Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune Recognition and Response in Glioma.

Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of cancer-testis antigens (CTA) in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using New York esophageal squamous cell carcinoma 1 (NY-ESO-1) as a representative inducible CTA, we demonstrate in patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres that basal CTA expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing to render NY-ESO-1 and other CTA into inducible tumor antigens at single-cell resolution. Functionally, NY-ESO-1 T-cell receptor-engineered effector cell targeting of DAC-induced antigen in primary glioma cells promotes specific and polyfunctional T-cell cytokine profiles. In addition to induction of CTA, DAC concomitantly reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I. Overall, we demonstrate that DAC induces targetable tumor antigen and enhances T-cell functionality against GBM, ultimately contributing to the improvement of targeted immune therapies in glioma. SIGNIFICANCE: This study dissects the tumor-intrinsic epigenetic and transcriptional mechanisms underlying enhanced T-cell functionality targeting decitabine-induced cancer-testis antigens in glioma. Our findings demonstrate concomitant induction of tumor antigens, reactivation of human endogenous retroviruses, and stimulation of interferon signaling as a mechanistic rationale to epigenetically prime human gliomas to immunotherapeutic targeting.

Approaches to the Middle Cerebellar Peduncle for Resection of Pontine Cavernomas.

INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE: The expanded retrosigmoid approach with splitting of the horizontal cerebellar fissure provides a more direct and shorter route for central and dorsolateral pontine lesions while minimizing retraction of tracts, nuclei, and cerebellum. 1-4. ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT: The middle cerebellar peduncle is partially covered by the petrosal surface of the cerebellum. The horizontal cerebellar fissure (petrosal fissure) divides the petrosal surface of the cerebellar hemisphere into superior and inferior parts. Splitting the petrosal fissure separates the superior and inferior petrosal surfaces and exposes the posterolateral middle cerebellar peduncle (posterior and lateral to the root entry zone of CN5). 1-4. ESSENTIALS STEPS OF THE PROCEDURE: Expanded retrosigmoid craniotomy is performed, including unroofing of the sigmoid sinus; petrosal fissure is split to expose the posterolateral middle cerebellar peduncle; entry point for resection of the cavernoma is identified; nims stimulator stimulator is used to confirm the absence of tracts and nuclei; myelotomy is performed; and cavernoma and its draining vein (but not the developmental venous anomaly) are removed using a combination of traction and countertraction against gliotic plane. PITFALLS/AVOIDANCE OF COMPLICATIONS: Wide splitting of the horizontal cerebellar fissure minimizes retraction or resection of the cerebellum and offers the best angle of attack. Knowledge of brainstem anatomy and use of intraoperative navigation are critical to avoid complications. VARIANTS AND INDICATIONS FOR THEIR USE: Far lateral through the middle cerebellar peduncle is a variant that can be used to resect pontine cavernomas if a caudocranial trajectory is preferred.The patient consented to the procedure and to the publication of her image.

Contralateral transfalcine approach for resection of right medial frontal AVM.

Brain arteriovenous malformations (AVMs) are high flow vascular lesions that can cause significant morbidity and mortality [1-6]. We present a case of a 23-year-old woman who initially presented to an outside institution with a ruptured right medial frontal Spetzler Martin grade II AVM. An EVD was placed and a diagnostic angiogram with partial embolization was performed. She was then transferred to our institution two months post rupture for further care. On arrival, she was trached with eyes opening to voice and localizing in bilateral upper extremities and withdrawing in bilateral lower extremities. Diagnostic angiogram demonstrated arterial supply from the right pericallosal and callosomarginal artery, right posterior cerebral artery callosomarginal branch, distal left anterior cerebral artery (ACA) branches with venous drainage via a cortical vein to the superior sagittal sinus. The patient underwent preoperative embolization of the ACA feeders followed by a contralateral interhemispheric transfalcine approach. An interhemispheric dissection was performed down to the corpus callosum and AVM feeders and draining veins were identified. The falx was then incised to expose the right medial frontal lobe. The AVM was circumferentially dissected and resected. Postoperative imaging demonstrated complete resection of the AVM. She remained at her neurological baseline immediately postoperatively and was discharged to inpatient rehab. The patient made a remarkable recovery and at three months follow up, she no longer required a tracheostomy and was neurologically intact with no complaints except for mild memory difficulties. In this video, we demonstrate the step-by-step surgical technique and review the benefits of the contralateral transfalcine approach for resection of a ruptured right medial frontal Spetzler Martin grade II AVM. The patient consented to the procedure and to the publication of her imaging in this surgical video.

Upper lumbar spine far lateral disc herniations masquerading as peripheral nerve sheath tumors: illustrative cases.

BACKGROUND: Migratory disc herniations can mimic neoplasms clinically and on imaging. Far lateral lumbar disc herniations usually compress the exiting nerve root and can be challenging to distinguish from a nerve sheath tumor due to the proximity of the nerve and characteristics on magnetic resonance imaging (MRI). These lesions can occasionally present in the upper lumbar spine region at the L1-2 and L2-3 levels. OBSERVATIONS: The authors describe 2 extraforaminal lesions in the far lateral space at the L1-2 and L2-3 levels, respectively. On MRI, both lesions tracked along the corresponding exiting nerve roots with avid postcontrast rim enhancement and edema in the adjacent muscle tissue. Thus, they were initially concerning for peripheral nerve sheath tumors. One patient underwent fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) screening and demonstrated moderate FDG uptake on PET-CT scan. In both cases, intraoperative and postoperative pathology revealed fibrocartilage disc fragments. LESSONS: Differential diagnosis for lumbar far lateral lesions that are peripherally enhancing on MRI should include migratory disc herniation, regardless of the level of the disc herniations. Accurate preoperative diagnosis can aid in decision making for management, surgical approach, and resection.

Machine learning predicts improvement of functional outcomes in traumatic brain injury patients after inpatient rehabilitation.

Survivors of traumatic brain injury (TBI) have an unpredictable clinical course. This unpredictability makes clinical resource allocation for clinicians and anticipatory guidance for patients difficult. Historically, experienced clinicians and traditional statistical models have insufficiently considered all available clinical information to predict functional outcomes for a TBI patient. Here, we harness artificial intelligence and apply machine learning and statistical models to predict the Functional Independence Measure (FIM) scores after rehabilitation for traumatic brain injury (TBI) patients. Tree-based algorithmic analysis of 629 TBI patients admitted to a large acute rehabilitation facility showed statistically significant improvement in motor and cognitive FIM scores at discharge.

Predictors of mortality and tumor recurrence in desmoplastic infantile ganglioglioma and astrocytoma-and individual participant data meta-analysis (IPDMA).

PURPOSE: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature. METHODS: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression. RESULTS: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression. CONCLUSION: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.

Selective scalp block decreases short term post-operative pain scores and opioid use after craniotomy: A case series.

There is no consensus on the management of post-craniotomy pain. Several randomized controlled trials have examined the use of a regional scalp block for post-craniotomy pain. We aim to investigate whether scalp block affected short or long-term pain levels and opioid use after craniotomy. This study prospectively administered selective scalp blocks (lesser occipital, preauricular nerve block + pin site block) in 20 consecutive patients undergoing craniotomy for semicircular canal dehiscence. Anesthesia, pain, and opioid outcomes in these patients were compared to 40 consecutive historic controls. There was no significant difference in patient demographics between the two groups and no complications related to selective scalp block. The time between the end of procedure and end of anesthesia decreased in the scalp block group (16 vs 21 min, P = 0.047). Pain scores were significantly less in the scalp block group for the first 4 h, after which there was no statistically significant difference. Time to opioid rescue was longer in the scalp block group (3.6 vs 1.8 h, HR 0.487, P = 0.0361) and opioid use in the first 7 h was significantly less in the scalp block group. Total opioid use, outpatient opioid use, and length of stay did not differ. Selective scalp block is a safe and effective tool for short-term management of postoperative pain after craniotomy and decreases the medication requirement during emergence and recovery. Selective scalp block can speed up OR turnover but is not efficacious in the treatment of postoperative pain beyond this point.

Superior Semicircular Canal Dehiscence Revision Surgery Outcomes: A Single Institution's Experience.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) is an abnormality of the otic capsule, which normally overlies the superior semicircular canal. Surgical management is indicated in patients with persistent and debilitating symptoms. Given the complexity of the disease, there are patients who experience less favorable surgical outcomes and require revision surgery. The purpose of this study was to report to the rate of postoperative symptomatic improvement in patients who required revision surgery. METHODS: A retrospective analysis of patients undergoing SSCD surgical repair at a single institution was performed. Information on patient demographics, primary and secondary surgical approaches, surgical outcomes, and follow-up length was collected. RESULTS: Seventeen patients underwent 20 revision surgeries. There were eleven (65%) females and six (35%) males. Mean age of the cohorts was 50 years (range 30-68 years), and mean follow-up length was 6.8 months (range 0.1-31.1 months). Cerebrospinal fluid leak was noted in 67% of cases. The greatest postoperative symptomatic resolution was reported in oscillopsia (100%), headache (100%), and internal sound amplification (71%), while the least postoperative symptomatic resolution was reported in tinnitus (42%), aural fullness (40%), and dizziness (29%). CONCLUSIONS: Revision surgery can provide symptomatic improvement in select SSCD patients; however, patients should be cautioned about the possibility of less favorable outcomes than in index surgery. Revision surgeries are associated with a considerably higher rate of perioperative cerebrospinal fluid leak.

Relationship Between Superior Semicircular Canal Dehiscence Volume with Clinical Symptoms: Case Series.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) is an osseous defect of the arcuate eminence of the petrosal temporal bone. Patients typically present with auditory and vestibular symptoms, such as hearing loss and disequilibrium. Using advanced imaging segmentation techniques, we evaluated whether the volume of SSCD correlated with preoperative symptoms and postoperative outcomes. METHODS: Our laboratory previously described a novel method of quantifying the size of an SSCD via manual segmentation. High-resolution computed tomography images of the temporal bones were imported into a specialized segmentation software. The volume of the dehiscence was outlined on consecutive slices of the coronal and axial planes via a single-pixel-thick paintbrush tool and was then calculated according to the number of nonzero image voxels. RESULTS: This study included 111 patients (70 women and 41 men; mean age, 55.1 years; age range, 24-87 years) with a total of 164 SSCDs. Mean postoperative follow-up time was 5.2 months (range, 0.03-59.5 months). The most common preoperative and postoperative symptoms were tinnitus (n = 85) and dizziness (n = 45), respectively. Surgery resulted in improvement of symptoms in most patients. The average volume of 164 SSCDs was 1.3 mm3. SSCD volume was not significantly associated with either preoperative symptoms or postoperative outcomes. CONCLUSIONS: Advances in imaging techniques have allowed increased visualization of SSCD. Further research will be necessary to evaluate the potential correlation of volume of the dehiscence with clinical variables.

Postoperative Admission of Adult Craniotomy Patients to the Neuroscience Ward Reduces Length of Stay and Cost.

BACKGROUND: The neurointensive care unit (NICU) has traditionally been the default recovery unit after elective craniotomies. OBJECTIVE: To assess whether admitting adult patients without significant comorbidities to the neuroscience ward (NW) instead of NICU for recovery resulted in similar clinical outcome while reducing length of stay (LOS) and hospitalization cost. METHODS: We retrospectively analyzed the clinical and cost data of adult patients undergoing supratentorial craniotomy at a university hospital within a 5-yr period who had a LOS less than 7 d. We compared those admitted to the NICU for 1 night of recovery versus those directly admitted to the NW. RESULTS: The NICU and NW groups included 340 and 209 patients, respectively, and were comparable in terms of age, ethnicity, overall health, and expected LOS. NW admissions had shorter LOS (3.046 vs 3.586 d, P < .001), and independently predicted shorter LOS in multivariate analysis. While the NICU group had longer surgeries (6.8 vs 6.4 h), there was no statistically significant difference in the cost of surgery. The NW group was associated with reduced hospitalization cost by $3193 per admission on average (P < .001). Clinically, there were no statistically significant differences in the rate of return to Operating Room, Emergency Department readmission, or hospital readmission within 30 d. CONCLUSION: Admitting adult craniotomy patients without significant comorbidities, who are expected to have short LOS, to NW was associated with reduced LOS and total cost of admission, without significant differences in postoperative clinical outcome.

Spontaneous Resolution of Dural and Pial Arteriovenous Fistulae Arising After Superficial Temporal Artery to Middle Cerebral Artery Bypass for Moyamoya Disease.

BACKGROUND: Superficial temporal artery (STA)-to-middle cerebral artery bypass is frequently performed for moyamoya disease. We discuss an unusual case in a moyamoya patient complicated by the development of dural and pial arteriovenous fistulae (AVF). Both AVF then spontaneously resolved 2 years after surgery. CASE DESCRIPTION: A patient in the fifth decade of life presented after multiple strokes resulting in right-sided weakness and numbness. Magnetic resonance imaging revealed remote strokes, and angiography revealed Suzuki grade 3 moyamoya angiopathy bilaterally. With a diminutive left STA, we initially performed left-sided dual-vessel pial synangioses. After radiographic evidence of robust revascularization and improved hemispheric perfusion, a combined right STA-middle cerebral artery bypass was done. However, routine 8-month postoperative angiography identified dural and pial AVF within the prior operative field. On the 2-year surveillance cerebral angiogram, both AVF were no longer present. CONCLUSIONS: AVF as a complication of revascularization surgery is rare. Here, we discuss the possible pathophysiologic mechanisms that we theorize may have contributed and current treatment options and indications. We also review the literature surrounding this phenomenon.

A systematic analysis of stereotactic radiosurgery surveys for residents in neurosurgery training programs.

OBJECT: The use of stereotactic radiosurgery (SRS) has increased. SRS training has not risen congruently. Neurosurgeons have conducted surveys and advocated implementation of widespread, standardized radiosurgery training. Here we analyze the SRS surveys conducted throughout the past decade. METHODS: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic literature review. A broad search of the literature was conducted in October 2018 through the PubMed, Scopus, Embase, and Web of Science databases. This study included surveys evaluating SRS training in neurosurgery and excluded those regarding other specialties. RESULTS: An overview of surveys showed that neurosurgery residents possess gaps in SRS knowledge and procedural competency that have persisted through the past decade. There is an overwhelming sentiment that current radiosurgery training is not adequate to prepare residents for future practice. Our recommendation is for residency programs to integrate formal SRS training electives, with a movement towards creating more options for extended SRS fellowships post-residency. CONCLUSIONS: We present data from SRS competency and current training surveys. Although resident SRS training still lags behind other subspecialties, we see indications for growth. To keep up with the role of SRS in neurosurgery, residencies need more formalized SRS rotations.

Thinning or dehiscence of bone in structures of the middle cranial fossa floor in superior semicircular canal dehiscence.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) is a rare inner ear disorder; currently, it is unknown whether the etiopathology underlying this structural irregularity affects neighboring structures. The goal is to investigate the prevalence of bone thinning in areas of the middle cranial fossa (MCF) floor in SSCD and non-SSCD patients. METHODS: This retrospective study analyzed 100 patients from March 2011 to June 2017 at a tertiary referral center. 100 patients undergoing 118 SSCD repair surgeries (18 bilateral) were identified. 12 SSCD ears were excluded due to lack of pre-operative computed tomography (CT) scans or history of prior SSCD repair at an outside facility. Non-SSCD ears were identified from routinely-obtained CT scans for temporal bone fracture (fractured sides excluded) for a total of 101 ears; 26 non-SSCD ears were excluded due to lack of high-resolution imaging. RESULTS: Univariate analyses reveal that SSCD diagnosis is associated with higher rates of geniculate ganglion (GG) dehiscence compared with non-SSCD controls (42.7 vs. 24%; χ2(1) = 9.69,P = 0.008). Individuals with SSCD depicted significantly thinner bone overlying the geniculate ganglion (GG) (0.23 ± 1.2 mm) compared to controls (0.28 ± 1.8 mm, (t(1 6 4)) = 2.1, P = 0.04). SSCD patients presented thinner bone overlying the internal auditory canal (IAC) (0.33 ± 1.3 mm) compared to patients without SSCD (0.46 ± 1.6 mm, (t(2 5 7) = 6.4, P < 0.001). CONCLUSIONS: The increased prevalence of dehiscence of the MCF in this cohort of SSCD patients compared to non-SSCD patients suggests that the etiology underlying SSCD affects surrounding structures.

Patient Safety Analysis in Radiation Burden of Head Computed Tomography Imaging in 1185 Neurosurgical Inpatients.

OBJECTIVE: We performed a retrospective analysis in a cohort of 1185 patients at our institution who were identified as undergoing ≥1 head computed tomography (CT) examinations during their inpatient stay on the neurosurgery service, to quantify the number, type, and associated radiation burden of head CT procedures performed by the neurosurgery service. METHODS: CT procedure records and radiology reports were obtained via database search and directly validated against records retrieved from manual chart review. Next, dosimetry data from the head CT procedures were extracted via automated text mining of electronic radiology reports. RESULTS: Among 4510 identified adult head CT procedures, 88% were standard head CT examinations. A total of 3.65 ± 3.60 head CT scans were performed during an average adult admission. The most common primary diagnoses were neoplasms, trauma, and other hemorrhage. The median cumulative effective dose per admission was 5.66 mSv (range, 1.06-84.5 mSv; mean, 8.56 ± 8.95 mSv). The median cumulative effective dose per patient was 6.4 mSv (range, 1.1-127 mSv; mean, 9.26 ± 10.0 mSv). CONCLUSIONS: The median cumulative radiation burden from head CT imaging in our cohort equates approximately to a single chest CT scan, well within accepted limits for safe CT imaging in adults. Refined methods are needed to characterize the safety profile of the few pediatric patients identified in our study.

Meta-analysis of tumor control rates in patients undergoing stereotactic radiosurgery for cystic vestibular schwannomas.

OBJECTIVE: The use of SRS for treatment of cystic vestibular schwannoma is a topic of mild controversy. This review serves to introduce a renewed understanding of the efficacy of SRS as a viable treatment modality for cystic VS. PATIENTS AND METHODS: This study was conducted in accordance with the PRISMA guidelines. A broad search of the literature was conducted in October 2018 through the PubMed, Scopus, Embase, Web of Science, and Cochrane databases. Meta-analysis was conducted on tumor control rates and heterogeneity between articles was assessed using τ2, Cochran's Q, and I2 statistics. RESULTS: A total of 246 patients underwent SRS for cystic VS, with reported mean or median follow-up ranging from 49.7 to 150 months, and an overall range of 6-201 months. Following SRS treatment for cystic VS across all studies, 92% of patients had tumor control at follow up, (95%-CI: 88-95%). Tumor control rate specifically for patients who underwent GammaKnife was 93% (95-CI: 88%-95%). CONCLUSION: Despite the paucity of pertinent data, the results of our meta-analysis suggest that SRS exhibits effective tumor control rates in patients with cystic VS. Therefore, SRS can be considered a viable treatment modality when choosing amongst interventions for cystic VS.