis. Cyst fenestration was performed in two patients (2.9%) that had arachnoid cysts measuring at least 3 cm in each dimension on prenatal imaging, one at eight months and one at six months of age. Patients with and without additional sonographic abnormalities had similar rates of AMA (23.1% vs 26.3%, p = .56), nulliparity (61.5% vs 70.2%, p = .38), obesity (0.0% vs 12.3%, p = .221), major medical comorbidities (38.5% vs 33.3%, p = .48) and pregnancy achieved via Assisted Reproductive Technology (38.5% vs 24.6%, p = .25), respectively. Patients with additional sonographic abnormalities were significantly more likely to have prenatal Magnetic Resonance Imaging (OR: 8.28, CI: 1.84-40.4, p = .07), prenatal neurosurgery consultation (OR: 8.25, CI: 1.23-69.05, p = .04) and invasive diagnostic genetic testing (OR: 11.25, CI: 2.33-64.35, p = .003).
Arachnoid cysts are infrequently found on prenatal screening. Size greater than 2 cm on second trimester ultrasound and location outside of the interhemispheric fissure may indicate the need for further evaluation and eventual fenestration. Prenatally diagnosed arachnoid cysts are not typically associated with other anatomic or genetic abnormalities, although the presence of additional abnormalities usually leads to more intensive prenatal and postnatal investigations.
BACKGROUND:Controversy surrounds the fate of cyst remnants after endoscopic colloid cyst resection.
OBJECTIVE:Our study evaluated recurrence rates in patients with total endoscopic resection of ...colloid cysts vs those with coagulated cyst remnants.
METHODS:Sixty-five consecutive patients and 67 procedures for endoscopic resection of colloid cysts from 1995 to 2011 were reviewed. Degree of resection was based on intraoperative assessment and postoperative magnetic resonance imaging (MRI). Recurrence rates were compared between patients with complete resection those with coagulated cyst remnants.
RESULTS:Data analysis was performed of 56 patients and 58 procedures, with no follow-up in 9 patients. All patients had MRI-defined complete resection. On intraoperative assessment, 9 procedures had coagulated remnants and 45 procedures had complete resection (4 data unknown). The overall recurrence rate was 6.89% (4/58), 33.3% (3/9) with cyst remnants, and 2.2% (1/45) with total resection (P = .0124). Maximum follow-up was 144 months (mean, 40.4 months). Mean follow-up was 66.0 months for cyst remnant cases, and 33.5 months for totally resected cases. There was no mortality or permanent morbidity. Transient morbidity included memory deficit (n = 2), aseptic meningitis (n = 1), and local wound infection (n = 1).
CONCLUSION:Endoscopic colloid cyst resection results in a low overall recurrence rate. Immediate postoperative MRI was insufficient for assessing degree of resection and was a poor predictor of recurrence. Ablation of cyst remnants rather than total removal is associated with a significantly higher rate of recurrence. The primary goal of endoscopic surgery should, therefore, be removal of all cyst contents and wall remnants.
A meta-analysis was performed to understand disparities in the representation of female authorship within the neurosurgical literature and implications for career advancement of women in ...neurosurgery.
Author names for articles published in 16 of the top neurosurgical journals from 2002 to 2019 were obtained from MEDLINE. The gender of each author was determined using automated prediction methods. Publication trends were compared over time and across subdisciplines. Female authorship was also compared to the proportionate composition of women in the field over time.
The metadata obtained from 16 major neurosurgical journals yielded 66,546 research articles. Gender was successfully determined for 96% (127,809/133,578) of first and senior authors, while the remainder (3.9%) were unable to be determined through prediction methods. Across all years, 13.3% (8826) of articles had female first authorship and 9.1% (6073) had female senior authorship. Female first authorship increased significantly over time from 5.8% in 2002 to 17.2% in 2019 (p < 0.001). Female senior authorship also increased significantly over time, from 5.5% in 2002 to 12.0% in 2019 (p < 0.001). The journals with the highest proportions of female first authors and senior authors were the Journal of Neurosurgery: Pediatrics (33.5%) and the Asian Journal of Neurosurgery (23.8%), respectively. Operative Neurosurgery had the lowest fraction of female first (12.4%) and senior (4.7%) authors. There was a significant difference between the year-by-year proportion of female neurosurgical trainees and the year-by-year proportion of female neurosurgical first (p < 0.001) and senior (p < 0.001) authors. Articles were also more likely to have a female first author if the senior author of the article was female (OR 2.69, CI 2.52-2.86; p < 0.001). From 1944 to 2019, the Journal of Neurosurgery showed a steady increase in female first and senior authorship, with a plateau beginning in the 1990s.
Large meta-analysis techniques have the potential to effectively leverage large amounts of bibliometric data to quantify the representation of female authorship in the neurosurgical literature. The proportion of female authors in major neurosurgical journals has steadily increased. However, the rate of increase in female senior authorship has lagged behind the rate of increase in first authorship, indicating a disparity in academic advancement in women in neurosurgery.
The diagnostic and surgical management of epilepsy has made enormous strides over the past 3 decades, concomitant with advances in technology and electrophysiologic understanding of neuronal ...connectivity. Distinct zones have been identified within this network that each communicate and play a role in the genesis of seizures. Invasive and noninvasive modalities for defining the epileptogenic lesion or region have been able to more accurately determine which patients are optimal candidates for treatment when their seizures are refractory to conventional conservative management. Ablative, palliative, and disconnecting procedures have been developed as alternatives for traditional open resection techniques, and in recent studies, they have shown excellent seizure control and mitigation of complications. In this review, we discuss the evolution of these advancements in the management of epilepsy and provide an overview of current and future neurosurgical therapeutic modalities.
Complications after craniosynostosis surgery occur in 11% to 36% of cases and may be precipitated by poor soft tissue coverage and concomitant exposure of non-sterile regions; sequelae may result in ...infection, osteomyelitis, and bone loss requiring complex reconstruction. In the pediatric population, autologous cranioplasty remains the gold standard due to growth potential and a more favorable complication profile than synthetic cranioplasty. Virtual surgery planning (VSP) and computer-assisted design (CAD)/computer-assisted manufacturing (CAM) technology can be utilized to create innovative, patient-specific autologous solutions, similar to the approach with synthetic cranioplasty. A novel surgical approach using VSP was used for an 18-month-old female with near total bifrontal bone loss. Surface area measurements were used to determine the amount of bone available to replace the infected frontal bone. VSP was utilized to determine the most efficient construct configuration possible to achieve maximal coverage via calculation of cranial bone surface area measurements. Surgical reconstruction of the defect was planned as a Modified Visor Bone Flap with Posterior Brain Cage. A construct was fashioned from available cranial bone struts to obtain widespread coverage. 3D Recon images from before and after surgery demonstrate almost complete re-ossification of the cranial vault with significant resulting clinical improvement. Reconstruction of total frontal bone loss is possible by utilizing this technique. VSP can improve the safety and efficiency of complex autologous cranial bone reconstructions. We propose a treatment algorithm to address the problem of near total frontal bone loss in young children for whom alloplastic implants are not suitable.
Cavernous malformations are rare cerebral pseudo-vascular lesions with annualized bleeding rates of 0.5-3% in most studies. Of the various explored risk factors for bleeding to date, only prior ...hemorrhage has shown significant correlation.
In this case, we describe a 65-year old man with a peri-ventricular atrial cavernous malformation that hemorrhaged after CSF diversion via ventriculoperitoneal shunting. Serial imaging showed that bleeding continued until the shunt was revised with a programmable valve set at maximum resistance with the addition of a gravitational unit, thereby lowering the trans-mural pressure differential across the cavernous malformation.
Given that other vascular lesions are subject to hemorrhage from alterations in trans-mural pressure dynamics, we hypothesize that cavernous malformations are similarly affected by trans-mural pressure gradients as they are composed of primitive vascular elements. This hypothesis is corroborated by the temporal correlation of interventions, imaging, and exam findings in the present case, and suggests a potentially important risk factor for hemorrhage in CM patients that affects prognostication and management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Closed-loop devices are associated with better seizure reduction and clinical outcomes at 9 months.•Differences between closed- and open-loop devices were not significant at 24 months.•Multiple ...seizure types and history of epilepsy surgery associated with worse outcomes.
A new class of heart-rate sensing, closed-loop vagal nerve stimulator (VNS) devices for refractory epilepsy may improve seizure control by using pre-ictal autonomic changes as an indicator for stimulation. We compared our experience with closed- versus open-loop stimulator implantation at a single institution.
We conducted a retrospective chart review of consecutive VNS implantations performed from 2004 to 2018. Bivariate and multivariable analyses were performed to compare changes in seizure frequency and clinical outcomes (Engel score) with closed- versus open-loop devices. Covariates included age, duration of seizure history, prior epilepsy surgery, depression, Lennox Gastaut Syndrome (LGS), tonic seizures, multiple seizure types, genetic etiology, and VNS settings. We examined early (9-month) and late (24-month) outcomes.
Seventy subjects received open-loop devices, and thirty-one received closed-loop devices. At a median of 8.5 months, there was a greater reduction of seizure frequency after use of closed-loop devices (median 75% IQR 10–89%) versus open-loop (50% 0–78%, p < 0.05), confirmed in multivariable analysis (odds ratio 2.72 95% CI 1.02 – 7.4). Similarly, Engel outcomes were better after closed-loop compared to open-loop confirmed in the multivariable analysis at the early timepoint (OR 0.26 95% CI 0.09 – 0.69). These differences did not persist at a median of 24.5 months.
This retrospective single-center study suggests the use of closed-loop VNS devices is associated with greater seizure reduction and more favorable clinical outcomes than open-loop devices at 9-months though not at 24-months. Expansion of this study to other centers is warranted to increase the generalizability of our study.
PDF
