Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

The role of reoperation in pediatric cerebellar pilocytic astrocytoma.

OBJECTIVE: Cerebellar pilocytic astrocytomas (cPAs) in childhood have long been recognized to have a good prognosis after total resection, but the outcome after incomplete resective surgery remains largely unpredictable, with the incidence of radiological progressive disease ranging from 18% to 100%. It has been traditionally thought that gross-total resection was required for long-term survival, and small residuals were classically resected in a subsequent operation. METHODS: The authors analyzed their pediatric low-grade glioma (PLGG) database for cases treated between 1985 and 2020 and filtered for intracranial PAs, to determine what clinical or radiological factors precipitated revisional resective surgery in their single quaternary care center cohort. RESULTS: Using the pediatric low-grade glioma database, 283 patients were identified to have a histopathological diagnosis of intracranial PA between 1985 and 2020, of which 200 lesions were within the cerebellum (70.7%). The majority of patients with cPA were between 1 and 10 years of age (n = 145, 72.5%) without gender predominance (M/F = 99:101), usually presenting with 1 lesion (n = 197, 98.5%). Gross-total resection was achieved in 74.5% (n = 149) of initial surgeries for cPA. In patients with subtotal resection, the mean largest diameter of the postoperative residual tumor was 1.06 cm (range 0-2.95 cm). Seven patients with subtotal resection did not require a second resective intervention. In 31 patients the neuro-oncology multidisciplinary team recommended a second resection at a mean time interval of 22.9 months (range 0.13-81.6 months) from the initial surgery. Proportionally, the children who underwent multiple resections were also more likely to receive adjuvant chemo/radiotherapy. Functionally, the children in the multiple operation cohort experienced more complications of therapy including ongoing endocrinopathy, treatment-associated hearing deficit, and neurocognitive deficits. CONCLUSIONS: Residual disease in cPA should be maintained under clinicocoradiological surveillance postoperatively with adoption of a more conservative approach when residual disease is not significantly changing over time.

Pediatric Congenital Anterior Skull Base Encephaloceles and Surgical Management: A Comparative Review of 22 Patients Treated With Transnasally, Transcranially, or Combined Approach With a Review of the Literature.

BACKGROUND AND OBJECTIVES: Anterior basal encephaloceles are considered a rare entity and are often associated with midline cerebral abnormalities. Those with a large skull base defect and herniation of brain parenchyma in the neonate or young infant present unique challenges for surgical management. METHODS: We analyzed the neurosurgical administrative and operative databases between 1986 and 2022 to determine clinical presentation, operative approach, and outcome of basal encephaloceles. RESULTS: Over the 36-year period, 27 pediatric anterior basal encephaloceles were managed, of which 22 had full documentation and images allowing comprehensive review. Mean age at presentation was 5 years (SD 4.94). The majority were transethmoidal encephaloceles (59%), followed by the transsphenoidal-sphenoethmoidal type (32%). Overall, 91% were managed surgically by a transcranial, endoscopic, or combined approach. Four children required subsequent procedures, predominantly for persistent cerebrospinal fluid leak. No significant differences in proportion of patients requiring interval/revision surgery after initial conservative, endoscopic endonasal, or transcranial surgery was identified. Neither age at surgery nor size of the defect on computed tomography scan was associated with the need for revision surgery. Size of cranial defect was significantly smaller in the endoscopic group (P = .01). There was a historic tendency for younger children with larger defects to have a transcranial approach. With the addition of endoscopic skull base expertise, smaller defects in older children were more recently treated endoscopically. CONCLUSION: Basal encephaloceles are rare and complex lesions and are optimally managed within a skull base multidisciplinary team able to provide multiple approaches. Large skull base defects with brain parenchymal involvement often require a transcranial or combined transcranial-endoscopic approach.

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.

Pharmacist Avoidance or Reductions in Medical Costs in Critically and Emergently Ill Pediatrics: PHARM-PEDS Study.

OBJECTIVES: To comprehensively classify interventions performed by pediatric critical care clinical pharmacists and quantify cost avoidance (CA) generated through their accepted interventions. DESIGN: A multicenter, prospective, observational study performed between August 2018 and January 2019. SETTING: Academic and community hospitals in the United States with pediatric critical care units. SUBJECTS: Pediatric clinical pharmacists. INTERVENTIONS: Pharmacist recommendations were classified into one of 38 total intervention categories associated with CA. MEASUREMENTS AND MAIN RESULTS: Nineteen pediatric pharmacists at five centers documented 1,458 accepted interventions during 112 shifts on 861 critically ill pediatric patients. This calculated to an associated CA of $450,590. The accepted interventions and associated CA in the six established categories included as follows: adverse drug event prevention (155 interventions, $118,901 CA), resource utilization (267 interventions; $59,020), individualization of patient care (898 interventions, $217,949 CA), prophylaxis (8 interventions, $453 CA), hands-on care (30 interventions, $35,509 CA), and administrative/supportive tasks (108 interventions, $18,758 CA). The average associated CA was $309 per accepted intervention, $523 per patient day, and $4,023.13 per pediatric clinical pharmacist shift. The calculated potential annualized CA of accepted interventions from a pediatric pharmacist was $965,550, resulting in a potential monetary-associated CA-to-pharmacist salary ratio between $1.5:1 and $5.2:1. CONCLUSIONS: There is potential for significant avoidance of healthcare costs when pediatric pharmacists are involved in the care of critically and emergently ill pediatric patients, with a monetary potential CA-to-pediatric pharmacist salary ratio to be between $1.5:1 and $5.2:1.

Within-person changes in aversive reactivity predict session-to-session reductions in anxiety and depression in the unified protocol.

ABSTRACTThe Unified Protocol (UP) theoretically leads to reductions in emotional disorder symptoms by reducing aversive reactions to emotions. However, aversive reactions can take many forms (e.g., non-acceptance, behavioral avoidance). We examined if (1) multiple aspects of aversive reactivity predicted session-to-session changes in anxiety and depression in the UP, (2) these aspects reflected a single latent construct, and (3) changes in this latent construct predicted changes in anxiety and depression. Participants (N = 70, Mage = 33.74, 67.1% female, 74.3% white) completed six sessions of UP modules and measures of aversive reactivity, anxiety, and depression before each session. We used hierarchical linear modeling and random-intercept cross-lagged panel models to test aspects of aversive reactivity and a latent factor of aversive reactivity, respectively, as predictors of session-to-session changes in anxiety and depression. Within-person improvements in four of five aspects of aversive reactivity predicted decreases in anxiety, and improvements in two aspects predicted decreases in depression. However, within-person improvements in latent aversive reactivity predicted decreases in anxiety at five sessions and in depression across all sessions. These results add to the growing literature highlighting the role of aversive reactivity as a potential transdiagnostic process involved in improvements in emotional disorder symptoms during treatment.

An effective kinase inhibition strategy for metastatic recurrent childhood medulloblastoma.

PURPOSE: Medulloblastomas (MBs) constitute the most common malignant brain tumor in children and adolescents. MYC-amplified Group 3 MBs are characterized by disease recurrence, specifically in the leptomeninges, whereby patients with these metastatic tumors have a mortality rate nearing 100%. Despite limited research on such tumors, studies on MB metastases at diagnosis suggest targeting kinases to be beneficial. METHODS: To identify kinase inhibitors that eradicate cells driving therapy evasion and tumor dissemination, we utilized our established patient-derived xenograft (PDX) mouse-adapted therapy platform that models human MB metastatic recurrences following standard chemoradiotherapy. High-throughput screens of 640 kinase inhibitors were conducted against cells isolated from mouse spines in the PDX model and human fetal neural stem cells to reveal compounds that targeted these treatment-refractory, metastatic cells, whilst sparing healthy cells. Blood-brain barrier permeability assays and additional in vitro experimentation helped select top candidates for in vivo studies. RESULTS: Recurrent Group 3 MB PDX spine cells were therapeutically vulnerable to a selective checkpoint kinase 1 (CHK1) inhibitor and small molecular inhibitor of platelet-derived growth factor receptor beta (PDGFRß). Inhibitor-treated cells showed a significant reduction in MB stem cell properties associated with treatment failure. Mice also demonstrated survival advantage when treated with a CHK1 inhibitor ex vivo. CONCLUSION: We identified CHK1 and PDGFRß inhibitors that effectively target MB cells fueling treatment-refractory metastases. With limited research on effective therapies for Group 3 MB metastatic recurrences, this work highlights promising therapeutic options to treat these aggressive tumors. Additional studies are warranted to investigate these inhibitors' mechanisms and recommended in vivo administration.

Psychopathy and antisocial personality disorder in the fifth edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders: An attempted replication of Wygant et al. (2016).

The fifth edition of the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Section III Alternative Model of Personality Disorder (AMPD) was developed to ameliorate some of the concerns of the DSM-5 Section II categorical model by moving away from the discrete boundaries of behaviorally specific criteria to a hybridized dimensional trait-based approach. Wygant et al. (2016) examined the extent to which the AMPD improved the operationalization of antisocial personality disorder to more closely align with psychopathy, a notable weakness of DSM-5 Section II (Crego & Widiger, 2015; Lynam & Vachon, 2012; Strickland et al., 2013). Wygant et al. found that the DSM-5 Section III AMPD outperformed Section II in predicting various operationalizations of psychopathy in a sample of 200 male inmates. In the spirit of the importance in exploring replication (Tackett et al., 2017), the current study sought to replicate and extend these findings by comparing the ability of the AMPD and alternative trait models to account for psychopathy. Analyses showed a partial replication of Wygant et al.'s findings, indicating that additional traits to account for psychopathy should be included in DSM-5 Section III. The current study was not preregistered. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Subarachnoid Hemorrhage, Delayed Cerebral Ischemia, and Milrinone Use in Canada.

INTRODUCTION: Delayed cerebral ischemia (DCI) is a complication of aneurysmal subarachnoid hemorrhage (aSAH) and is associated with significant morbidity and mortality. There is little high-quality evidence available to guide the management of DCI. The Canadian Neurosurgery Research Collaborative (CNRC) is comprised of resident physicians who are positioned to capture national, multi-site data. The objective of this study was to evaluate practice patterns of Canadian physicians regarding the management of aSAH and DCI. METHODS: We performed a cross-sectional survey of Canadian neurosurgeons, intensivists, and neurologists who manage aSAH. A 19-question electronic survey (Survey Monkey) was developed and validated by the CNRC following a DCI-related literature review (PubMed, Embase). The survey was distributed to members of the Canadian Neurosurgical Society and to Canadian members of the Neurocritical Care Society. Responses were analyzed using quantitative and qualitative methods. RESULTS: The response rate was 129/340 (38%). Agreement among respondents was limited to the need for intensive care unit admission, use of clinical and radiographic monitoring, and prophylaxis for the prevention of DCI. Several inconsistencies were identified. Indications for starting hyperdynamic therapy varied. There was discrepancy in the proportion of patients who felt to require IV milrinone, IA vasodilators, or physical angioplasty for treatment of DCI. Most respondents reported their facility does not utilize a standardized definition for DCI. CONCLUSION: DCI is an important clinical entity for which no homogeneity and standardization exists in management among Canadian practitioners. The CNRC calls for the development of national standards in the definition, identification, and treatment of DCI.

Experimental Manipulation of the BFI-2, IPIP-NEO-120, and the IPC-5.

Research assessing the relationship of the five-factor model (FFM) to personality disorder symptomatology has generally been confirmatory, with three exceptions. The exceptions have been failures to confirm associations of conscientiousness with the obsessive-compulsive personality disorder, agreeableness with dependent, and openness with schizotypal. Haigler and Widiger demonstrated empirically years ago that this was occurring because the predominant FFM measure at that time, the NEO Personality Inventory-Revised, does not include a sufficient representation of maladaptive variants of the respective FFM personality trait domains. Research since their study has continued to fail to confirm the FFM hypotheses, using other measures of the FFM. The current study extended the work of Haigler and Widiger by considering three additional FFM measures, the Big Five Inventory-2 (BFI-2), the International Item Pool-NEO-120 (IPIP-NEO-120), and the Inventory of Personal Characteristics-5 (IPC-5). Data were obtained from a community sample of adults with experience of mental health treatment. The results confirmed an improvement in the FFM-personality disorder relationships when the experimentally manipulated versions of the BFI-2, IPIP-NEO-120, and IPC-5 were used. The implications of the findings for existing and future FFM-personality disorder research are discussed.

A Canadian National Survey of the Neurosurgical Management of Intracranial Abscesses.

OBJECTIVE: Intracerebral abscess is a life-threatening condition for which there are no current, widely accepted neurosurgical management guidelines. The purpose of this study was to investigate Canadian practice patterns for the medical and surgical management of primary, recurrent, and multiple intracerebral abscesses. METHODS: A self-administered, cross-sectional, electronic survey was distributed to active staff and resident members of the Canadian Neurosurgical Society and Canadian Neurosurgery Research Collaborative. Responses between subgroups were analyzed using the Chi-square test. RESULTS: In total, 101 respondents (57.7%) completed the survey. The majority (60.0%) were staff neurosurgeons working in an academic, adult care setting (80%). We identified a consensus that abscesses >2.5 cm in diameter should be considered for surgical intervention. The majority of respondents were in favor of excising an intracerebral abscess over performing aspiration if located superficially in non-eloquent cortex (60.4%), located in the posterior fossa (65.4%), or causing mass effect leading to herniation (75.3%). The majority of respondents were in favor of reoperation for recurrent abscesses if measuring greater than 2.5 cm, associated with progressive neurological deterioration, the index operation was an aspiration and did not include resection of the abscess capsule, and if the recurrence occurred despite prior surgery combined with maximal antibiotic therapy. There was no consensus on the use of topical intraoperative antibiotics. CONCLUSION: This survey demonstrated heterogeneity in the medical and surgical management of primary, recurrent, and multiple brain abscesses among Canadian neurosurgery attending staff and residents.

Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma.

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

Retrospective Review of the Clinical Outcomes of Surgically Managed Patients with Intracranial Abscesses: A Single-Center Review.

OBJECTIVE: This study analyzed patient, radiologic, and clinical factors associated with operative brain abscesses and patients' functional outcomes. METHODS: A retrospective analysis was conducted of neurosurgical cases of brain abscesses from 2009 to 2019 at a Canadian center. Functional outcome was recorded as Modified Rankin Scale score and Extended Glasgow Outcome Scale score. Multivariate analysis was conducted to identify relevant prognostic factors. RESULTS: We identified 139 patients managed surgically for brain abscesses. Resection alone was performed in 64% of patients, whereas 26.6% underwent aspiration alone. Most were adults (93.2%) and male (68.3%). Immunocompromise risk factors included diabetes (24.5%), cancer (23.7%), and immunosuppressive therapy (11.5%). Likely sources were postoperative (17.3%), systemic spread (16.5%), and poor dentition (12.9%). Microorganisms cultured from abscess samples were mixed growth (28%), Streptococcus anginosus (24.5%), and Staphylococcus aureus (7.9%). Disposition was home (42.4%) or repatriation to a home hospital (50.4%). By Extended Glasgow Outcome Scale, 25.2% had an unfavorable outcome including a mortality of 11.5%. Factors on multivariate analysis associated with poor outcome included diabetes (odds ratio, 2.8; 95% confidence interval [CI], 1.2-5.0) and ventricular rupture (odds ratio, 5.0; 95% CI, 1.7-13.5; hazard ratio, 12; 95% CI, 3.9-37.0). Supratentorial superficial eloquently located abscess was also associated with poor outcome (hazard ratio, 5.5; 95% CI, 1.8-16.7). Outcomes were similar with surgical excision and aspiration. CONCLUSIONS: Ventricular rupture and diabetes are significant risk factors for poor outcomes in intraparenchymal brain abscesses. No clear difference in outcomes was found between surgical excision or aspiration in our retrospective cohort.

Temporal profiling of therapy resistance in human medulloblastoma identifies novel targetable drivers of recurrence.

Medulloblastoma (MB) remains a leading cause of cancer-related mortality among children. The paucity of MB samples collected at relapse has hindered the functional understanding of molecular mechanisms driving therapy failure. New models capable of accurately recapitulating tumor progression in response to conventional therapeutic interventions are urgently needed. In this study, we developed a therapy-adapted PDX MB model that has a distinct advantage of generating human MB recurrence. The comparative gene expression analysis of MB cells collected throughout therapy led to identification of genes specifically up-regulated after therapy, including one previously undescribed in the setting of brain tumors, bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4). Subsequent functional validation resulted in a markedly diminished in vitro proliferation, self-renewal, and longevity of MB cells, translating into extended survival and reduced tumor burden in vivo. Targeting endothelial nitric oxide synthase, a downstream substrate of BPIFB4, impeded growth of several patient-derived MB lines at low nanomolar concentrations.

A systematic review of the efficacy of surgical intervention in the management of symptomatic Tarlov cysts: a meta-analysis.

Introduction: Tarlov cysts (TC) are sacral perineural cysts that are often found incidentally during spinal imaging. In a small fraction, symptomatic TC can cause pain, bowel, bladder and/or sexual dysfunction, as well as motor and sensory deficits. While many surgeons regard TCs as a non-operative entity, there have been suggestions that operative intervention in carefully selected symptomatic patients may be beneficial. The aim of this meta-analysis is to identify whether surgical treatment for symptomatic TCs is beneficial with an acceptable complication profile.Materials and methods: The authors conducted a systematic outcome analysis of symptomatic TCs treated either with surgery or conservatively managed.Results: Sixteen studies (N = 238) met the inclusion criteria for final meta-analysis. The literature search was performed using PubMed, Ovid MEDLINE, CINAHL, and EMBASE databases up to September 2017 and with an updated search in April 2019. The post-operative complication rate in patients undergoing surgical intervention was 16.9 (11.8 to 22.7) and cyst recurrence was 8.5 (3.5 to 15.4). When a complication occurred, the most frequent complication of surgical intervention was the development of a surgical site infection and/or CSF leak. Of the 15 studies reporting long-term follow-up, 81.0 (74.0-88.0) of patients remained symptom-free for more than 1 year (Mean: 27.5 months, SD = 11.5).Conclusion: We rigorously analyse the efficacy of open surgical decompression and repair of symptomatic TCs and corroborate the findings of sustained long-term resolution of symptoms.

Advances in Mechanical Thrombectomy for Acute Ischemic Stroke Due to Large Vessel Occlusion.

Acute ischemic stroke (AIS) is a significant cause of global morbidity and mortality, with functional implications for quality of life and long-term disability. The limitations of intravenous thrombolytic therapy for the treatment of AIS, especially for emergent large vessel occlusion (ELVO), have paved the way for alternative therapies and the rapidly evolving landscape of endovascular therapy (EVT). Here, we summarize the major landmark trials that have advanced the field largely due to ongoing biomedical engineering device development that have translated into significantly improved clinical outcomes. Our review describes the clinical success of EVT, and current and future trends.

Wnt activation as a therapeutic strategy in medulloblastoma.

Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB. With single cell RNA-seq technology, we demonstrate the presence of rare Wnt-active cells in non-Wnt MBs, which functionally retain the impaired tumorigenic potential of Wnt MB. In treating MB xenografts with a Wnt agonist, we provide a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MB and thereby support emerging data for a context-dependent tumor suppressive role for Wnt/ß-catenin signaling.