1.Yue, Q., Yu, Y., Shi, Z., Wang, Y., Zhu, W., Du, Z., … Mao, Y. (2018). Prediction of BRAF mutation status of craniopharyngioma using magnetic resonance imaging features. Journal of Neurosurgery, 129(1), 27–34. https://doi.org/10.3171/2017.4.JNS163113

Classically, craniopharyngiomas are divided into 2 histological subtypes: squamous-papillary and adamantinous. The squamous-papillary craniopharyngiomas arise from squamous-cell nests formed by metaplastic cells of the pars tuberalis of the adenohypophysis and are characterized by well-differentiated, nonkeratinizing squamous epithelium and little adhesion to surrounding tissues. In contrast, the adamantinous craniopharyngiomas originate from cell remnants of the craniopharyngeal duct and are characterized by multicystic components, nodules containing wet keratin, and invasion into the brain parenchyma. Despite this histopathologic difference, no obvious difference in the recurrence rate, postoperative outcome, or mortality has been discovered between the 2 subtypes.

The BRAF protein is from the RAF kinase family and regulates cell growth through the mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase (ERK) signaling pathway. Its mutations, among which V600E is the most common, are discovered in a variety of tumors and are considered to promote tumor progression as oncogenic drivers.

BRAF is the most widely studied molecular characteristic of craniopharyngioma,
and its V600E mutation is present in nearly all squamous-papillary craniopharyngiomas. Treatment with inhibitors targeting the BRAF V600E mutation, which has exhibited satisfactory efficacy for several malignancies, has been recently reported to be associated with shrinkage of recurrent craniopharyngiomas. If primary craniopharyngiomas could be diagnosed as BRAF V600E mutated via noninvasive methods, the inhibitors might serve as first-line treatment instead of surgery, or at least partially reduce the tumor size to facilitate subsequent surgery. Moreover, a precise pretreatment diagnosis of BRAF V600E–mutated craniopharyngioma is necessary for further clinical trials to assess the inhibitors’ efficacy in a larger population.

In this study, eight of the 52 patients had BRAF-mutated craniopharyngiomas, and the remaining 44 had BRAF WT tumors. A comparison of findings in the 2 patient groups showed that BRAF-mutated craniopharyngiomas tended to be suprasellar, spherical, predominantly solid, and homogeneously enhancing, and that patients with these tumors tended to have a thickened pituitary stalk. When at least 3 of these 5 features were present, a tumor might be identified as BRAF mutated with a sensitivity of 1.00 and a specificity of 0.91.

Limitations include limited sample size, with 52 cases analyzed, but only 8 of the tumors were BRAF mutated. There was a distinct selection bias, with few cases involving children were included.
3 Figures, 3 Tables

 

2. Grossberg, J. A., Rebello, L. C., Haussen, D. C., Bouslama, M., Bowen, M., Barreira, C. M., … Nogueira, R. G. (2018). Beyond Large Vessel Occlusion Strokes. Stroke, 49(7), 1662–1668. https://doi.org/10.1161/STROKEAHA.118.020567

This was a retrospective review of a prospectively collected endovascular database (2010–2015, n=949) for all patients with distal intracranial occlusions treated endovascularly. Distal occlusions were defined as any segment of the anterior cerebral artery (ACA), posterior cerebral artery, or occlusion at or distal to the middle cerebral artery (MCA)-M3 opercular segment. On angiography, this was defined as any occlusion distal to the first vertical MCA branch on anterior–posterior angiography, which has been previously been used to use to define the M2 segment.

Distal occlusions were treated in 69 patients. The mean age was 66.7 and 57% were male. Patients 42% received intravenous tPA. The median preprocedure NIH Stroke Scale score was 18. The distal occlusion was the primary treatment location in 45 patients, in 23 patients the distal occlusion was treated as a rescue strategy after successful treatment of a proximal large vessel occlusion strokes, and 1 patient had both primary and rescue treatment. The locations of the primary cases were MCA-M3 (n=21), ACA alone (n=8), ACA with a concomitant MCA-M1 or MCA-M2 (n=10), ACA with a concomitant MCA-M3 (n=3), and posterior cerebral artery (n=3). The most common treatment modalities used were stent-retrievers (54%), intra-arterial tPA (52%), and thromboaspiration (45%). Near complete or complete reperfusion of the distal territory (mTICI 2b-3) was achieved in 57 cases (83%).

There was a 7% rate of parenchymal hemorrhage, which the authors considered is within the 2% to 8% range of symptomatic hemorrhage in the landmark thrombectomy clinical trials. Also, there were no cases of vessel perforation or extravasations. The authors conclude that this retrospective study demonstrates the ability to endovascularly treated distal intracranial occlusions safely and with acceptable radiographic results.
3 Figures and 2 Tables

 

3. Lin, A., Rawal, S., Agid, R., & Mandell, D. M. (2018). Cerebrovascular Imaging: Which Test is Best? Neurosurgery, 83(1), 5–18. https://doi.org/10.1093/neuros/nyx325

This is a review article from neuroradiologists at the University of Toronto that discusses specific strategies for choosing the optimal imaging exam in patients with intracranial aneurysms, arteriovenous malformations (AVM), dural arteriovenous fistulas (DAVF), and intracranial arterial steno-occlusive disease.

Three-dimensional TOF-MRA at 3 T is an ideal exam for screening and follow-up of unruptured, untreated saccular aneurysms. Older studies found that MRA had limited sensitivity for detection of small aneurysms, but MRA techniques continue to improve, and 3-D TOF-MRA at 3 T has sensitivity of 98% to 99% and specificity of 93% to 95% (compared with DSA) for diagnosis of intracranial aneurysms smaller than 5 mm.

Regarding aneurysmal SAH, CTA is an ideal initial exam. The authors cover the neck arteries
as well to identify arterial access issues prior to possible DSA. Three-dimensional volume rendering of the arteries can increase the conspicuity of small aneurysms, and aid in treatment
planning. A meta-analysis of studies performed between 1995 and 2010 reported sensitivity of 97% and specificity of 98% for diagnosis of aneurysms using CTA compared with DSA on a per-patient basis.

If CTA fails to identify the cause of subarachnoid hemorrhage (SAH), then decisions about further imaging depend on the hemorrhage pattern: for diffuse or central SAH, DSA is generally warranted. If DSA fails to identify a cause of hemorrhage, then repeat CTA and DSA after 1 to 2 weeks are generally warranted; among patients with diffuse SAH and a negative DSA, 10% had an aneurysm evident on delayed angiography. For a perimesencephalic hemorrhage pattern, research suggests that DSA is unnecessary, but many centers still perform DSA. For peripheral SAH, CTA is often sufficient, but catherter angio can be used if there is question of vasculitis.

MRI of the brain and/or cervical spine occasionally identifies a source of angiogram-negative acute SAH such as a thrombosed aneurysm, cavernous malformation, cerebral amyloid angiopathy, or spinal vascular malformation, but the overall diagnostic yield is low.

For fusiform aneurysms, CE-MRA or CTA are often better options than TOF-MRA to assess a fusiform aneurysm as these aneurysms often have slower or internally recirculating blood flow. Imaging the vessel wall of a fusiform aneurysm, using either standard MRI pulse sequences or optimized vessel wall sequences, can be helpful for differentiating between a fusiform aneurysm that is simply an ectatic arterial segment, and a fusiform aneurysm which grows over time by repeated intramural hemorrhage.

CTA is an optimal initial exam to diagnose vascular causes of intraparenchymal hemorrhage. CTA can also show contrast material accumulation within an acute hematoma, a risk factor for subsequent hematoma expansion. Depending on the clinical history and hemorrhage location, CT venography or MR venography is occasionally warranted as well. If the cause of hemorrhage remains unknown after clinical assessment and noninvasive imaging, then DSA is generally warranted as it may identify a small AVM or another cause such as vasculitis.
8 Figures and 1 Table.

 

4. Harston, G. W. J., Carone, D., Sheerin, F., Jenkinson, M., & Kennedy, J. (2018). Quantifying Infarct Growth and Secondary Injury Volumes. Stroke, 49(7), 1647–1655. https://doi.org/10.1161/STROKEAHA.118.020788

Lesion expansion in the week after acute stroke involves both infarct growth (IG) and anatomic distortion (AD) because of edema and hemorrhage. Enabling separate quantification would allow clinical trials targeting these distinct pathological processes. The authors developed an objective and automated approach to quantify these processes at 24 hours and 1 week.

37 patients with acute ischemic stroke were scanned at presentation, 24 hours, and 1 week in an MRI cohort study. Infarct growth and anatomic distortion were calculated from follow-up lesion masks after linear and nonlinear registration to a presenting MRI scan. Performance of IG and anatomic distortion was compared with edema quantified using cerebrospinal fluid displacement. The use of alternative reference images to define anatomic distortion, including template MRI, mirrored MRI, and presenting computed tomographic scan, was explored.

Using nonlinear registration to correct for anatomic distortion provides not only improved estimates of infarct growth but also quantifies the lesion expansion associated with edema and hemorrhagic transformation. Anatomic distortion can be quantified automatically across a range of infarct volumes in the absence of presenting MRI. Of the alternate reference images, the presenting CT scan provided the best comparator when compared against the benchmark presenting MRI. In this study, anatomic distortion, when measured at 24 hours, could predict a clinically significant volume of anatomic distortion at 1 week.
4 Figures, 2 Tables

 

5. Esquenazi, Y., Moussazadeh, N., Link, T. W., Hovinga, K. E., Reiner, A. S., DiStefano, N. M., … Tabar, V. (2018). Thalamic Glioblastoma: Clinical Presentation, Management Strategies, and Outcomes. Neurosurgery, 83(1), 76–85. https://doi.org/10.1093/neuros/nyx349

This was a retrospective review of all patients with thalamic glioblastoma over a 10-yr period. Presenting clinical, radiological, and outcome data were collected. Chi-squared and Fisher’s exact tests were used to compare clinical characteristics across tumor groups. Cox proportional hazard models were utilized to investigate variables of interest with regard to overall survival.

Fifty-seven patients met inclusion criteria, with a median age of 53 and median Karnofsky Performance Scale (KPS) score of 80. The most common presenting symptoms were weakness, confusion, and headache. Hydrocephalus was present in 47% of patients preoperatively. Stereotactic biopsy was performed in 47 cases, and 10 patients underwent craniotomy. The median overall survival was 12.2 mo. Higher KPS, younger age, and cerebrospinal fluid (CSF) diversion were correlated with better overall survival univariately, respectively, while the presence of language deficits at initial presentation was associated with poorer survival. In multivariate analysis, the only significant predictor of survival was presenting KPS.

The overall survival of patients with thalamic glioblastoma is comparable to unresectable lobar supratentorial GBMs (i.e, subtotal resection). While the authors do not embrace a strategy of treatment without tissue confirmation, empiric treatment in this population may not be unreasonable considering recent advances in diagnostic brain tumor imaging as well as a high rate of complications that can result from a needle biopsy (15%). While extent of resection remains a key prognostic factor in glioblastoma, they did not find a difference in survival outcomes in patients undergoing stereotactic biopsy vs craniotomy.
2 Tables, 5 Figures including MR

 

6. Desjardins, A., Gromeier, M., Herndon, J. E., Beaubier, N., Bolognesi, D. P., Friedman, A. H., … Bigner, D. D. (2018). Recurrent Glioblastoma Treated with Recombinant Poliovirus. New England Journal of Medicine, 379(2), 150–161. https://doi.org/10.1056/NEJMoa1716435

The authors conducted a dose-finding and toxicity study, evaluating convection enhanced, intratumoral delivery of the recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO). Convection enhanced means targeted delivery of therapeutic agents to the CNS with a pressure gradient through a catheter. PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment.

From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Consecutive adult patients were enrolled who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses first in a dose-escalation phase and then in a dose-expansion phase.

The median overall survival among all 61 patients who received PVSRIPO was 12.5 months, which was longer than the 11.3 months in the historical control group and the 6.6 months in another approved treatment, the Novo-TTF-100A treatment group (so-called tumor treatment fields; alternating electrical current applied to the head).

However, overall survival among the patients who received PVSRIPO reached a plateau beginning at 24 months, with the overall survival rate being 21% at 24 months and 36 months, whereas overall survival in the historical control group continued to decline, with overall survival rates of 14% at 24 months and 4% at 36 months.

As with other types of immunotherapy, complete and partial responses to PVSRIPO were easily recognizable, but assessment of tumor progression was difficult. Initially, most patients had increased FLAIR signal abnormalities that receded over time. From the standpoint of disease shown on contrast enhancement, an initial increase in lesion size that was associated with polycystic degradation (“soap bubble” appearance) was observed in all the patients.

In summary, the authors present the results of this phase 1 clinical trial with dose expansion of intratumoral delivery of PVSRIPO in patients with recurrent WHO grade IV malignant glioma. A total of 61 patients underwent successful infusion of PVSRIPO, and there was no evidence of viral neuropathogenicity or virus shedding. At the time of this writing, the survival rate at 24 months and 36 months was 21% with patients remaining alive more than 70 months, more than 69 months, and more than 57 months after the PVSRIPO infusion.

Seven of the authors own equity in the start-up company, Istari Oncology. Patents for PVSRIPO have been licensed from Duke University to Istari Oncology.
3 Tables, 3 Figures including MR

 

7. Diebo, B. G., Lafage, V., Varghese, J. J., Gupta, M., Kim, H. J., Ames, C., … Schwab, F. J. (2018). After 9 Years of 3-Column Osteotomies, Are We Doing Better? Performance Curve Analysis of 573 Surgeries With 2-Year Follow-up. Neurosurgery, 83(1), 69–75. https://doi.org/10.1093/neuros/nyx338

Patients who underwent 3CO for spinal deformity with intra/postoperative and revision data collected up to 2 yr were included. Patients were chronologically divided into 4 even groups. Demographics, baseline deformity/correction, and surgical metrics were compared using Student t-test. Postoperative and revision rates were compared.

Patients were categorized into 4 groups with similar number of surgeries from older to more recent. Group 1 (n=143, surgeries performed between February 2004 and April 2008 by 10 surgeons), group 2 (n = 142, April 2008-September 2009 by 10 surgeons), group 3 (n = 144, September 2009-November 2010 by 12 surgeons), group 4 (n = 144 November 2010-January 2013 by 12 surgeons). Ten of the same surgeons were represented in all 4 groups, while 2 additional surgeons were represented in groups 3 and 4.

Overall, 206 out of 573 patients were revised during the last 9 yr (35.9%). Revision rates significantly decreased among the groups at 2-yr follow-up: group 2004 to 2008: 45%; group 2008 to 2009: 35%; group 2009 to 2010: 33%; and group 2010 to 2013: 30%.

Overall complication rate was 48% (274 out of 573 cases). The complication rate significantly improved from 57% in 2004 to 2008 to 39% in 2010 to 2013.

Data collected over 9 yr of spinal osteotomy utilization revealed that recent surgeries are performed on a more disabled population with better technical ability reflected by increased bone resection angle. These surgeries are performed with similar operating times and with reductions in revisions and complications rates by 15% and 18%, respectively.

The authors note the limitation that patient-reported outcomes were not investigated over time and longer follow-up is important to examine the durability of surgical outcomes. Moreover, the data were unable to follow up with patients who decided to move their health care to centers outside the group.
6 Tables, 3 Figures

 

8. Tønnesen, J., Inavalli, V. V. G. K., & Nägerl, U. V. (2018). Super-Resolution Imaging of the Extracellular Space in Living Brain Tissue. Cell, 172(5), 1108–1111.e15. https://doi.org/10.1016/j.cell.2018.02.007

To visualize the spatial organization of the ECS in live brain tissue, they developed super-resolution shadow imaging (SUSHI). It is based on 3D-STED microscopy (stimulated emission depletion) and labeling of the extracellular fluid with a diffusible fluorophore that does not permeate cell membranes. The extracellular labeling scheme is effectively insensitive to photobleaching and permits intense 3D-STED time-lapse imaging of large fields of view without signs of phototoxicity. Using mouse organotypic hippocampal slices, they show that SUSHI gives unprecedented optical access to the structure and dynamics of the ECS. They document distinctive ECS structural changes in response to a variety of physiologically relevant stimuli, including osmotic challenges, epileptiform discharges and glutamate uncaging. Moreover, as SUSHI produces super-resolved negative images of all cells, it reveals the micro-anatomical organization of live brain tissue in its entirety. This makes it possible to detect synaptic clefts, to generate 3D reconstructions of unlabeled cells, to visualize perineuronal spaces, and to monitor cell migration while the surrounding anatomical context is also visible.

7 complicated figures, but worth taking a look.

 

9. Olson, C. A., Vuong, H. E., Yano, J. M., Liang, Q. Y., Nusbaum, D. J., & Hsiao, E. Y. (2018). The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell, 173(7), 1728–1741.e13. https://doi.org/10.1016/j.cell.2018.04.027

The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. The authors show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia (A. muciniphila) and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial crossfeeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.

In other words, they demonstrate that the KD alters the gut microbiota across two seizure mouse models, and changes in the microbiota are necessary and sufficient for conferring seizure protection.

7 super-complicated figures.