Effectiveness of pulpotomy in managing carious exposure in mature permanent teeth: A systematic review and meta-analysis.

OBJECTIVES: This quantitative systematic review evaluated whether pulpotomy performed with hydraulic calcium silicate cements may be used as an alternative to root canal treatment (RCT) in mature permanent teeth with carious pulp exposure. DATA SOURCES: A comprehensive search was conducted in PubMed, Web of Science, Scopus, and the Cochrane Library. No language restrictions were applied. The search included randomised controlled trials that compared pulpotomy to root canal treatment for managing carious exposure in mature permanent teeth. STUDY SELECTION: Studies were selected based on predetermined inclusion criteria: randomised controlled trials involving mature permanent teeth with carious pulp exposure, using hydraulic calcium silicate cements for pulpotomy. Non-comparative studies, case reports, and trials involving primary or immature permanent teeth were excluded. DATA: Data were extracted on success rates, clinical outcomes, follow-up periods, pain profiles, and potential complications. A meta-analysis was performed, revealing no statistically significant differences in success rates between pulpotomy and RCT. Both interventions demonstrated success rates exceeding 90 % at one-year and two-year follow-up periods. Pain profiles consistently showed lower post-operative pain intensity in the pulpotomy group compared to the RCT group during the first week. Potential complications, such as non-responsive pulp and difficulties in determining pulp vitality, were reported more frequently in the pulpotomy group. CONCLUSIONS: Pulpotomy with bioactive hydraulic calcium silicate cements shows comparable success rates to RCT in managing carious pulp exposure in mature permanent teeth. The results suggest pulpotomy as a viable, less invasive alternative to RCT, particularly in cases where preservation of pulp vitality is paramount. CLINICAL SIGNIFICANCE: This systematic review highlights pulpotomy as a less invasive and cost-effective alternative to root canal treatment in mature permanent teeth. With comparable success rates and lower post-operative pain, pulpotomy offers a promising approach to managing carious exposure and preserving tooth vitality.

Three-dimensional imaging in craniofacial surgery: utilization of a novel 3D mobile application to evaluate the surgical outcomes of a skull recontouring procedure for cephalohematoma.

OBJECTIVE: Cranial abnormalities are common birth defects that frequently alter skull shape and appearance. Despite their prevalence, objective quantification of defect severity pre- and posttreatment is limited. The authors evaluated the ability of MirrorMe3D, a novel 3D mobile iPhone application, to measure changes in the contour of the skull for patients undergoing contouring of a calcified cephalohematoma. METHODS: The heads of two 20-month-old patients with disfiguring right parietal cephalohematomas undergoing a skull recontouring operation were scanned pre- and postsurgery. Four scans of the cranial abnormality were taken throughout the procedure and intraoperative 3D models were generated. Models of the head were overlapped pre- and postsurgery and compared using a depth analyzer built into MirrorMe3D. RESULTS: Depth analysis revealed 6.0-mm and 9.9-mm differences for patients 1 and 2, respectively. Volume analysis revealed 33-cm3 and 85-cm3 differences for patients 1 and 2, respectively. Currently, no standard for quantitative measurement of the surgical outcomes of a skull reconstruction procedure exists. CONCLUSIONS: MirrorMe3D provides an efficient method for monitoring patients with simple topographic scans that create accurate models of the head. The authors show the app's ability to capture the severity of a calcified cephalohematoma and quantify the changes in the contour of the skull before and after surgery.

Clinical Features and Management of Skull Base Fractures in the Pediatric Population: A Systematic Review.

Pediatric basilar skull fractures (BSFs) are a rare type of traumatic head injury that can cause debilitating complications without prompt treatment. Here, we sought to review the literature and characterize the clinical features, management, and outcomes of pediatric BSFs. We identified 21 relevant studies, excluding reviews, meta-analyses, and non-English articles. The incidence of pediatric BSFs ranged from 0.0001% to 7.3%, with falls from multi-level heights and traffic accidents being the primary causes (9/21). The median presentation age ranged from 3.2 to 12.8 years, and the mean age of patients across all studies was 8.68 years. Up to 55% of pediatric BSFs presented with intracranial hematoma/hemorrhage, along with pneumocephalus and edema. Cranial nerve palsies were a common complication (9/21), with the facial nerve injured most frequently (7/21). While delayed cranial nerve palsy was reported in a few studies (4/21), most resolved within three months post-admission. Other complications included CSF leaks (10/21) and meningitis (4/21). Management included IV fluids, antiemetics, and surgery (8/21) to treat the fracture directly, address a CSF leak, or achieve cranial nerve compression. Despite their rarity, pediatric skull base fractures are associated with clinical complications, including CSF leaks and cranial nerve palsies. Given that some of these complications may be delayed, patient education is critical.

Nuanced Management of a Skull Base Tumor in the Setting of Relapsed Acute Lymphoblastic Leukemia.

Introduction Relapsed acute lymphoblastic leukemia (ALL) involving the central nervous system (CNS) is a significant issue that contributes to both morbidity and mortality. Given the poor outcomes in patients with CNS relapse, understanding how ALL involving intracranial relapse presents and is treated is critical. Here, we present a complex case of relapsed recurrent ALL in a pediatric patient. Case Report An 11-year-old patient presented with double relapse of ALL in the form of an extensive skull base lesion and again with leptomeningeal disease. For the skull base lesion, she was treated nonsurgically with chemotherapy and radiation, which led to a remarkable reduction in the size of the lesion. However, she was found to have early recurrence with leptomeningeal enhancement resulting in hydrocephalus 5 months after completing therapy. A shunt was placed successfully. Currently, she is being managed with monthly intrathecal chemotherapy with cerebrospinal fluid sampling and bone marrow biopsies every 2 months. Discussion We report the significant effect of chemotherapy and radiotherapy in reducing the size of the extensive skull base lesion, saving the patient from the risks associated with surgery. This patient's initial relapse, with a large skull base lesion that had intracranial involvement, is an unusual presentation of relapsed ALL. The additional early recurrence of leptomeningeal disease further makes this case unique and the management even more nuanced. Here, we demonstrate a multidisciplinary approach for the successful treatment of our patient, which can help guide the management of similar patients in the future.

CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy.

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

A Case Report of Infant-Type Hemispheric Glioma with a Novel GAB1-ABL2 Kinase Fusion Treated with Dasatinib.

INTRODUCTION: Infant-type hemispheric glioma (IHG) is a rare form of cancer that affects newborns and infants. It is classified as a pediatric-type high-grade glioma and typically harbors receptor tyrosine kinase (RTK) gene fusions. Here, we present the finding of a novel gene fusion IHG treated with a targeted therapy that has yet to be implemented for any other IHG case to date. CASE PRESENTATION: We report the case of a 12-month-old boy with IHG who presented with obstructive hydrocephalus due to a large mass in the right frontal lobe. The patient initially underwent mass resection, but subsequent imaging showed rapid interval progression of the residual tumor. Comprehensive molecular analysis of the tumor tissue revealed a novel GAB1-ABL2 gene fusion, and the patient was started on dasatinib, an ABL kinase inhibitor. Shortly after initiation of dasatinib treatment, there was a significant reduction in tumor size and enhancement, followed by stabilization of disease. DISCUSSION: The patient's robust response to treatment suggests that dasatinib is an effective targeted therapy for IHG harboring a GAB1-ABL2 gene fusion. This finding may inform future investigations into the disease processes of IHG and help guide the diagnosis and treatment of IHG in the absence of previously identified gene fusions, improving clinical management of this vulnerable patient population.

Flow-field inference from neural data using deep recurrent networks.

Computations involved in processes such as decision-making, working memory, and motor control are thought to emerge from the dynamics governing the collective activity of neurons in large populations. But the estimation of these dynamics remains a significant challenge. Here we introduce Flow-field Inference from Neural Data using deep Recurrent networks (FINDR), an unsupervised deep learning method that can infer low-dimensional nonlinear stochastic dynamics underlying neural population activity. Using population spike train data from frontal brain regions of rats performing an auditory decision-making task, we demonstrate that FINDR outperforms existing methods in capturing the heterogeneous responses of individual neurons. We further show that FINDR can discover interpretable low-dimensional dynamics when it is trained to disentangle task-relevant and irrelevant components of the neural population activity. Importantly, the low-dimensional nature of the learned dynamics allows for explicit visualization of flow fields and attractor structures. We suggest FINDR as a powerful method for revealing the low-dimensional task-relevant dynamics of neural populations and their associated computations.

Case Report: Treatment of the rare B-cell lymphoblastic lymphoma with scalp lesion using rotation flap.

Introduction: Leukemia is the most frequently occurring cancer in children, and lymphoblastic lymphoma (LBL) is a rare subtype. LBL are lymphoid neoplasms of B or T cell origin and are primarily treated with chemotherapy. Although cure rates among children are excellent, these patients must be monitored for relapse. Cutaneous lesions involving B-cell LBL (B-LBL) are extremely rare and here we present a patient with a worsening B-LBL scalp mass who required radical surgical excision. Case report: A 6-year-old female patient with a history of a nontender scalp mass discovered at approximately 2-3 years of age was evaluated for resection of the nodule due to its size and treatment history. The patient was originally diagnosed with follicular lymphoma by punch biopsy; excision was successfully performed on this 4 cm lesion and upon examination of the skin biopsy did we get a diagnosis of B-LBL. Reconstruction of the scalp was done through the rotation flap method. The patient's scalp healed well, and adjuvant chemotherapy was continued. There has been no reoccurrence. Discussion: Here we report the rarity of B-LBL cases involving extranodal involvement in the scalp. The most common reconstruction of scalp lesions has been using free flap from the anterolateral thigh (ALT) and latissimus dorsi (LD). Our case used the rotation flap, which has its functional and cosmetic benefits. The importance of monitoring this patient is emphasized due to the dangerous consequences of B-LBL relapse. Ultimately, our successful treatment and care of this rare case can be used as guidance for similar patients in the future.

Transitions in dynamical regime and neural mode underlie perceptual decision-making.

Perceptual decision-making is the process by which an animal uses sensory stimuli to choose an action or mental proposition. This process is thought to be mediated by neurons organized as attractor networks 1,2 . However, whether attractor dynamics underlie decision behavior and the complex neuronal responses remains unclear. Here we use an unsupervised, deep learning-based method to discover decision-related dynamics from the simultaneous activity of neurons in frontal cortex and striatum of rats while they accumulate pulsatile auditory evidence. We show that contrary to prevailing hypotheses, attractors play a role only after a transition from a regime in the dynamics that is strongly driven by inputs to one dominated by the intrinsic dynamics. The initial regime mediates evidence accumulation, and the subsequent intrinsic-dominant regime subserves decision commitment. This regime transition is coupled to a rapid reorganization in the representation of the decision process in the neural population (a change in the "neural mode" along which the process develops). A simplified model approximating the coupled transition in the dynamics and neural mode allows inferring, from each trial's neural activity, the internal decision commitment time in that trial, and captures diverse and complex single-neuron temporal profiles, such as ramping and stepping 3-5 . It also captures trial-averaged curved trajectories 6-8 , and reveals distinctions between brain regions. Our results show that the formation of a perceptual choice involves a rapid, coordinated transition in both the dynamical regime and the neural mode of the decision process, and suggest pairing deep learning and parsimonious models as a promising approach for understanding complex data.

AxonQuantifier: A semi-automated program for quantifying axonal density from whole-mounted optic nerves.

BACKGROUND: Here, we present a semi-automated method for quantifying retinal ganglion cell (RGC) axon density at different distances from the optic nerve crush site using longitudinal, confocal microscopy images taken from whole-mounted optic nerves. This method employs the algorithm AxonQuantifier which operates on the freely available program, ImageJ. NEW METHOD: To validate this method, seven adult male Long Evans rats underwent optic nerve crush injury followed by in vivo treatment with electric fields of varying strengths for 30 days to produce optic nerves with a wide range of axon densities distal to the optic nerve crush site. Prior to euthanasia, RGC axons were labelled with intravitreal injections of cholera toxin B conjugated to Alexa Fluor 647. After dissection, optic nerves underwent tissue clearing, were whole-mounted, and imaged longitudinally using confocal microscopy. COMPARISON WITH EXISTING METHODS: Five masked raters quantified RGC axon density at 250, 500, 750, 1000, 1250, 1500, 1750, and 2000 µm distances past the optic nerve crush site for the seven optic nerves manually and using AxonQuantifier. Agreement between these methods was assessed using Bland-Altman plots and linear regression. Inter-rater agreement was assessed using the intra-class coefficient. RESULTS: Semi-automated quantification of RGC axon density demonstrated improved inter-rater agreement and reduced bias values as compared to manual quantification, while also increasing time efficiency 4-fold. Relative to manual quantification, AxonQuantifier tended to underestimate axon density. CONCLUSIONS: AxonQuantifier is a reliable and efficient method for quantifying axon density from whole mount optic nerves.

Care coordination across healthcare systems: development of a research agenda, implications for practice, and recommendations for policy based on a modified Delphi panel.

OBJECTIVE: For large, integrated healthcare delivery systems, coordinating patient care across delivery systems with providers external to the system presents challenges. We explored the domains and requirements for care coordination by professionals across healthcare systems and developed an agenda for research, practice and policy. DESIGN: The modified Delphi approach convened a 2-day stakeholder panel with moderated virtual discussions, preceded and followed by online surveys. SETTING: The work addresses care coordination across healthcare systems. We introduced common care scenarios and differentiated recommendations for a large (main) healthcare organisation and external healthcare professionals that contribute additional care. PARTICIPANTS: The panel composition included health service providers, decision makers, patients and care community, and researchers. Discussions were informed by a rapid review of tested approaches to fostering collaboration, facilitating care coordination and improving communication across healthcare systems. OUTCOME MEASURES: The study planned to formulate a research agenda, implications for practice and recommendations for policy. RESULTS: For research recommendations, we found consensus for developing measures of shared care, exploring healthcare professionals' needs in different care scenarios and evaluating patient experiences. Agreed practice recommendations included educating external professionals about issues specific to the patients in the main healthcare system, educating professionals within the main healthcare system about the roles and responsibilities of all involved parties, and helping patients better understand the pros and cons of within-system and out-of-system care. Policy recommendations included supporting time for professionals with high overlap in patients to engage regularly and sustaining support for care coordination for high-need patients. CONCLUSIONS: Recommendations from the stakeholder panel created an agenda to foster further research, practice and policy innovations in cross-system care coordination.

Internal neurolysis versus intraoperative glycerin rhizotomy for trigeminal neuralgia.

OBJECTIVE: Internal neurolysis (IN) and intraoperative glycerin rhizotomy (ioGR) are emerging surgical options for patients with trigeminal neuralgia without neurovascular contact. The objective of this study was to compare the neurological outcomes of patients who underwent IN with those of patients who underwent ioGR. METHODS: The authors retrospectively reviewed all patients who underwent IN or ioGR for trigeminal neuralgia at our institution. Patient demographic characteristics and immediate postoperative outcomes, as well as long-term neurological outcomes, were compared. RESULTS: Of 1044 patients who underwent open surgical treatment for trigeminal neuralgia, 56 patients underwent IN and 91 underwent ioGR. Of these 147 patients, 37 had no evidence of intraoperative neurovascular conflict. All patients who underwent IN and 96.7% of patients who underwent ioGR had immediate postoperative pain relief. At last follow-up, patients who underwent IN had lower Barrow Neurological Institute (BNI) pain intensity scores (p = 0.05), better BNI facial numbness scores (p < 0.01), and a greater degree of pain improvement (p = 0.05) compared with those who underwent ioGR. Patients who underwent IN also had significantly lower rates of symptomatic pain recurrence (p < 0.01) at last follow-up over an average of 9.5 months. CONCLUSIONS: IN appears to provide patients with a greater degree of pain relief, lower rates of facial numbness, and lower rates of pain recurrence compared with ioGR. Future prospective studies will better characterize long-term pain recurrence and outcomes.

A Potential Role for Steroids in Acute Pain Management in Patients with Trigeminal Neuralgia.

OBJECTIVE: Effective therapies for acute pain management in trigeminal neuralgia (TN) are limited. We aimed to investigate the role of steroids in TN patients experiencing acute pain flares. METHODS: We retrospectively reviewed patients presenting to the emergency department of a tertiary care institution between 2014 and 2020 for acute TN pain flares. Patients were divided into those who received steroids versus those who did not. Presenting characteristics, admission and surgical intervention rates, Barrow Neurological Institute pain scores, pain recurrence rates, and surgical intervention within 6 months of discharge were obtained for each patient. RESULTS: Our cohort comprised 151 patients, of whom 40 (26.5%) received steroids before admission and/or discharge. These patients were less likely to undergo surgical intervention to treat acute pain (P = 0.023). Specifically, patients receiving steroids were less likely to undergo combined glycerin and radiofrequency rhizotomy compared with patients not receiving steroids (P = 0.012). Frequency and dosage of opioid administration did not differ between groups. The steroids group demonstrated a lower average Barrow Neurological Institute pain score on discharge compared with the no steroids group (P = 0.013). Patients receiving steroids for acute pain management were less likely to undergo surgical intervention within 6 months of discharge than patients who did not receive steroids (P = 0.033). CONCLUSIONS: Steroid administration in patients with acute TN pain flares may reduce the likelihood of surgical intervention both during admission and within 6 months of discharge. Future prospective studies should examine the efficacy of steroids as an adjunctive medication in acute TN pain management.

Multimodal interventions to optimize spinal cord perfusion in patients with acute traumatic spinal cord injuries: a systematic review.

OBJECTIVE: The authors systematically reviewed current evidence for the utility of mean arterial pressure (MAP), intraspinal pressure (ISP), and spinal cord perfusion pressure (SCPP) as predictors of outcomes after traumatic spinal cord injury (SCI). METHODS: PubMed, Cochrane Reviews Library, EMBASE, and Scopus databases were queried in December 2020. Two independent reviewers screened articles using Covidence software. Disagreements were resolved by a third reviewer. The inclusion criteria for articles were 1) available in English; 2) full text; 3) clinical studies on traumatic SCI interventions; 4) involved only human participants; and 5) focused on MAP, ISP, or SCPP. Exclusion criteria were 1) only available in non-English languages; 2) focused only on the brain; 3) described spinal diseases other than SCI; 4) interventions altering parameters other than MAP, ISP, or SCPP; and 5) animal studies. Studies were analyzed qualitatively and grouped into two categories: interventions increasing MAP or interventions decreasing ISP. The Scottish Intercollegiate Guidelines Network level of evidence was used to assess bias and the Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate confidence in the anticipated effects of each outcome. RESULTS: A total of 2540 unique articles were identified, of which 72 proceeded to full-text review and 24 were included in analysis. One additional study was included retrospectively. Articles that went through full-text review were excluded if they were a review paper (n = 12), not a full article (n = 12), a duplicate paper (n = 9), not a human study (n = 3), not in English (n = 3), not pertaining to traumatic SCI (n = 3), an improper intervention (n = 3), without intervention (n = 2), and without analysis of intervention (n = 1). Although maintaining optimal MAP levels is the current recommendation for SCI management, the published literature supports maintenance of SCPP as a stronger indicator of favorable outcomes. Studies also suggest that laminectomy and durotomy may provide better outcomes than laminectomy alone, although higher-level studies are needed. Current evidence is inconclusive on the effectiveness of CSF drainage for reducing ISP. CONCLUSIONS: This review demonstrates the importance of assessing how different interventions may vary in their ability to optimize SCPP.

Safety and Cost Savings Associated with Reduced Inpatient Hospitalization for Microvascular Decompression.

OBJECTIVES: Microvascular decompression (MVD) has grown as a first-line surgical intervention for severe facial pain from trigeminal neuralgia and/or hemifacial spasm. We sought to examine the safety and cost-benefits of discharging patients with MVD within 1 day of admission. METHODS: We retrospectively reviewed patients undergoing MVD at our institution from 2008 to 2020. Patients were sorted by 1 day, 2 days, or >2 days until discharge and by year from 2008 to 2013, 2014 to 2018, or 2019 to 2020. Patient presenting characteristics, intraoperative measures, and complications were documented. Statistical differences were calculated by one-way analysis of variance and χ2 analyses. RESULTS: Our cohort included 976 patients undergoing MVD, with 231 (23.6%) between 2008 and 2013, 517 (52.9%) between 2014 and 2018, and 228 (23.3%) between 2019 and 2020. Over time, postoperative admission rates to the critical care unit, total inpatient hospital admission times, and Barrow Neurological Institute scores at first follow-up decreased. Postoperative complications, including cerebrospinal fluid leak, decreased significantly. In addition, patients discharged within 1 day of admission incurred a total hospital cost of $26,689, which was $3588 lower than patients discharged within more than 1 day of admission, P < 0.0001. Discharging carefully selected patients who are appropriate for discharge within 1 day of admission could translate to a potential cost-savings of $255,346 per year in our clinical practice. CONCLUSIONS: In our experience, MVDs are a safe, elective intervention. Our findings suggest that postoperative day 1 discharge in patients with an uncomplicated postoperative course may be safe while improving hospital resource use.

Advances in monitoring for acute spinal cord injury: a narrative review of current literature.

Spinal cord injury (SCI) is a devastating condition that affects about 17,000 individuals every year in the United States, with approximately 294,000 people living with the ramifications of the initial injury. After the initial primary injury, SCI has a secondary phase during which the spinal cord sustains further injury due to ischemia, excitotoxicity, immune-mediated damage, mitochondrial dysfunction, apoptosis, and oxidative stress. The multifaceted injury progression process requires a sophisticated injury-monitoring technique for an accurate assessment of SCI patients. In this narrative review, we discuss SCI monitoring modalities, including pressure probes and catheters, micro dialysis, electrophysiologic measures, biomarkers, and imaging studies. The optimal next-generation injury monitoring setup should include multiple modalities and should integrate the data to produce a final simplified assessment of the injury and determine markers of intervention to improve patient outcomes.

Rhomboencephalosynapsis: Review of the Literature.

Rhombencephalosynapsis is a rare congenital anomaly, characterized by partial or total agenesis of the cerebellar vermis with midline fusion of the cerebellar hemispheres, dentate nuclei, and the superior cerebellar peduncles, creating the distinctive keyhole appearance of the fourth ventricle. Rhombencephalosynapsis can be isolated or can occur in association with other congenital anomalies and syndromes such as Gómez-López-Hernández syndrome (GLHS) or VACTERL: vertebral anomalies (V), anal atresia (A), cardiovascular defects (C), esophageal atresia and/or tracheoesophageal fistula (TE), and renal (R) and limb/radial (L) anomalies. Recent advances in prenatal imaging have resulted in an increasing rate of prenatal diagnosis of abnormalities of the posterior fossa including rhombencephalosynapsis. Patients with rhombencephalosynapsis may present with motor developmental delay, ataxia, swallowing difficulties, muscular hypotonia, spastic quadriparesis, abnormal eye movements, and a characteristic "figure-of-eight" head shaking. Cognitive outcome varies from severe intellectual disability to normal intellectual function. Rhombencephalosynapsis with VACTERL is often associated with severe cognitive disabilities, whereas patients with GLHS may have better cognitive function. The most common associated findings with rhombencephalosynapsis include hydrocephalus, mesencephalosynapsis, holoprosencephaly, pontocerebellar hypoplasia, corpus callosum dysgenesis, and absence of septum pellucidum. Patients can be categorized into 4 groups: 1) rhombencephalosynapsis associated with GLHS; 2) rhombencephalosynapsis with VACTERL; 3) rhombencephalosynapsis with atypical holoprosencephaly, and 4) isolated rhomboencephalosynapsis. The etiology of rhombencephalosynapsis is unknown. Here, we discuss several hypotheses about its etiology.

Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma.

OBJECTIVE: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM. METHODS: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry. RESULTS: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05). CONCLUSIONS: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Emerging Technologies for Non-invasive Monitoring of Treatment Response to Immunotherapy for Brain Tumors.

Glioblastoma is the most common primary malignant brain tumor and one of the most aggressive tumors across all cancer types with remarkable resistance to any treatment. While immunotherapy has shown a robust clinical benefit in systemic cancers, its benefit is still under investigation in brain cancers. The broader use of immunotherapy in clinical trials for glioblastoma has highlighted the challenges of traditional methods of monitoring progression via imaging. Development of new guidelines, advanced imaging techniques, and immune profiling have emerged to counter premature diagnoses of progressive disease. However, these approaches do not provide a timely diagnosis and are costly and time consuming. Surgery is currently the standard of care for diagnosis of pseudoprogression in cases where MRI is equivocal. However, it is invasive, risky, and disruptive to patient's lives and their oncological treatment. With its increased vascularity, glioblastoma is continually shedding tumor components into the vasculature including tumor cells, genetic material, and extracellular vesicles. These elements can be isolated from routine blood draws and provide a real-time non-invasive indicator of tumor progression. Liquid biopsy therefore presents as an attractive alternative to current methods to guide treatment. While the initial evaluation of liquid biopsy for brain tumors via identification of mutations in the plasma was disappointing, novel technologies and use of alternatives to plasma cell-free DNA analytes provide promise for an effective liquid biopsy approach in brain tumors. This review aims to summarize developments in the use of liquid biopsy to monitor glioblastoma, especially in the context of immunotherapy.

Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma.

Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan-Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone (P = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ (P < .0001) and CD8+ IFN-γ (P = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain (P = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy.