BACKGROUND Suprasellar masses commonly include craniopharyngiomas and pituitary adenomas. Suprasellar glioblastoma is exceedingly rare with only a few prior case reports in the literature. Suprasellar glioblastoma can mimic craniopharyngioma or other more common suprasellar etiologies preoperatively. OBSERVATIONS A 65-year-old male with no significant history presented to the emergency department with a subacute decline in mental status. Work-up revealed a large suprasellar mass with extension to the right inferior medial frontal lobe and right lateral ventricle, associated with significant vasogenic edema. The patient underwent an interhemispheric transcallosal approach subtotal resection of the interventricular portion of the mass. Pathological analysis revealed glioblastoma, MGMT partially methylated, with a BRAF V600E mutation. LESSONS Malignant glioblastomas can mimic benign suprasellar masses and should remain on the differential for a diverse set of brain masses with a broad range of radiological and clinical features. For complex cases accessible from the ventricle where the pituitary complex cannot be confidently preserved via a transsphenoidal approach, an interhemispheric approach is also a practical initial surgical option. In addition to providing diagnostic value, molecular profiling may also reveal therapeutically significant gene alterations such as BRAF mutations.

A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to determine the relationship between the expression of these stem cell markers and the clinical outcome in GBM patients. We quantified the intensity of expression of the proteins CD133 and SOX2 by immunohistochemistry (IHC) in a cohort of 86 patients with IDH-wildtype GBM, and evaluated patient outcomes using Kaplan–Meier and Cox proportional hazards analysis. In our patients, MGMT promoter methylation status and age were predictors of overall survival and progression free survival. The levels of SOX2 and CD133 were not associated with outcome in univariate analysis; however, stratification of tumors based on low or high levels of CD133 or SOX2 expression revealed that MGMT methylation was a predictor of progression-free survival and overall survival only for tumors with high levels of expression of CD133 or SOX2. Tumors with low levels of expression of CD133 or SOX2 did not show any relationship between MGMT methylation and survival. This relationship between MGMT and stem cell markers was confirmed in a second patient cohort, the TCGA dataset. Our results show that stratification of GBM by the level of expression of CD133 and SOX2 improved the prognostic power of MGMT promoter methylation status, identifying a low-expressing group in which the clinical outcome is not associated with MGMT promoter methylation status, and a high-expressing group in which the outcome was strongly associated with MGMT promoter methylation status. These findings support the concept that the presence of a high stem cell phenotype in GBM, as marked by expression of SOX2 or CD133, may be associated with the clinical response to treatment.

While the bone marrow (BM) microenvironment is significantly remodelled in acute myeloid leukaemia (AML), molecular insight into AML-specific alterations in the microenvironment has been historically limited by the analysis of liquid marrow aspirates rather than core biopsies that contain solid-phase BM stroma. We assessed the effect of anthracycline- and cytarabine-based induction chemotherapy on both haematopoietic and non-haematopoietic cells directly in core BM biopsies using RNA-seq and histological analysis. We compared matched human core BM biopsies at diagnosis and 2 weeks after cytarabine- and anthracycline-based induction therapy in responders (<5% blasts present after treatment) and non-responders (≥5% blasts present after treatment). Our data indicated enrichment in vimentin (VIM), platelet-derived growth factor receptor beta (PDGFRB) and Snail family transcriptional repressor 2 (SNAI2) transcripts in responders, consistent with the reactivation of the mesenchymal population in the BM stroma. Enrichment of osteoblast maturation-related transcripts of biglycan (BGN), osteopontin (SPP1) and osteonectin (SPARC) was observed in non-responders. To the best of our knowledge, this is the first report demonstrating distinct osteogenic and mesenchymal transcriptome profiles specific to AML response to induction chemotherapy assessed directly in core BM biopsies. Detailing treatment response-specific alterations in the BM stroma may inform optimised therapeutic strategies for AML.

Abstract Background Glioblastoma (GBM) is an aggressive, age‐associated malignant glioma that contains populations of cancer stem cells. These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well known to increase cancer initiation, the extent to which the mechanisms supporting GSC tumorigenicity are related to physiological aging remains unknown. Aims Here, we investigate the transcriptional mechanisms by which Forkhead Box O3 (FOXO3), a transcriptional regulator that promotes healthy aging, affects GSC function and the extent to which FOXO3 transcriptional networks are dysregulated in aging and GBM. Methods and results We performed transcriptome analysis of clinical GBM tumors and observed that high FOXO3 activity is associated with gene expression signatures of stem cell quiescence, reduced oxidative metabolism, and improved patient outcomes. Consistent with these findings, we show that elevated FOXO3 activity significantly reduces the proliferation of GBM‐derived GSCs. Using RNA‐seq, we find that functional ablation of FOXO3 in GSCs rewires the transcriptional circuitry associated with metabolism, epigenetic stability, quiescence, and differentiation. Since FOXO3 has been implicated in healthy aging, we then investigated the extent to which it regulates common transcriptional programs in aging neural stem cells (NSCs) and GSCs. We uncover a shared transcriptional program and, most strikingly, find that FOXO3‐regulated pathways are associated with altered mitochondrial functions in both aging and GBM. Conclusions This work identifies a FOXO‐associated transcriptional program that correlates between GSCs and aging NSCs and is enriched for metabolic and stemness pathways connected with GBM and aging.

Background Pulmonary tumor embolism (PTE) is difficult to detect before death, and it is unclear whether the discrepancy between antemortem clinical and postmortem diagnosis improves with the advance of the diagnostic technologies. In this study we determined the incidence of PTE and analyzed the discrepancy between antemortem clinical and postmortem diagnosis. Methods We performed a retrospective autopsy study on patients with the history of malignant solid tumors from 1990 to 2020 and reviewed all the slides of the patients with PTE. We also analyzed the discrepancies between antemortem clinical and postmortem diagnosis in 1999, 2009 and 2019 by using the Goldman criteria. Goldman category major 1 refers to cases in which an autopsy diagnosis was the direct cause of death and was not recognized clinically, but if it had been recognized, it may have changed treatment or prolonged survival. Results We found 20 (3%) cases with PTE out of the 658 autopsy cases with solid malignancies. Out of these 20 cases, urothelial carcinoma (30%, 6/20) and invasive ductal carcinoma of the breast (4/20, 20%) were the most common primary malignancies. Seven patients with shortness of breath died within 3–17 days (average 8.4±2.2 days) after onset of the symptoms. Pulmonary embolism was clinically suspected in seven out of twenty (35%, 7/20) patients before death, but only two patients (10, 2/20) were diagnosed by imaging studies before death. The rate of Goldman category major 1 was 13.2% (10/76) in 1999, 7.3% (4/55) in 2009 and 6.9% (8/116) in 2019. Although the rate of Goldman category major 1 appeared decreasing, the difference was not statistically significant. The autopsy rate was significantly higher in 2019 (8.4%, 116/1386) than in 2009 (4.4%, 55/1240). Conclusions The incidence of PTE is uncommon. Despite the advances of the radiological techniques, radiological imaging studies did not detect the majority of PTEs. The discrepancy between the antemortem clinical and the postmortem diagnosis has not improved significantly over the past 30 years, emphasizing the value of autopsy.

Abstract Recent studies identified the presence of ALK/ROS/NTRK/MET alterations in a subset of infantile hemispheric gliomas. We report a case of GOPC-ROS1 fused congenital hemispheric glioma with a sustained response to crizotinib. An infant born at 28 weeks gestation was diagnosed with a large hemispheric mass at 2 weeks of life. The tumor was partially resected at 7 weeks of life. Histological evaluation confirmed a neoplasm with a spindle cell growth pattern, hypercellularity, nuclear pleomorphism, endothelial proliferation and necrosis consistent with glioblastoma. Fresh tissue was submitted for targeted panel sequencing (Oncopanel) which identified the presence of a GOPC-ROS1 fusion (exon 36:intron 4). This was confirmed by copy number analysis which showed a focal intragenic deletion with a breakpoint in ROS1 on 6q22. Given the lack of preclinical native models for ROS1 and other congenital kinase-driven gliomas, live cells were utilized to attempt to establish a patient derived cell line (organoid/neurosphere model) and intracranial patient derived xenograft model, the results of which are pending and will be reported. The GOPC-ROS1 rearrangement was structurally predicted to respond to kinase inhibitors with activity against ROS1 and crizotinib was started at 280 mg/m2/dose twice daily at 6 months of life with progressive tumor noted on imaging. Three months after initiating therapy, a 56% reduction in the tumor size and subsequent imaging revealed additional response. Our report is the first to demonstrate clinical response to crizotinib in a GPOC-ROS1 fused congenital glioblastoma and describe the development of a renewable resources for future analysis.

A rare anatomic variant of a markedly enlarged anterior external arcuate fasciculus (AEAF) on the ventral medullary surface is reported and compared to two controls. The hypertrophic AEAF was nine times larger in diameter than normal, whereas the arcuate nucleus (AN) and inferior olivary nucleus (ION) appeared histologically normal in size and neuronal distribution, and morphometric analysis of the AN confirmed that it was within the normal range. Calbindin-2 (calretinin, CALB2) expression was identified in the AN and in the fibers of the normal AEAF. The hypertrophic AEAF did not contain calbindin-2–expressing fibers. CALB2 expression was also present in the ventrolateral portion of the ION, both in the index case and in one of the control cases. The origin of the additional fibers was not identified; however, the potential origin of these fibers and its implications for the development of the AEAF are discussed.

The interpretation of muscle biopsies is complex and provides the most useful information when integrated with the clinical presentation of the patient. These biopsies are performed for workup of a wide range of diseases including dystrophies, metabolic diseases, and inflammatory processes. Recent insights have led to changes in the classification of inflammatory myopathies and have changed the role that muscle biopsies have in the workup of inherited diseases. These changes will be reviewed. This review follows a morphology-driven approach by discussing diseases of skeletal muscle based on a few basic patterns that include cases with (1) active myopathic damage and inflammation, (2) active myopathic damage without associated inflammation, (3) chronic myopathic changes, (4) myopathies with distinctive inclusions or vacuoles, (5) biopsies mainly showing atrophic changes, and (6) biopsies that appear normal on routine preparations. Each of these categories goes along with certain diagnostic considerations and pitfalls. Individual biopsy features are only rarely pathognomonic. Establishing a firm diagnosis therefore typically requires integration of all of the biopsy findings and relevant clinical information. With this approach, a muscle biopsy can often provide helpful information in the diagnostic workup of patients presenting with neuromuscular problems.

Social media use continues to grow among pathologists. Discussions of current topics, posts of educational information, and images of pathological entities are commonly found and distributed on popular sites such as Facebook and Twitter. However, little is known about the presence of neuropathology content in social media and the audience for such content. We designed and distributed a survey to assess the demographics of users viewing neuropathology content and their opinions about neuropathology in social media. User posts on the Facebook group, Surgical Neuropathology, were also analyzed. The results show that there is a demand for neuropathology content of high quality, curated by experts, and that this demand is present among both specialists and nonspecialists. These findings suggest that social media may be useful for rapid dissemination of information in the field of neuropathology. This format also offers a unique opportunity to extend the reach of information to nonneuropathologists who may not receive neuropathology journals or have access to specialty-level neuropathology training, to build networks between professionals, and potentially to influence public opinion of neuropathology on an international scale.

OBJECTIVES/HYPOTHESIS:The hypoglossal nerve (XII) has been used as a donor nerve in facial and laryngeal reinnervation. The purpose of this study was to investigate the neuromuscular changes that occur within the tongue following partial or complete transection of XII using a canine model. STUDY DESIGN:Histopathological comparison of tongue denervation following two types of XII resection in a canine model. METHODS:Ten adult canines underwent complete unilateral resection of XII or resection of only the medial terminal branch of the hypoglossal nerve (mXII). After 6 months of recovery, tongue specimens were analyzed histopathologically using whole cross-sections. Routine histologic sections were assessed by two neuropathologists blinded to the type of denervation. The cross-sectional area was calculated of both sides of the tongue, and the amount of myosin was quantified morphometrically using immunohistochemistry for myosin (antimyosin heavy chain, fast isotype). Statistical comparison between partial and complete denervation was performed using the Student t test. RESULTS:Six months following XII transection, quantitative measures of the cross-sectional area of the tongue and content of myosin demonstrated severe muscle atrophy on the operated side of the tongue for both groups, compared to the nonoperated side. For partial transection involving only mXII, the degree of atrophy was less severe (P < .05). CONCLUSIONS:This study provides new histological information demonstrating that partial resection of the hypoglossal nerve, sacrificing only the proximal medial branch of the hypoglossal nerve (mXII), results in less severe atrophy of the tongue than complete transection of the entire hypoglossal nerve. LEVEL OF EVIDENCE:NA Laryngoscope, 126:2689-2693, 2016.

The autopsy has long been a fundamental aspect of medical practice and research. However, in the last 50 years, the proportion of deaths for which an autopsy is performed has decreased dramatically. Here we examine some of the reasons for the decline of the autopsy, as well as several interventions that have been proposed to revive it. We also present autopsy utilization data from the Lifespan system, which mirrors nationwide trends. [Full article available at http://rimed.org/rimedicaljournal-2016-10.asp].

Objective: To report a rare case of alpha-synuclein pathology in the colonic biopsy of a suspected multiple system atrophy patient. Background: Alpha-synuclein aggregates are commonly detected on routine colonic biopsies in Parkinson’s disease (PD), but have been rarely reported in multiple system atrophy (MSA). Method: Case report Results: A 72 year old man with hypothyroidism presented with a 12 year history of progressive gait ataxia and an ataxic dysarthria, associated with anti-gliadin antibodies, but without GI symptoms. His response to a gluten-free diet was unclear. He had urinary urgency and incontinence, mild lightheadedness but no dream-enactment. He had no family members with any neurological problems. His MMSE was 18. Eye movements were full, with saccadic pursuit and no nystagmus. He was rigid and hperreflexic but without spasticity or Babinski reflexes. He had limb ataxia, normal strength and normal sensation. He arose from a chair with effort but without pushing-off. His stance was mildly wide-based. Posture was normal. He had mild titubation and lost his balance to either side. His stride was reduced, more on the left and arm-swing was minimal. Balance was poor. Neuroimaging revealed moderate atrophy of the cerebellum and cervical spine. Colonic biopsy taken at routine colonoscopy revealed a polyp which stained positive for alpha-synuclein. Conclusion: Extension of alpha-synuclein pathology beyond the CNS and into the gastrointestinal tract is well-recognized in PD, but has been reported rarely in MSA. Our patient is the second case reported of presumed MSA with alpha-synuclein pathology in the gut. The full extent and significance of this finding warrant further study. Disclosure: Dr. Akbar has nothing to disclose. Dr. Stopa has nothing to disclose. Dr. Anthony has nothing to disclose. Dr. Donahue has nothing to disclose. Dr. Friedman has received personal compensation for activities with Teva, General Electric, UCB Pharma, Addex Therapeutics, Roche, and Lundbeck Research USA, Inc. as a consultant and/or speaker.

Glioblastoma(GBM)is the most common and most aggressive primary brain tumor in adults.The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis.In this study,we performed an in-depth analysis of the DNA methylation landscape in GBMderived cancer stem cells(GSCs).Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls(a neural stem cell(NSC)line and normal brain tissue)identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls,primary GBMs,and their counterpart GSC lines,respectively.Interestingly,concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT,AJAP1 and PTPRN2.These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes.Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down-regulated in GBMs such as SPINT2,NEFM and PENK.Forced re-expression of SPINT2 reduced glioma cell proliferative capacity,anchorage independent growth,cell motility,and tumor sphere formation in vitro.The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM.

This chapter is a basic introduction to the techniques used for processing and analyzing peripheral nerve biopsies. The most informative method depends on the clinical context of the biopsy. Procedures for each individual technique are described, with a discussion of the fixation and handling required for each. Knowledge of the clinical differential diagnosis aids in the decision on which methods are likely to be the most informative; all methods may not be utilized in individual biopsies. Selected references are provided for detailed descriptions.