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Simple Summary: Intracranial Epidermoid Cysts (IECs) are rare tumors. Despite their benign course, IECs can adhere to critical brain structures resulting in impairment and morbidity. The primary treatment is surgery; however, cyst adherence often complicates complete removal, resulting in notably high progression rates after subtotal resection. Due to the rarity of IECs, there has been limited research focused on understanding the mechanisms of the disease and advancing therapeutic options. As a result, there are currently no effective drug therapies available for treating patients with IECs. Targeted therapy is an effective form of treatment for tumors. It focuses on mutations that turn healthy cells into tumor cells. The mutation profile of IECs has not been investigated. We aimed to investigate the somatic landscape of IECs to gain insights into tumor biology and identify mutations that could potentially serve as targets for additional therapies. Surgery is still the most effective treatment for these patients. Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor genetic profiling has revealed potential targets for drug development, including FDA-approved options and reshaping treatment. The genetic landscape of IECs has not been explored. We applied Whole Exome Sequencing (WES) to IECs to gain insights into the mechanisms of oncogenesis and identify potential therapeutic targets. Methods: We performed WES on tumor tissue and matched blood samples, when available. Following GATK best practices, we conducted read processing, quality control, somatic variant calling, and copy-number inference. Data analyses and visualization were conducted in R. Results: Top altered genes are associated with the immune system and tumor microenvironment, suggesting a mechanism of immune evasion. Gene and pathway enrichment revealed a high mutation burden in genes associated with Extracellular Matrix (ECM) and PI3K-AKT-mTOR cascades. Recurrent and deleterious alterations in NOTCH2 and USP8 were identified in 50% and 30% of the cohort, respectively. Frequent amplifications in deubiquitinases and beta-defensins strengthened the involvement of immune mechanisms for oncogenic transformation. Conclusions: Top altered genes and recurrent mutations may play a role in shaping the microenvironment and modulating immune evasion in IECs. USP8 and NOTCH2 may serve as clinically relevant target for IECs. Finally, we present evidence that the crosstalk between the PI3K-Akt-mTOR and ECM signaling pathways may play a role in modulating the immune escape mechanism in IECs. [ABSTRACT FROM AUTHOR]

Background Meningomas represent the most common primary intracranial tumor. Themajority are benignWorld Health Organization (WHO) Grade I lesions, but a subset of these behave in an aggressivemanner. Protein biomarkers are needed to distinguish aggressive from benign Grade I lesions. Materials and Methods Pooled protein lysates were derived from five clinically aggressive Grade I and five typically benign WHO Grade I tumors snap frozen at the time of surgery. Proteins were separated in each group using two-dimensional gel electrophoresis (2DGE) and protein spots of interest were identified using liquid chromatography-mass spectrometry (LC-MS). Potential biomarker candidates were validated using western blot assays in individual tumor samples and by tissue microarray (TMA). Results Seven candidate biomarkers were obtained from the 2DGE and validated via western blot and TMA. Biomarker validation data allowed for the creation of predictive models using binary logistical regression that correctly identified 85.9% of aggressive tumors within the larger cohort of Grade I meningioma. Conclusion Simple protein separation by 2DGE and identification of candidate biomarkers by LC-MS allowed for the identification of seven candidate biomarkers that when used in predictive models accurately distinguish aggressive from benign behavior in WHO Grade I meningioma. [ABSTRACT FROM AUTHOR]

Background and purpose Hemangiopericytomas (HPCs) are rare dural-based neoplasms. Preoperative embolization of these notoriously hypervascular tumors can be challenging as they often receive their dominant blood supply from pial feeders arising from the internal carotid artery (ICA) or vertebrobasilar (VB) circulation. This study reviews our historical experience with HPC embolization and introduces the transtumoral technique for backfilling pial tumor vasculature by delivering Onyx-18 through diminutive external carotid artery (ECA) feeders. Methods A retrospective review of all preoperative HPC embolizations performed at Anonymous University #1 (September 2002-November 2014) and Anonymous University #2 (January 2014-November 2014) is presented. Results Fifteen patients with pathologically confirmed HPC underwent 17 embolizations. More extensive devascularization percentages were achieved for HPCs with primarily ECA blood supply (76.4±10.7%; n=6) than with HPCs supplied via the ICA/VB circulation (57.9 ±26.9%; n=8; p=0.046). There was a trend towards greater devascularization of ICA/VB-dominant HPCs embolized with Onyx (70.0±34.6%; n=4) versus polyvinyl alcohol particles (33.3±15.3%; n=3). The extent of angiographic devascularization negatively correlated with intraoperative blood loss (rho=-0.71; p=0.005). There were no embolization-related complications. Conclusions The extent of preoperative embolization of HPCs correlates with decreased intraoperative blood loss. However, HPCs with an ICA/VB-dominant blood supply remain challenging embolization targets, demonstrating reduced devascularization percentages compared with ECA-dominant counterparts. The authors favor the use of Onyx for ICA/VB-dominant HPCs, noting a trend towards an improved devascularization rate. [ABSTRACT FROM AUTHOR]

The article discusses a computer modeled multiportal approaches to the skull base. A computer model was developed to analyze and optimize combinations of transorbital and transnasal portals to surgically access 11 specific locations in the sellar and parasellar regions. Results showed modeling's potential use in the design, analysis and testing of new surgical approaches, as well as in the selection of the optimal approach strategy for the unique pathology of an individual patient.

The article discusses a study on the efficacy of transorbital neuroendoscopic surgery (TONES) for the management of sinogenic complications involving the frontal sinus, orbit and anterior cranial fossa in a prospective series of 13 patients presented with these symptoms. Results demonstrated the safety and efficacy of TONES in the management of sinogenic complications and the procedure's use as a primary surgical modality or in multiportal combination with endonasal approaches.

The purpose of this study was to activate a vagovagal reflex by using esophageal distension and nicotine and test whether hindbrain nitric oxide and norepinephrine are involved in this reflex function. We used double-labeling immunocytochemical methods to determine whether esophageal distension (and nicotine) activates c-Fos expression in nitrergic and noradrenergic neurons in the nucleus tractus solitarii (NTS). We also studied c-Fos expression in the dorsal motor nucleus of the vagus (DMV) neurons projecting to the periphery. Esophageal distension caused 19.7 ± 2.3% of the noradrenergic NTS neurons located 0.60 mm rostral to the calamus scriptorius (CS) to be activated but had little effect on c-Fos in DMV neurons. Intravenous administration of nicotine caused 19.7 ± 4.2% of the noradrenergic NTS neurons 0.90 mm rostral to CS to be activated and, as reported previously, had no effect on c-Fos expression in DMV neurons. To determine whether norepinephrine and nitric oxide were central mediators of esophageal distension-induced decrease in intragastric pressure (balloon recording), NG-nitro-L-arginine methyl ester microinjected into the NTS (n = 5), but not into the DMV, blocked the vagovagal reflex. Conversely, α2-adrenergic blockers microinjected into the DMV (n = 7), but not into the NTS, blocked the vagovagal reflex. These data, in combination with our earlier pharmacological microinjection data with nicotine, indicate that both esophageal distension and nicotine produce nitric oxide in the NTS, which then activates noradrenergic neurons that terminate on and inhibit DMV neurons. [ABSTRACT FROM AUTHOR]

We reported previously that intravenously administered D-glucose acts in the central nervous system to inhibit gastric motility induced by hypoglycemia in anesthetized rats. The purpose of this study was to determine whether this effect is due to inhibition of dorsal motor nucleus of the vagus (DMV) cholinergic motoneurons, which synapse with postganglionic cholinergic neurons, or to excitation of DMV cholinergic neurons, which synapse with postganglionic nonadrenergic, noncholinergic (NANC) neurons, particularly nitrergic neurons. Three approaches were employed: 1) assessment of the efficacy of D-glucose-induced inhibition of gastric motility in hypoglycemic rats with and without inhibition of nitric oxide synthase [10 mg/kg iv nitro-L-arginine methyl ester (L-NAME)], 2) assessment of the efficacy of intravenous bethanechol (30 µg·kg-1·min-1) to stimulate gastric motility in hypoglycemic rats during the time of D-glucose-induced inhibition of gastric motility, and 3) determination of c-Fos expression in DMV neurons after intravenous D-glucose was administered to normoglycemic rats. Results obtained demonstrated that L-NAME treatment had no effect on D-glucose-induced inhibition of gastric motility; there was no reduction in the efficacy of intravenous bethanechol to increase gastric motility, and c-Fos expression was not induced by D-glucose in DMV neurons that project to the stomach. These findings indicate that excitation of DMV cholinergic motoneurons that synapse with postganglionic NANC neurons is not a significant contributing component of n-glucose-induced inhibition of gastric motility. [ABSTRACT FROM AUTHOR]

Our purposes were to 1) develop an animal model where intravenously (iv) administered D-glucose consistently inhibited antral motility, and 2) use this model to assess whether iv glucose acts to inhibit motility from a peripheral or a central nervous system site and to elucidate the factor(s) that determine(s) whether stomach motor function is sensitive to changes in blood glucose. Rats were anesthetized with α-chloralose-urethane, and antral motility was measured by a strain-gauge force transducer sutured to the antrum. In some cases, antral motility and gastric tone were measured by monitoring intragastric balloon pressure. Increases in blood glucose were produced by continuous iv infusion of 25% D-glucose at 2 ml/h. Inhibition of antral motility and gastric tone was observed when gastric contractions were induced by hypoglycemia (subcutaneously administered insulin, 2.5 IU/animal). In contrast, no inhibition of gastric motor function was observed when glucose infusion was tested on gastric contractions that were 1) spontaneously occurring, 2) evoked by iv administered bethanechol in vagotomized animals, and 3) evoked by the TRH analog RX77368, microinjected into the dorsal motor nucleus of the vagus. Using the model of insulin-induced hypoglycemia to increase gastric motor activity, we found that neither sectioning the hepatic branch of the vagus (n = 5), nor treating animals with capsaicin to destroy sensory vagal afferent nerves (n = 5) affected the ability of iv D-glucose to inhibit gastric motor function. Our results indicate that an important factor determining whether stomach motor function will be sensitive to changes in blood glucose is the method used to stimulate gastric contractions, and that the primary site of the inhibitory action of iv glucose on gastric motility is the central nervous system rather than the periphery. [ABSTRACT FROM AUTHOR]

Our purpose was to determine whether endogenously released GABA in the ventrolateral nucleus of the solitary tract (vlNTS) of the rat influences respiration. Experiments were carried out in anesthetized, vagotomized and spontaneously breathing rats, and diaphragm electromyogram activity was measured while drugs affecting GABAergic neurotransmission were microinjected into the vlNTS and medial NTS (mNTS). Bilateral microinjection of nipecotic acid, 5 or 25 nmol, into the vlNTS (but not in the mNTS) produced dose-dependent increases in inspiratory duration (TI) frequently culminating in apneustic breathing. Neither unilateral microinjection of bicuculline nor CGP-35348 (GABA[sub B] receptor antagonist) reversed this response; however, a combination of both GABA receptor antagonists effectively reversed apneustic breathing. Bilateral microinjection of either muscimol or baclofen into the vlNTS mimicked the effect of nipecotic acid. Microinjection of the bicuculline produced apnea, whereas microinjection of CGP-35348 produced a decrease in TI and an increase in expiratory duration. Immunohistochemical analysis of the vlNTS region revealed GABAA receptors densely localized to processes, whereas GABAn immunoreactivity was localized to cell bodies. Our data indicate that GABA activity in the vlNTS is important for respiratory function. [ABSTRACT FROM AUTHOR]

A response by Manuel Ferreira to a letter to the editor about his article "Hindbrain Chemical Mediators of Reflex-Induced Inhibition of Gastric Tone Produced by Esophageal Distension and Intravenous Nicotine" is presented.