Edited by Charles E. SamuelRNA editing is a cellular process that precisely alters nucleotide sequences, thus regulating gene expression and generating protein diversity. Over 60% of human transcripts undergo adenosine to inosine RNA editing, and editing is required for normal development and proper neuronal function of animals. Editing of one adenosine in the transcript encoding the glutamate receptor subunit B, glutamate receptor ionotropic AMPA 2 (GRIA2), modifies a codon, replacing the genomically encoded glutamine (Q) with arginine (R); thus this editing site is referred to as the Q/R site. Editing at the Q/R site of GRIA2 is essential, and reduced editing of GRIA2 transcripts has been observed in patients suffering from glioblastoma. In glioblastoma, incorporation of unedited GRIA2 subunits leads to a calcium-permeable glutamate receptor, which can promote cell migration and tumor invasion. In this study, we identify adenosine deaminase that acts on RNA 3 (ADAR3) as an important regulator of Q/R site editing, investigate its mode of action, and detect elevated ADAR3 expression in glioblastoma tumors compared with adjacent brain tissue. Overexpression of ADAR3 in astrocyte and astrocytoma cell lines inhibits RNA editing at the Q/R site of GRIA2. Furthermore, the double-stranded RNA binding domains of ADAR3 are required for repression of RNA editing. As the Q/R site of GRIA2 is specifically edited by ADAR2, we suggest that ADAR3 directly competes with ADAR2 for binding to GRIA2 transcript, inhibiting RNA editing, as evidenced by the direct binding of ADAR3 to the GRIA2 pre-mRNA. Finally, we provide evidence that both ADAR2 and ADAR3 expression contributes to the relative level of GRIA2 editing in tumors from patients suffering from glioblastoma.Adenosine deaminases that act on RNA (ADARs) 2 catalyze the hydrolytic deamination of adenosine residues within double-stranded RNA (dsRNA) structures that form by base pairing of nearby complementary sequences (1-3). This RNA editing event creates a non-canonical nucleoside, inosine, which base pairs similarly to guanosine (4). RNA editing affects gene expression through modification of codons to create novel protein isoforms (5). Furthermore, editing can alter microRNA and siRNA binding sites, splice acceptor or splice donor sites, or RNA structure and stability (6 -9). A majority of the targets of RNA editing are found in the nervous system, and RNA editing is critical for maintaining proper neuronal function (10). Furthermore, transcripts encoding proteins involved in neurotransmission are often targets of RNA editing, which alters the protein amino acid sequence and physiological function of these ion channels and receptors (11,12).In mammals, three ADAR proteins, ADAR1, ADAR2, and ADAR3, and two ADAR-like proteins, ADAD1 and ADAD2, have been identified (13-17). The ADAR and ADAR-like protein family members contain several common modular domains that are important for function (18,19). Most strikingly, the human ADAR and ADAR-like proteins contain at least one ds...

Although metastatic melanoma to the brain continues to have a foreboding prognosis for long-term survival, gamma knife radiosurgery seems to be a relatively safe, noninvasive, palliative therapy, halting or reversing neurological progression in 77.8% of treated patients (35 of 45 patients). The survival rate matches or exceeds those previously reported for surgery and other forms of radiotherapy. Only 7.7% of the patients in our study population who died as a result of metastatic melanoma (2 of 26 patients) died as a result of neurological disease. The routine use of therapeutic level antiseizure medication is emphasized, considering the findings of our review.

to the internal carotid artery (ICA) during endoscopic endonasal skull base surgery does not typically occur as an isolated circumstance but often is the result of multiple factors.OBJECTIVE To assess the factors associated with ICA injury in an effort to reduce its occurrence. DESIGN, SETTING, AND PARTICIPANTSThis quality improvement study used a multicenter root cause analysis of ICA injuries sustained during endoscopic endonasal skull base surgery performed at 11 tertiary care centers across 4 continents (North America, South America, Europe, and Asia) from January 1, 1993, to December 31, 2018. A fishbone model was built to facilitate the root cause analysis. Patients who underwent an expanded endoscopic endonasal approach that carried a substantial potential risk of an ICA injury were included in the analysis. A questionnaire was completed by surgeons at the centers to assess relevant human, patient, process, technique, instrument, and environmental factors associated with the injury. MAIN OUTCOMES AND MEASURESRoot cause analysis of demographic, human, patient, process, technique, instrument, and environmental factors as well as mortality and morbidity data. RESULTS Twenty-eight cases of ICA injury occurred during 7160 expanded endoscopic endonasal approach procedures (incidence of 0.4%). The mean age of the patients was 49 years, with a female to male predominance ratio of 1.8:1 (18 women to 10 men). Anatomical (23 [82%]), pathological (15 [54%]), and surgical resection (26 [93%]) factors were most frequently reported. The surgeon's mental or physical well-being was reported as inadequate in 4 cases (14%). Suboptimal imaging was reported in 6 cases (21%). The surgeon's experience level was not associated with ICA injury. The ICA injury was associated with use of powered or sharp instruments in 20 cases (71%), and use of new instruments or technology in 7 cases (25%). Two patients (7%) died in the operating room, and 3 (11%) were alive with neurological deficits. Overall, patient-related factors were the most frequently reported risk factors (in 27 of 28 cases [96%]). Factors associated with ICA injury catalyzed a list of preventive recommendations. CONCLUSIONS AND RELEVANCEThis study found that human factors were associated with intraoperative ICA injuries; however, they were usually accompanied by other deficiencies. These findings suggest that identifying risk factors is crucial for preventing such injuries. Preoperative planning and minimizing the potential for ICA injury also appear to be essential.

Endoscopic approaches to the midline ventral skull base have been extensively developed and refined for resection of cranial base tumors over the past several years. As these techniques have improved, both the degree of resection and complication rates have proven comparable to those for transcranial approaches, while visual outcomes may be better via endoscopic endonasal surgery and hospital stays and recovery times are often shorter. Yet for all of the progress made, the steep learning curve associated with these techniques has hampered more widespread implementation and adoption. The authors address this obstacle by coupling a thorough description of the technical nuances for endoscopic endonasal craniopharyngioma resection with detailed illustrations of the important steps in the operation. Traditionally, transsphendoidal approaches to craniopharyngiomas have been restricted to lesions mostly confined to the sella. However, recently, endoscopic endonasal resections are more frequently employed for extrasellar and purely third ventricle craniopharyngiomas, whose typical retrochiasmatic location makes them ideal candidates for endoscopic transnasal surgery. The endonasal endoscopic approach offers many advantages, including direct access to the long axis of the tumor, early tumor debulking with minimal manipulation of the optic apparatus, more precise visualization of tumor planes, particularly along the undersurface of the chiasm and the roof of the third ventricle, and a minimal-access corridor that obviates the need for brain retraction. Although much emphasis has been placed on technical tenets of exposure and “how to get there,” this article focuses on nuances of tumor resection “when you are there.” Three operative videos illustrate our discussion of technical tenets.

Background Surgical tumor resection is the primary treatment option for diffuse glioma, the most common malignant brain cancer. The intraoperative diagnosis of gliomas from tumor core samples can be improved by use of molecular diagnostics. Further, residual tumor at surgical margins is a primary cause of tumor recurrence and malignant progression. This study evaluates a desorption electrospray ionization mass spectrometry (DESI-MS) system for intraoperative isocitrate dehydrogenase (IDH) mutation assessment, estimation of tumor cell infiltration as tumor cell percentage (TCP), and disease status. This information could be used to enhance the extent of safe resection and so potentially improve patient outcomes. Methods A mobile DESI-MS instrument was modified and used in neurosurgical operating rooms (ORs) on a cohort of 49 human subjects undergoing craniotomy with tumor resection for suspected diffuse glioma. Small tissue biopsies (ntotal = 203) from the tumor core and surgical margins were analyzed by DESI-MS in the OR and classified using univariate and multivariate statistical methods. Results Assessment of IDH mutation status using DESI-MS/MS to measure 2-hydroxyglutarate (2-HG) ion intensities from tumor cores yielded a sensitivity, specificity, and overall diagnostic accuracy of 89, 100, and 94%, respectively (ncore = 71). Assessment of TCP (categorized as low or high) in tumor margin and core biopsies using N-acetyl-aspartic acid (NAA) intensity provided a sensitivity, specificity, and accuracy of 91, 76, and 83%, respectively (ntotal = 203). TCP assessment using lipid profile deconvolution provided sensitivity, specificity, and accuracy of 76, 85, and 81%, respectively (ntotal = 203). Combining the experimental data and using PCA-LDA predictions of disease status, the sensitivity, specificity, and accuracy in predicting disease status are 63%, 83%, and 74%, respectively (ntotal = 203). Conclusions The DESI-MS system allowed for identification of IDH mutation status, glioma diagnosis, and estimation of tumor cell infiltration intraoperatively in a large human glioma cohort. This methodology should be further refined for clinical diagnostic applications.

Dissemination of glioma in humans can occur as leptomeningeal nodules, diffuse leptomeningeal lesions, or ependymal lesions. Cerebrospinal fluid (CSF) drop metastasis of glioma is not well-recognized in dogs. Ten dogs with at least two anatomically distinct and histologically confirmed foci of glioma were included in this study. The 10 dogs underwent 28 magnetic resonance imaging (MRI) examinations, with distant CSF drop metastasis revealed in 13 MRIs. The CSF drop metastases appeared as leptomeningeal nodules in four dogs, diffuse leptomeningeal lesions in six dogs, and ependymal lesions in seven dogs; six dogs had a combination of lesion types. Primary tumors were generally T2-heterogeneous and contrast-enhancing. Many metastases were T2-homogeneous and non-enhancing. Diffuse leptomeningeal lesions were seen as widespread extra-axial contrast-enhancement, again very dissimilar to the intra-axial primary mass. Primary masses were rostrotentorial, whereas metastases generally occurred in the direction of CSF flow, in ventricles, CSF cisterns, and the central canal or leptomeninges of the cervical or thoracolumbar spinal cord. Seven of the dogs had received therapy limited to the primary mass, such as surgery or stereotactic radiation, then developed metastasis in the following months. CSF drop metastasis of glioma may take a very different appearance on MRI to the primary mass, including periventricular lesions that are more homogeneous and less contrast-enhancing, rostral horn signal changes, or leptomeningeal enhancement ventral to the brainstem or encircling the spinal cord.

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