National multicentered retrospective review of clinical and intraoperative factors associated with the development of cerebellar mutism after pediatric posterior fossa tumor resection.

BACKGROUND: Cerebellar mutism (CM) is characterized by a significant loss of speech in children following posterior fossa (PF) surgery. The biological origin of CM remains unclear and is the subject of ongoing debate. Significant recovery from CM is less likely than previously described despite rigorous multidisciplinary neuro-rehabilitational efforts. METHODS: A national multi-centered retrospective review of all children undergoing PF resection in four midsized Canadian academic pediatric institutions was undertaken. Patient, tumor and surgical factors associated with the post-operative development of CM were reviewed. Retrospective identification of PF surgery patients including those developing and those that did not (internal control). RESULTS: The study identified 258 patients across the 4 centers between 2010 and 2020 (mean age 6.73 years; 42.2% female). Overall, CM was experienced in 19.5% of patients (N = 50). Amongst children who developed CM histopathology included medulloblastoma (35.7%), pilocytic astrocytoma (32.6%) and ependymoma (17.1%). Intraoperative impression of adherence to the floor of the 4th ventricle was positive in 36.8%. Intraoperative abrupt changes in blood pressure and/or heart rate were identified in 19.4% and 17.8% of cases. The clinical resolution of CM was rated to be complete, significant resolution, slight improvement, no improvement and deterioration in 56.0%, 8.0%, 20.0%, 14.0% and 2.0%, respectively. In the cohort of children who experienced post-operative CM as compared to their no-CM counterpart, proportionally more tumors were felt to be adherent to the floor of the 4th ventricle (56.0% vs 49.5%), intraoperative extent of resection was a GTR (74% vs 68.8%) and changes in heart rate were noted (≥ 20% from baseline) (26.0% vs 15.9%). However, a multiple regression analysis identified only abrupt changes in HR (OR 5.97, CI (1.53, 23.1), p = 0.01) to be significantly associated with the development of post-operative CM. CONCLUSION: As a devastating surgical complication after posterior fossa tumor surgery with variable clinical course, identifying and understanding the operative cues and revising intraoperative plans that optimizes the child's neurooncological and clinical outcome are essential.

Bone marrow monocytes and macrophages from mice lacking ßENaC and ASIC2 have a reduced chemotactic migration response and polarization.

The monocyte-macrophage system plays an important role in phagocytosis of pathogens and cellular debris following infection or tissue injury in several pathophysiological conditions. We examined ENaC/ASIC subunit transcript expression and the importance of select subunits in migration of bone marrow derived monocytes (freshly isolated) and macrophages (monocytes differentiated in culture). We also examined the effect of select subunit deletion on macrophage phenotype. BM monocytes were harvested from the femurs of male and female WT and KO mice (6-12 weeks of age). Our results show that α, ß, γENaC, and ASIC1-5 transcripts are expressed in BM macrophages and monocytes to varying degrees. At least αENaC, ßENaC, and ASIC2 subunits contribute to chemotactic migration responses in BM monocyte-macrophages. Polarization markers (CD86, soluble TNFα) in BM macrophages from mice lacking ASIC2a plus ßENaC were shifted towards the M1 phenotype. Furthermore, select M1 phenotypic markers were recovered with rescue of ßENaC or ASIC2. Taken together, these data suggest that ßENaC and ASIC2 play an important role in BM macrophage migration and loss of ßENaC and/or ASIC2 partially polarizes macrophages to the M1 phenotype. Thus, targeting ENaC/ASIC expression in BM macrophages may regulate their ability to migrate to sites of injury.

Frequency of Leaks from Conical Centrifuge Tubes.

Introduction: Threaded conical centrifuge tubes are ubiquitous in biological laboratories and are frequently used for the storage/transport of potentially biohazardous samples. However, limited data are available on how frequently and from where these tubes leak. These data are valuable for laboratory biorisk management and to inform future studies on risks arising from the routine use of laboratory consumables. Methods: The frequency of leaks from threaded conical centrifuge tubes was tested using a Glo Germ solution as a tracer. Conical tubes (15 and 50 mL) from several brands were filled, inverted, and placed on their side on the benchtop. After 1 h, the presence or absence of leaks on the benchtop surface, tube threads, and exterior was recorded. Results: We observed that liquid leaked out of tubes that were apparently properly threaded in 2% of 15 mL tubes (confidence interval [95% CI] 1.4-2.6) and 1.4% of 50 mL tubes (95% CI 0.2-1.5). After opening, liquid was found on the threads on the outside of the tube in 20% of 15 mL tubes (95% CI 10-31) and 14% of 50 mL tubes (95% CI 1-28). We did not find sufficient evidence that differences in leak rates among brands were practically significant. Conclusions: The fact that leaks were not uncommonly observed from conical centrifuge tubes suggests that mitigations for any hazard posed by a leak should be a component of every biorisk management strategy for protocols involving the manipulation of hazardous substances in these tubes. Further research should be conducted on other activities that could cause tubes to leak (such as centrifugation or vortexing) and should be completed to understand the risks associated with this consumable. Research into the costs and benefits of mitigating the risk of leaks from conical tubes is recommended.

Canadian Consensus for Treatment of BRAF V600E Mutated Pediatric and AYA Gliomas.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.