Faculty Bibliography

INTRODUCTION/BACKGROUND:Gangliogliomas rarely occur in the sella or suprasellar region and are almost never seen in the pituitary stalk. Seven cases of gangliogliomas occurring in this region have been reported; only one case involved a tumor within the pituitary stalk. Of the six tumors external to the pituitary stalk, two occurred in the neurohypophysis, one was in the adenohypophysis, the location of one was unspecified, and two extensively invaded the optic chiasm, hypothalamus and brainstem. This is only the second reported case of a pituitary stalk ganglioglioma, and it is unique in its use of an extended endoscopic endonasal approach for biopsy. CASE REPORT/METHODS:A 51-year old woman presented with an eleven-month history of polydipsia and polyuria leading to the diagnosis of diabetes insipidus. Magnetic Resonance Imaging of the brain revealed contrast-enhanced thickening and anterior bowing of the hypophyseal stalk. An extended endoscopic endonasal approach permitted midline removal of the tuberculum sella, opening of underlying dura, and exposure of the pituitary stalk. A firm, white, 4 mm diameter mass, integral to the right side of the enlarged pituitary stalk was seen and biopsied. Histopathological analysis was consistent with WHO grade 1 ganglioglioma. The patient tolerated the procedure well and required no endocrinologic treatment other than desmopressin. CONCLUSION/CONCLUSIONS:Pituitary stalk gangliogliomas are extremely rare. The diagnosis should be considered in patients with pituitary stalk enlargement. Endoscopic endonasal approach is a safe surgical approach to establish a tissue diagnosis which is essential for pathologic certainty given the wide differential diagnosis of stalk lesions.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare central nervous system (CNS) tumor diagnosed primarily in infants and usually portends a poor prognosis. Despite being the most common embryonal tumor in children less than 1 year old, diagnosis is difficult to make based on clinical findings or imaging alone. A complete diagnosis of AT/RT requires identification of loss of integrase interactor 1 (INI1) protein or the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) gene, in its most common presentation. Moreover, their presentation with other primary rhabdoid tumors in the body raises significant suspicion for rhabdoid tumor predisposition syndrome (RTPS). We report a case of a one-month-old infant admitted for worsening emesis and failure to thrive, who was later found to have brain and bladder masses on radiologic imaging. Autopsy with subsequent immunoprofile and molecular testing were crucial in establishing the absence of INI1 nuclear expression and possible homozygous deletion of SMARCB1 in the urinary bladder tumor tissue. Sequencing of the peripheral blood demonstrated probable single copy loss at the SMARCB1 locus. The constellation of findings in tumor and peripheral blood sequencing suggested the possibility of germline single copy SMARCB1 loss, followed by somatic loss of the remaining SMARCB1 allele due to copy neutral loss-of-heterozygosity. Such a sequence of genetic events has been described in malignant rhabdoid tumors (MRT). Dedicated germline testing of this patient's family members could yield answers as to whether rhabdoid tumor predisposition syndrome will continue to have implications for the patient's family.

Histone H3.3 mutations are a hallmark of pediatric gliomas, but their core oncogenic mechanisms are not well-defined. To identify major effectors, we used CRISPR-Cas9 to introduce H3.3K27M and G34R mutations into previously H3.3-wildtype brain cells, while in parallel reverting the mutations in glioma cells back to wildtype. ChIP-seq analysis broadly linked K27M to altered H3K27me3 activity including within super-enhancers, which exhibited perturbed transcriptional function. This was largely independent of H3.3 DNA binding. The K27M and G34R mutations induced several of the same pathways suggesting key shared oncogenic mechanisms including activation of neurogenesis and NOTCH pathway genes. H3.3 mutant gliomas are also particularly sensitive to NOTCH pathway gene knockdown and drug inhibition, reducing their viability in culture. Reciprocal editing of cells generally produced reciprocal effects on tumorgenicity in xenograft assays. Overall, our findings define common and distinct K27M and G34R oncogenic mechanisms, including potentially targetable pathways.

Background  Exostoses and osteomas are benign, insidious lesions of the bone involving the internal acoustic canal (IAC). We present two cases of IAC exostoses managed with surgical decompression and review the clinical outcomes of previously reported cases in the literature. Methods  A comprehensive search was conducted using PubMed Central, Web of Science Core Collection, and Google Scholar databases to identify previous reports of IAC exostoses and osteomas. A total of 26 reported cases were identified, and patient presenting symptoms, management strategies, and response to surgery was obtained when available. Results  Of the 13 patients who underwent surgical decompression, 8 patients had resolution of vertigo symptoms, 10 patients had improvement of tinnitus symptoms, and all patients maintained some level of serviceable hearing. Conclusion  IAC exostoses and osteomas are rare lesions that lead to insidious onset of debilitating symptoms from vestibulocochlear nerve dysfunction. Although the role of surgical decompression remains unclear, it appears that patients presenting with vertigo have more favorable response to surgical decompression as compared with those presenting with tinnitus and sensorineural hearing loss.

Rationale: As more information emerges on metabolic changes in the brain from genetic mutations and disease, mass spectrometry methodologies are needed to investigate cellular changes in primary brain tumors. Many approaches use technologies that lack sensitivity and selectivity, which hinders discovery of potential novel diagnostic and prognostic features. Here, we present a new high throughput sample preparation for the use of clinical metabolomics applied to meningiomas.
Method(s): Fresh frozen tissue from 12 patients (57% women, 43% men; mean age: 48) who underwent surgical resection for newly diagnosed meningiomas. We collected 10 mg of tissue and extracted for GC-TOF (primary metabolism), RPLC-QTOF ESI(6) (lipidomics) and HILIC-HRMS ESI(6) (biogenic amines) analyses.
Result(s): Our novel methods allow us to use isotope standards and MS2 quantification of key disease metabolites in addition to untargeted analysis for both metabolomics and lipidomics. These methods allow us to provide quantification for knowns with the ability to also measure unknown features. Primary metabolism and lipidomics showed significant differences between Grade I and Grade II tumors. Over one thousand total metabolites were identified and annotated. Metabolites were grouped into one of fifteen classes based on chemical ontology and function. The classes detected were as follows: total amino acids (AA), basic AA, cyclic AA, sulfur-containing AA, branchedchain AA, dipeptides, histidine-containing dipeptides, vitamins and cofactors, glutathione metabolites, acylcarnitine's, sphingomyelins, phosphatidylethanolamines, phosphatidylinositol's, cardiolipins, and nucleic acids. Bis(monoacylglycero) phosphates were over 2-fold increased in atypical meningiomas versus Grade I, indicating lysosome activation. Thymine containing nucleic acids and biogenic monoamines were 2-fold higher in Grade I compared to Grade II tumors.
Conclusion(s): Using novel combined targeted and untargeted metabolomics, we found multiple classes of metabolites that were enriched in Grade II meningiomas compared to Grade I, pointing towards possible pathways that drive malignancy and biomarkers that could be useful for diagnosis and treatment selection

Background/UNASSIGNED:) gene. FXTAS is characterized by the presence of ubiquitin-positive inclusions in neurons and astrocytes and by cerebellar tremor and ataxia. Parkinsonism has been reported in FXTAS, but most patients lack the characteristic rest tremor and severe rigidity seen in idiopathic Parkinson's disease (PD). Objective/UNASSIGNED:To describe the frequency of concomitant PD in FXTAS. Methods/UNASSIGNED:We reviewed the medical record of 40 deceased patients diagnosed with FXTAS and performed a pathology analysis to confirm both FXTAS and PD. Results/UNASSIGNED:Clinical histories indicated that 5 FXTAS patients were diagnosed with idiopathic PD and 2 with atypical parkinsonian syndrome. After pathological examination, we found that 7 patients in the PD clinical diagnosis group had dopaminergic neuronal loss; however, only 2 of 7 presented Lewy bodies (LBs) in the substantia nigra. Therefore, a total of 5% of the 40 cohort patients met the pathologic criteria for the concomitant diagnosis of FXTAS and PD. In addition, 2 patients not clinically diagnosed with PD also had nigral neuronal loss with LBs in substantia nigra. In total 10% of these 40 patients had LBs. Conclusion/UNASSIGNED:should be recognized as one of the exceptional genetic causes of parkinsonism with presynaptic dopaminergic loss and LBs.

Current clinical brain imaging techniques used for surgical planning of tumor resection lack intraoperative and real-time feedback; hence surgeons ultimately rely on subjective evaluation to identify tumor areas and margins. We report a fluorescence lifetime imaging (FLIm) instrument (excitation: 355 nm; emission spectral bands: 390/40 nm, 470/28 nm, 542/50 nm and 629/53 nm) that integrates with surgical microscopes to provide real-time intraoperative augmentation of the surgical field of view with fluorescent derived parameters encoding diagnostic information. We show the functionality and safety features of this instrument during neurosurgical procedures in patients undergoing craniotomy for the resection of brain tumors and/or tissue with radiation damage. We demonstrate in three case studies the ability of this instrument to resolve distinct tissue types and pathology including cortex, white matter, tumor and radiation-induced necrosis. In particular, two patients with effects of radiation-induced necrosis exhibited longer fluorescence lifetimes and increased optical redox ratio on the necrotic tissue with respect to non-affected cortex, and an oligodendroglioma resected from a third patient reported shorter fluorescence lifetime and a decrease in optical redox ratio than the surrounding white matter. These results encourage the use of FLIm as a label-free and non-invasive intraoperative tool for neurosurgical guidance.

BACKGROUND:Bilateral thalamic astrocytomas in children are exceedingly rare. These highly malignant tumors seldom respond to conventional treatment strategies and carry a grim prognosis for patients. However, recent advances in molecular oncology have had a positive impact on prognostication and treatment strategies of these tumors. CASE-BASED REVIEW/UNASSIGNED:We present a new case of WHO grade III bilateral thalamic astrocytoma in a child and review the pathophysiology, molecular oncogenesis, and relevant treatment strategies for this rare disease. CONCLUSIONS:High-grade thalamic astrocytomas affecting both thalami pose a challenge to pediatric neurosurgeons, neuro-oncologists, and neuropathologists given the lack of effective treatment strategies. Understanding recent revelations in the field of molecular oncology can assist clinicians in adequately formulating a treatment plan in this patient population.

BACKGROUND:Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene. Expansions of more than 200 CGG repeats give rise to fragile X syndrome, the most common inherited form of cognitive impairment. Fragile X-associated tremor/ataxia syndrome is characterized by cerebellar tremor and ataxia, and the presence of ubiquitin-positive inclusions in neurons and astrocytes. It has been previously suggested that fragile X-associated tremor/ataxia syndrome is associated with an inflammatory state based on signs of oxidative stress-mediated damage and iron deposition. OBJECTIVE:Determine whether the pathology of fragile X-associated tremor/ataxia syndrome involves microglial activation and an inflammatory state. METHODS:Using ionized calcium binding adaptor molecule 1 and cluster differentiation 68 antibodies to label microglia, we examined the number and state of activation of microglial cells in the putamen of 13 fragile X-associated tremor/ataxia syndrome and 9 control postmortem cases. RESULTS:Nearly half of fragile X-associated tremor/ataxia syndrome cases (6 of 13) presented with dystrophic senescent microglial cells. In the remaining fragile X-associated tremor/ataxia syndrome cases (7 of 13), the number of microglial cells and their activation state were increased compared to controls. CONCLUSIONS:The presence of senescent microglial cells in half of fragile X-associated tremor/ataxia syndrome cases suggests that this indicator could be used, together with the presence of intranuclear inclusions and the presence of iron deposits, as a biomarker to aid in the postmortem diagnosis of fragile X-associated tremor/ataxia syndrome. An increased number and activation indicate that microglial cells play a role in the inflammatory state present in the fragile X-associated tremor/ataxia syndrome brain. Anti-inflammatory treatment of patients with fragile X-associated tremor/ataxia syndrome may be indicated to slow neurodegeneration. © 2018 International Parkinson and Movement Disorder Society.

Histological examination of tissues is central to the diagnosis and management of neoplasms and many other diseases and is a foundational technique for preclinical and basic research. However, commonly used bright-field microscopy requires prior preparation of micrometre-thick tissue sections mounted on glass slides-a process that can require hours or days, contributes to cost and delays access to critical information. Here, we introduce a simple, non-destructive slide-free technique that, within minutes, provides high-resolution diagnostic histological images resembling those obtained from conventional haematoxylin and eosin histology. The approach, which we named microscopy with ultraviolet surface excitation (MUSE), can also generate shape and colour-contrast information. MUSE relies on ~280 nm ultraviolet light to restrict the excitation of conventional fluorescent stains to tissue surfaces and it has no significant effects on downstream molecular assays (including fluorescence in situ hybridization and RNA sequencing). MUSE promises to improve the speed and efficiency of patient care in both state-of-the-art and low-resource settings and to provide opportunities for rapid histology in research.