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Background and PurposeSurgical decompression of the posterior fossa is often performed in cases with a space-occupying cerebellar infarction to prevent coma and death. In this study, we analyzed our institutional experience with this condition. We specifically attempted to address timing issues and investigated the role of cerebellar necrosectomy using imaging data and conducting volumetric analyses.MethodsWe retrospectively studied pertinent clinical and imaging data, including computerized volumetric analyses (preoperative/postoperative infarction volume, necrosectomy volume, and posterior fossa volume), from all 49 patients who underwent posterior fossa decompression surgery for cerebellar infarction in our department from January 2012 to January 2021.ResultsThirty-five (71%) patients had a Glasgow Coma Scale (GCS) of 14–15 at admission vs. only 14 (29%) before vs. 41 (84%) following surgery. Seven (14%) patients had preventive surgery (initial GCS 14–15, preoperative GCS change ≤ 1). Only 18 (37%) patients had an mRS score of 0–3 at discharge. Estimated overall survival was 70.5% at 1 year. Interestingly, 18/20 (90%) surviving cases had a modified Rankin Scale (mRS) outcome of 0–3 (mRS 0–2: 12/20 [60%]) 1 year after surgery. Surgical timing, including preventive surgery and mass effect of the infarct, in the posterior fossa assessed semi-quantitatively (Kirollos grade) and with volumetric parameters that were not predictive of the patients' (functional) outcomes.ConclusionPosterior fossa decompression for cerebellar infarction is a life-saving procedure, but rapid recovery of the GCS after surgery does not necessarily translate into good functional outcome. Many patients died during follow-up, but long-term mRS outcomes of 4–5 are rare. Surgery should probably aim primarily at pressure relief, and our clinical as well as volumetric data suggest that the impact of removing an infarcted tissue may be limited. It is presumably relatively safe to initially withhold surgery in cases with a GCS of 14–15.

Background Intermediate nerve neuralgia (INN) is a rare and often overlooked form of primary otalgia. The pathophysiological mechanism is unknown, although one of the possible contributing factors is a neurovascular conflict at the root entry zone of the intermediate nerve. The pain can be severely debilitating, and the palette of treatment options is small. Objective To assess the outcome of microvascular decompression (MVD) of the VII/VIII cranial nerve complex for treating INN. Methods We retrospectively reviewed the records of a group of 8 consecutive patients with INN who underwent MVD of the VII/VIII cranial nerve complex in the period 1994 to 2015. Results In total, 7 of the 8 patients experienced almost immediate and complete relief of pain, which remained at long-term follow-up (mean 35 mo ± 24 mo, range 8-84 mo). Postoperatively, 1 patient had a cerebrospinal fluid (CSF) leak, 3 patients experienced permanent ipsilateral hearing loss, and 3 patients had temporary complaints associated with excessive drainage of CSF. Conclusion This study suggests MVD as a valid treatment for medically refractory INN. MVD carries surgical risk, but given the severity of complaints of these patients, we believe the treatment benefits outweigh the associated complications.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The mechanisms that confer GBM cells their invasive behavior are poorly understood. The electroneutral Na+-K+-2Cl− co-transporter 1 (NKCC1) is an important cell volume regulator that participates in cell migration. We have shown that inhibition of NKCC1 in GBM cells leads to decreased cell migration, in vitro and in vivo. We now report on the role of NKCC1 on cytoskeletal dynamics. We show that GBM cells display a significant decrease in F-actin content upon NKCC1 knockdown (NKCC1-KD). To determine the potential actin-regulatory mechanisms affected by NKCC1 inhibition, we studied NKCC1 protein interactions. We found that NKCC1 interacts with the actin-regulating protein Cofilin-1 and can regulate its membrane localization. Finally, we analyzed whether NKCC1 could regulate the activity of the small Rho-GTPases RhoA and Rac1. We observed that the active forms of RhoA and Rac1 were decreased in NKCC1-KD cells. In summary, we report that NKCC1 regulates GBM cell migration by modulating the cytoskeleton through multiple targets including F-actin regulation through Cofilin-1 and RhoGTPase activity. Due to its essential role in cell migration NKCC1 may serve as a specific therapeutic target to decrease cell invasion in patients with primary brain cancer., Highlights • NKCC1 ion co-transporter regulates actin cytoskeleton dynamics in glioblastoma, which plays a key role in cell migration. • NKCC1 interacts with actin-regulating protein Cofilin, potentially regulating its activity. • The NKCC1-Cofilin interaction brings the opportunity of finding new targets to treat patients with brain cancer. Glioblastoma is a devastating brain tumor with prominent cell migration and invasion capabilities. Its invasiveness makes surgical resection ineffective, resulting in a high recurrence rate. Glioblastoma cells utilize multiple mechanisms to travel through the brain. One of such mechanisms is cell volume modulation, regulated by ion transporters like NKCC1. In our study, we observed that NKCC1 also regulates glioblastoma cell migration in a volume-independent way by controlling the cytoskeleton. Specifically, by interacting with the actin-regulating protein Cofilin. Our observations identify a significant target to inhibit glioblastoma cell dispersal, which is crucial given that current therapies only target cell proliferation.

Glioblastoma (GBM) is the most aggressive and deadliest primary human brain tumor in adults due to the extensive tumor cell migration throughout surrounding brain parenchyma. The capacity to form new tumors, distant from the original location, resides in a specific cell subpopulation called brain tumor initiating cells (BTICs). Combined local and systemic therapies have been ineffective at targeting these invasive cells; furthermore, the mechanisms that confer GBM cells their invasive behavior have not been fully elucidated. The electroneutral Na+-K+-Cl- cotransporter 1 (NKCC1) is an important cell volume regulator that is implicated in cell migration and overexpressed in GBM compared to non-cancer brain tissue. We have shown that both downregulation and pharmacological inhibition (using Bumetanide, BMT) of NKCC1 in BTICs lead to decreased cell migration, in vitro and in vivo. In addition, we reported that NKCC1 knockdown cells (NKCC1 KD) show significantly larger focal adhesions, suggesting a potential role of NKCC1 in cell adhesion. We now report the role of NKCC1 on cytoskeletal dynamics. We found that glioma cells display a significant decrease in cell spreading capacity upon NKCC1 KD or inhibition by BMT. Further, F-actin organization (observed with phalloidin staining) showed dramatic changes upon NKCC1 KD in BTICs. These changes include concentration of actin filaments on the membrane periphery in a ring shaped form and decreased bundled actin content. To analyze actin changes in a dynamic model, we transduced BTICs with the Lifeact-RFP construct for live imaging of F-actin. We observed that upon EGF stimulation, control cells responded by uniform spreading, as reflected by an increased cell circularity within seconds after stimulation, while NKCC1 KD cells did not respond. This suggests that the dynamic response of the actin cytoskeleton to external stimuli is decreased when NKCC1 is down-regulated. To determine the potential actin-regulatory mechanisms affected by NKCC1 inhibition we studied the small Rho-GTPases, RhoA and Rac1. We observed that the levels of active (GTP-bound) forms of RhoA and Rac1 were decreased in NKCC1 KD cells. Moreover, when BTICs were treated with the ROCK1 inhibitor, Y-27632, they showed a dose-dependent decrease in cell migration and activity of MLC (ROCK substrate). These effects were significantly weaker when the ROCK inhibitor was applied on NKCC1 KD or BMT-treated cells, suggesting that decreased RhoA and ROCK1 activity mediates the effects of NKCC1 inhibition. In summary, NKCC1 regulates BTIC migration beyond cell volume changes, by modulating the cytoskeleton through multiple targets that include F-actin regulation and RhoA and Rac1 activity. Due to its essential role in cell migration and high expression in GBM, NKCC1 may serve as a specific therapeutic target to decrease BTIC cell invasion and increase survival in patients with primary brain cancer. Citation Format: Paula V. Schiapparelli, Roxana Magaña-Maldonado, Susan Hamilla, Eric Goulin Lippi Fernandes, Sara Ganaha, Chuan-Hsiang Huang, Hugo Guerrero-Cazares, Helim Aranda-Espinoza, Peter N. Devreotes, Alfredo Quiñones-Hinojosa. NKCC1 regulates migration of glioblastoma tumor initiating cells by interacting with the actin cytoskeleton. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4152. doi:10.1158/1538-7445.AM2015-4152