Surgical outcomes of open and laser interstitial thermal therapy approaches for corpus callosotomy in pediatric epilepsy.

OBJECTIVE: Corpus callosotomy (CC) is a palliative surgical intervention for patients with medically refractory epilepsy that has evolved in recent years to include a less-invasive alternative with the use of laser interstitial thermal therapy (LITT). LITT works by heating a stereotactically placed laser fiber to ablative temperatures under real-time magnetic resonance imaging (MRI) thermometry. This study aims to (1) describe the surgical outcomes of CC in a large cohort of children with medically refractory epilepsy, (2) compare anterior and complete CC, and (3) review LITT as a surgical alternative to open craniotomy for CC. METHODS: This retrospective cohort study included 103 patients <21 years of age with at least 1 year follow-up at a single institution between 2003 and 2021. Surgical outcomes and the comparative effectiveness of anterior vs complete and open versus LITT surgical approaches were assessed. RESULTS: CC was the most common surgical disconnection (65%, n = 67) followed by anterior two-thirds (35%, n = 36), with a portion proceeding to posterior completion (28%, n = 10). The overall surgical complication rate was 6% (n = 6/103). Open craniotomy was the most common approach (87%, n = 90), with LITT used increasingly in recent years (13%, n = 13). Compared to open, LITT had shorter hospital stay (3 days [interquartile range (IQR) 2-5] vs 5 days [IQR 3-7]; p < .05). Modified Engel class I, II, III, and IV outcomes at last follow-up were 19.8% (n = 17/86), 19.8% (n = 17/86), 40.2% (n = 35/86), and 19.8% (n = 17/86). Of the 70 patients with preoperative drop seizures, 75% resolved postoperatively (n = 52/69). SIGNIFICANCE: No significant differences in seizure outcome between patients who underwent only anterior CC and complete CC were observed. LITT is a less-invasive surgical alternative to open craniotomy for CC, associated with similar seizure outcomes, lower blood loss, shorter hospital stays, and lower complication rates, but with longer operative times, when compared with the open craniotomy approach.

Axis-specific analysis and predictors of endocrine recovery and deficits for non-functioning pituitary adenomas undergoing endoscopic transsphenoidal surgery.

PURPOSE: Endoscopic transsphenoidal surgery (ETSS) is a well-established treatment for patients with nonfunctioning pituitary adenomas (NFPAs). Data on the rates of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS and the predictors of endocrine function before and after ETSS are scarce. This study is purposed to analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA. METHODS: A retrospective review of 601 consecutive patients who underwent ETSS between 2010 and 2018 at one institution was performed. Recovery or development of new hypopituitarism was analyzed in 209 NFPA patients who underwent ETSS. RESULTS: Patients with preoperative endocrine deficits (59.8%) in one or more pituitary axes had larger tumor volumes (P = 0.001) than those without preoperative deficits. Recovery of preoperative pituitary deficit occurred in all four axes, with overall mean recovery of 29.7%. The cortisol axis showed the highest recovery whereas the thyroid axis showed the lowest, with 1-year cumulative recovery rates of 44.3% and 6.1%, respectively. Postoperative hypopituitarism occurred overall in 17.2%, most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Axis-specific predictors of post-operative recovery and deficiency were identified. CONCLUSIONS: Dynamic alterations in pituitary hormones were observed in a proportion of patients following ETSS in NFPA patients. Postoperative endocrine vulnerability, recovery, and factors that predicted recovery or loss of endocrine function depended on the hormonal system, necessitating an axis-specific surveillance strategy postoperatively.

Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding.

Zeta-chain associated protein of 70 kDa (ZAP-70) and spleen tyrosine kinase (Syk) are non-receptor tyrosine kinases that are essential for T-cell and B-cell antigen receptor signalling respectively. They are recruited, via their tandem-SH2 (Src-homology domain 2) domains, to doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) on invariant chains of immune antigen receptors. Because of their critical roles in immune signalling, ZAP-70 and Syk are targets for the development of drugs for autoimmune diseases. We show that three thiol-reactive small molecules can prevent the tandem-SH2 domains of ZAP-70 and Syk from binding to phosphorylated ITAMs. We identify a specific cysteine residue in the phosphotyrosine-binding pocket of each protein (Cys39 in ZAP-70, Cys206 in Syk) that is necessary for inhibition by two of these compounds. We also find that ITAM binding to ZAP-70 and Syk is sensitive to the presence of H2O2 and these two cysteine residues are also necessary for inhibition by H2O2. Our findings suggest a mechanism by which the reactive oxygen species generated during responses to antigen could attenuate signalling through these kinases and may also inform the development of ZAP-70 and Syk inhibitors that bind covalently to their SH2 domains.

Molecular and cellular heterogeneity: the hallmark of glioblastoma.

There has been increasing awareness that glioblastoma, which may seem histopathologically similar across many tumors, actually represents a group of molecularly distinct tumors. Emerging evidence suggests that cells even within the same tumor exhibit wide-ranging molecular diversity. Parallel to the discoveries of molecular heterogeneity among tumors and their individual cells, intense investigation of the cellular biology of glioblastoma has revealed that not all cancer cells within a given tumor behave the same. The identification of a subpopulation of brain tumor cells termed "glioblastoma cancer stem cells" or "tumor-initiating cells" has implications for the management of glioblastoma. This focused review will therefore summarize emerging concepts on the molecular and cellular heterogeneity of glioblastoma and emphasize that we should begin to consider each individual glioblastoma to be an ensemble of molecularly distinct subclones that reflect a spectrum of dynamic cell states.

Laser interstitial thermal therapy compared with open resection for treating subependymal giant cell astrocytoma.

OBJECTIVE: Subependymal giant cell astrocytomas (SEGAs) are WHO grade 1 tumors associated with tuberous sclerosis that classically arise from the ventricular wall near the caudate groove and foramen of Monro. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique, which works by heating a stereotactically placed laser fiber to ablative temperatures under MRI thermometry monitoring. In this paper, the authors present LITT as a surgical alternative to open resection of SEGAs. METHODS: Twelve patients with SEGAs who underwent 16 procedures between 2007 and 2022 at a single institution were retrospectively reviewed. These patients underwent either open resection or LITT. Clinical data, imaging, recurrence rate, further treatments, and related complications were analyzed. RESULTS: Among the 16 procedures, 9 were open resection and 7 were LITT. An external ventricular drain was placed in 66% (6/9) of open procedures and 57.1% (4/7) of LITT cases. A septostomy was performed in 56% (5/9) of open procedures and 29% (2/7) of LITT cases. Complication rates were higher in open cases than in LITT procedures (44% vs 0%, p < 0.05). Complications included hydrocephalus, transient venous ischemia, wound infection, and bone flap migration. The median length of hospital stay was 4 days (IQR 3.3-5.5 days) for open cases and 4 days (IQR 3.0-7.0 days) for LITT procedures. Recurrence or progression occurred after 3 open cases and 2 LITT cases (33% vs 33%, p = 0.803). For the recurrences, 2 open cases underwent stereotactic radiosurgery, 1 open case underwent LITT, and 1 LITT case underwent repeat LITT. Among the LITT cases, only the patients with no decrease in tumor size by 6 months experienced tumor progression afterward. The 2 LITT cases with progression were the only ones with calcification present on preoperative imaging. The median follow-up times for cases assessed for progression were 8.4 years (IQR 3.8-14.4 years) for open resection and 3.9 years (IQR 3.4-5.1 years) for LITT. CONCLUSIONS: The small size of this case series limits generalizability or adequate comparison of safety. However, this series adds to the literature supporting LITT as a less invasive surgical alternative to open resection of SEGAs and demonstrates that LITT has similar recurrence and/or progression rates to open resection. Additional studies with more data are necessary for comprehensive comparisons between open resection and LITT for treating SEGA.

Subependymal giant-cell astrocytomas in the absence of tuberous sclerosis.

OBJECTIVE: Tuberous sclerosis is a rare genetic condition caused by TSC1 or TSC2 mutations that can be inherited, sporadic, or the result of somatic mosaicism. Subependymal giant-cell astrocytoma (SEGA) is a major diagnostic feature of tuberous sclerosis complex (TSC). This study aimed to present a series of cases in which a pathological diagnosis of SEGA was not diagnostic of tuberous sclerosis. METHODS: The authors retrospectively reviewed a clinical case series of 5 children who presented with a SEGA tumor to Johns Hopkins All Children's Hospital and St. Louis Children's Hospital between 2010 and 2022 and whose initial genetic workup was negative for tuberous sclerosis. All patients were treated with craniotomy for SEGA resection. TSC genetic testing was performed on all SEGA specimens. RESULTS: The children underwent open frontal craniotomy for SEGA resection from the ages of 10 months to 14 years. All cases demonstrated the classic imaging features of SEGA. Four were centered at the foramen of Monro and 1 in the occipital horn. One patient presented with hydrocephalus, 1 with headaches, 1 with hand weakness, 1 with seizures, and 1 with tumor hemorrhage. Somatic TSC1 mutation was present in the SEGA tumors of 2 patients and TSC2 mutation in 1 patient. Germline TSC mutation testing was negative for all 5 cases. No patient had other systemic findings of tuberous sclerosis on ophthalmological, dermatological, neurological, renal, or cardiopulmonary assessments and thus did not meet the clinical criteria for tuberous sclerosis. The average follow-up was 6.7 years. Recurrence was noted in 2 cases, in which 1 patient underwent radiosurgery and 1 was started on a mammalian target of rapamycin (mTOR) inhibitor (rapamycin). CONCLUSIONS: There may be intracranial implications of somatic mosaicism associated with tuberous sclerosis. Children who are diagnosed with SEGA do not necessarily have a diagnosis of tuberous sclerosis. Tumors may carry a TSC1 or TSC2 mutation, but germline testing can be negative. These children should continue to be followed with serial cranial imaging for tumor progression, but they may not require the same long-term monitoring as patients who are diagnosed with germline TSC1 or TSC2 mutations.

Sirtuin 1 Mediates Protection Against Delayed Cerebral Ischemia in Subarachnoid Hemorrhage in Response to Hypoxic Postconditioning.

Background Many therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in aneurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection. Methods and Results In this study, we found that hypoxic postconditioning (8% O2 for 2 hours) initiated 3 hours after SAH provides strong protection against cerebral vasospasm, microvessel thrombi, and neurological deficits. By pharmacologic and genetic inhibition of SIRT1 (sirtuin 1) using EX527 and global Sirt1-/- mice, respectively, we demonstrated that this multifaceted DCI protection is SIRT1 mediated. Moreover, genetic overexpression of SIRT1 using Sirt1-Tg mice, mimicked the DCI protection afforded by hypoxic postconditioning. Finally, we found that post-SAH administration of resveratrol attenuated cerebral vasospasm, microvessel thrombi, and neurological deficits, and did so in a SIRT1-dependent fashion. Conclusions The present study indicates that hypoxic postconditioning provides powerful DCI protection when initiated at clinically relevant time points, and that pharmacologic augmentation of SIRT1 activity after SAH can mimic this beneficial effect. We conclude that conditioning-based therapies administered after SAH hold translational promise for patients with SAH and warrant further investigation.

SIRT1 mediates hypoxic preconditioning induced attenuation of neurovascular dysfunction following subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Vasospasm and delayed cerebral ischemia (DCI) contribute significantly to the morbidity/mortality associated with aneurysmal subarachnoid hemorrhage (SAH). While considerable research effort has focused on preventing or reversing vasospasm, SAH-induced brain injury occurs in response to a multitude of concomitantly acting pathophysiologic mechanisms. In this regard, the pleiotropic epigenetic responses to conditioning-based therapeutics may provide an ideal SAH therapeutic strategy. We previously documented the ability of hypoxic preconditioning (PC) to attenuate vasospasm and neurological deficits after SAH, in a manner that depends on the activity of endothelial nitric oxide synthase. The present study was undertaken to elucidate whether the NAD-dependent protein deacetylase sirtuin isoform SIRT1 is an upstream mediator of hypoxic PC-induced protection, and to assess the efficacy of the SIRT1-activating polyphenol Resveratrol as a pharmacologic preconditioning therapy. METHODS: Wild-type C57BL/6J mice were utilized in the study and subjected to normoxia or hypoxic PC. Surgical procedures included induction of SAH via endovascular perforation or sham surgery. Multiple endpoints were assessed including cerebral vasospasm, neurobehavioral deficits, SIRT1 expression via quantitative real-time PCR for mRNA, and western blot for protein quantification. Pharmacological agents utilized in the study include EX-527 (SIRT1 inhibitor), and Resveratrol (SIRT1 activator). RESULTS: Hypoxic PC leads to rapid and sustained increase in cerebral SIRT1 mRNA and protein expression. SIRT1 inhibition blocks the protective effects of hypoxic PC on vasospasm and neurological deficits. Resveratrol pretreatment dose-dependently abrogates vasospasm and attenuates neurological deficits following SAH - beneficial effects that were similarly blocked by pharmacologic inhibition of SIRT1. CONCLUSION: SIRT1 mediates hypoxic preconditioning-induced protection against neurovascular dysfunction after SAH. Resveratrol mimics this neurovascular protection, at least in part, via SIRT1. Activation of SIRT1 is a promising, novel, pleiotropic therapeutic strategy to combat DCI after SAH.

A novel fluorescent imaging technique for assessment of cerebral vasospasm after experimental subarachnoid hemorrhage.

Various techniques have been developed to study changes in the cerebral vasculature in numerous neuropathological processes including subarachnoid hemorrhage (SAH). One of the most widely employed techniques uses India ink-gelatin casting, which presents numerous challenges due to its high viscosity, rapid solidification, and its impact on immunohistochemical analysis. To overcome these limitations, we developed a novel technique for assessing cerebral vasospasm using cerebrovascular perfusion with ROX, SE (5-Carboxy-X-Rhodamine, Succinimidyl Ester), a fluorescent labeling dye. We found that ROX SE perfusion achieves excellent delineation of the cerebral vasculature, was qualitatively and quantitatively superior to India ink-gelatin casting for the assessment of cerebral vasospasm, permits outstanding immunohistochemical examination of non-vasospasm components of secondary brain injury, and is a more efficient and cost-effective experimental technique. ROX SE perfusion is therefore a novel and highly useful technique for studying cerebrovascular pathology following experimental SAH.

Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase-9 inhibition.

Objective: Delayed cerebral ischemia (DCI) is an independent risk factor for poor outcome after aneurysmal subarachnoid hemorrhage (SAH) and is multifactorial in etiology. While prior studies have suggested a role for matrix metalloproteinase-9 (MMP-9) in early brain injury after SAH, its contribution to the pathophysiology of DCI is unclear. Methods: In the first experiment, wild-type (WT) and MMP-9-/- mice were subjected to sham or endovascular perforation SAH surgery. In separate experiments, WT and MMP-9-/-mice were administered vehicle or minocycline either pre- or post-SAH. All mice underwent assessment of multiple components of DCI including vasospasm, neurobehavioral function, and microvessel thrombosis. In another experiment, rabbits were subjected to sham or cisterna magna injection SAH surgery, and administered vehicle or minocycline followed by vasospasm assessment. Results: MMP-9 expression and activity was increased after SAH. Genetic (MMP-9-/- mice) and pharmacological (pre-SAH minocycline administration) inhibition of MMP-9 resulted in decreased vasospasm and neurobehavioral deficits. A therapeutically feasible strategy of post-SAH administration of minocycline resulted in attenuation of multiple components of DCI. Minocycline administration to MMP-9-/- mice did not yield additional protection. Consistent with experiments in mice, both pre- and post-SAH administration of minocycline attenuated SAH-induced vasospasm in rabbits. Interpretation: MMP-9 is a key player in the pathogenesis of DCI. The consistent attenuation of multiple components of DCI with both pre- and post-SAH administration of minocycline across different species and experimental models of SAH, combined with the excellent safety profile of minocycline in humans suggest that a clinical trial in SAH patients is warranted.