Management of moyamoya disease: a review of current and future therapeutic strategies.

Moyamoya disease (MMD) is characterized by idiopathic, progressive stenosis of the circle of Willis and the terminal portion of the internal carotid arteries with the development of prominent small collateral vessels and a characteristic moyamoya or puff-of-smoke radiographic appearance. The incidence and prevalence of MMD varies by region, age, and sex, with higher rates in Asian and East Asian populations compared to North American or European populations. There is a bimodal distribution of patients diagnosed with MMD. Pediatric patients are more commonly diagnosed within the 1st decade of life, whereas adult patients present in the 5th or 6th decade of life. Overall, there is a nearly 2:1 female-to-male ratio. Ischemic symptoms are the most common presentation in pediatric and adult populations, but adult patients are nearly twice as likely to present with intracranial hemorrhage compared to their pediatric counterparts. Surgical revascularization is indicated in symptomatic cases, and antiplatelet therapy may be a useful adjunct to prevent recurrent symptoms. Direct and combined bypass procedures seem to be more effective in adults, whereas children respond well to indirect bypass. The identification of key genetic, molecular, and environmental factors including RNF213 and GUCY1A3 loss-of-function mutations, angiogenic growth factors, autoantibodies, CNS infections, and radiation exposure suggest multiple pathways for the development of moyamoya arteriopathy. Further research is needed to better understand the heterogeneity of pathogenetic mechanisms that lead to moyamoya and to identify novel therapeutic targets to prevent, stabilize, and treat MMD.

Endovascular Applications for the Management of High-Grade Gliomas in the Modern Era.

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood-brain barrier (BBB) penetration, hemodynamic complexities, and drug-tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.

Incidence and Risk Model of Post-Traumatic Hydrocephalus in Patients with Traumatic Brain Injury.

OBJECTIVE: Post-traumatic hydrocephalus (PTH) is a complication following traumatic brain injury (TBI). Early diagnosis and treatment are essential to improving outcomes. We report the incidence and risk factors of PTH in a large TBI population while considering death as a competing risk. METHODS: We conducted a retrospective cohort study on consecutive TBI patients with radiographic intracranial abnormalities admitted to our academic medical center from 2009 to 2015. We assessed patient demographics, perioperative data, and in-hospital data as risk factors for PTH using survival analysis with death as a competing risk. RESULTS: Among 7,473 patients, the overall incidence of PTH requiring shunt surgery was 0.94%. The adjusted cumulative incidence was 0.99%. The all-cause cumulative hazard for death was 32.6%, which was considered a competing risk during analysis. Craniectomy (HR 11.53, P < 0.001, 95% CI 5.57-223.85), venous sinus injury (HR 4.13, P = 0.01, 95% CI 1.53-11.16), and age ≤5 (P < 0.001) were significant risk factors for PTH. Glasgow Coma Score (GCS) > 13 was protective against shunt placement (HR 0.50, P = 0.04, 95% CI 0.26-0.97). Shunt surgery occurred after hospital discharge in 60% of patients. CONCLUSIONS: We describe the incidence and risk factors for PTH in a large traumatic brain injury (TBI) population. Most cases of PTH were diagnosed after hospital discharge, suggesting that close follow-up and multidisciplinary diagnostic vigilance for PTH are needed to prevent morbidity and disability.

Deep Brain Stimulation of Bilateral Centromedian Thalamic Nuclei in Pediatric Patients with Lennox-Gastaut Syndrome: An Institutional Experience.

BACKGROUND: Surgical management of pediatric patients with nonlesional, drug-resistant epilepsy, including patients with Lennox-Gastaut syndrome (LGS), remains a challenge given the lack of resective targets in most patients and shows seizure freedom rates <50% at 5 years. The efficacy of deep brain stimulation (DBS) is less certain in children than in adults. This study examined clinical and seizure outcomes for pediatric patients with LGS undergoing DBS targeting of the centromedian thalamic nuclei (CMTN). METHODS: An institutional review board-approved retrospective analysis was performed of patients aged ≤19 years with clinical diagnosis of LGS undergoing bilateral DBS placement to the CMTN from 2020 to 2021 by a single surgeon. RESULTS: Four females and 2 males aged 6-19 years were identified. Before surgery, each child experienced at least 6 years of refractory seizures; 4 children had experienced seizures since infancy. All took antiseizure medications at the time of surgery. Five children had previous placement of a vagus nerve stimulator and 2 had a previous corpus callosotomy. The mean length of stay after DBS was 2 days. No children experienced adverse neurologic effects from implantation; the mean follow-up time was 16.3 months. Four patients had >60% reduction in seizure frequency after surgery, 1 patient experienced 10% reduction, and 1 patient showed no change. No children reported worsening seizure symptoms after surgery. CONCLUSIONS: Our study contributes to the sparse literature describing CMTN DBS for children with drug-resistant epilepsy from LGS. Our results suggest that CMTN DBS is a safe and effective therapeutic modality that should be considered as an alternative or adjuvant therapy for this challenging patient population. Further studies with larger patient populations are warranted.

A single-cell based precision medicine approach using glioblastoma patient-specific models.

Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multi-omic single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multi-omic data with single-cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that modulate cell state transitions across subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches to an individual patient in a concurrent, adjuvant, or recurrent setting.

Impact of surgeon rhBMP-2 cost awareness on complication rates and health system costs for spinal arthrodesis.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used in spinal arthrodesis procedures to enhance bony fusion. Research has suggested that it is the most cost-effective fusion enhancer, but there are significant upfront costs for the healthcare system. The primary objective of this study was to determine whether intraoperative dosing and corresponding costs changed with surgeon cost awareness. The secondary objective was to describe surgical complications before and after surgeon awareness of rhBMP-2 cost. METHODS: A retrospective medical record review was conducted to identify patients who underwent spinal arthrodesis procedures performed by a single surgeon, supplemented with rhBMP-2, from June 2016 to June 2018. Collected data included rhBMP-2 dosage, rhBMP-2 list price, and surgical complications. Expected Medicare reimbursement was calculated. Data were analyzed before and after surgeon awareness of rhBMP-2 cost. RESULTS: Forty-eight procedures were performed using rhBMP-2, 16 before and 32 after surgeon cost awareness. Prior to cost awareness, the most frequent rhBMP-2 dosage level was x-small (38.9%, n = 7), followed by large (27.8%, n = 5) and small (22.2%, n = 4). After cost awareness, the most frequent rhBMP-2 dosage was xx-small (56.8%, n = 21), followed by x-small (21.6%, n = 8) and large (13.5%, n = 5). The rhBMP-2 average cost per surgery was $4116.56 prior to surgeon cost awareness versus $2268.38 after. Two complications were observed in the pre-cost awareness surgical group; 2 complications were observed in the post-cost awareness surgical group. CONCLUSIONS: Surgeon awareness of rhBMP-2 cost resulted in use of smaller rhBMP-2 doses, decreased rhBMP-2 cost per surgery, and decreased overall hospital admission charges, without a detectable increase in surgical complications.

Cellular allograft for multilevel stand-alone anterior cervical discectomy and fusion.

OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is the most common treatment for degenerative disease of the cervical spine. Given the high rate of pseudarthrosis in multilevel stand-alone ACDF, there is a need to explore the utility of novel grafting materials. In this study, the authors present a single-institution retrospective study of patients with multilevel degenerative spine disease who underwent multilevel stand-alone ACDF surgery with or without cellular allograft supplementation. METHODS: In a prospectively collected database, 28 patients who underwent multilevel ACDF supplemented with cellular allograft (ViviGen) and 25 patients who underwent multilevel ACDF with decellularized allograft between 2014 and 2020 were identified. The primary outcome was radiographic fusion determined by a 1-year follow-up CT scan. Secondary outcomes included change in Neck Disability Index (NDI) scores and change in visual analog scale scores for neck and arm pain. RESULTS: The study included 53 patients with a mean age of 53 ± 0.7 years who underwent multilevel stand-alone ACDF encompassing 2.6 ± 0.7 levels on average. Patient demographics were similar between the two cohorts. In the cellular allograft cohort, 2 patients experienced postoperative dysphagia that resolved by the 3-month follow-up. One patient developed cervical radiculopathy due to graft subsidence and required a posterior foraminotomy. At the 1-year CT, successful fusion was achieved in 92.9% (26/28) of patients who underwent ACDF supplemented with cellular allograft, compared with 84.0% (21/25) of patients who underwent ACDF without cellular allograft. The cellular allograft cohort experienced a significantly greater improvement in the mean postoperative NDI score (p < 0.05) compared with the other cohort. CONCLUSIONS: Cellular allograft is a low-morbidity bone allograft option for ACDF. In this study, the authors determined favorable arthrodesis rates and functional outcomes in a complex patient cohort following multilevel stand-alone ACDF supplemented with cellular allograft.

The Kempe incision for decompressive craniectomy, craniotomy, and cranioplasty in traumatic brain injury and stroke.

OBJECTIVE: Decompressive craniectomy (DC) is an effective, lifesaving option for reducing intracranial pressure (ICP) in traumatic brain injury (TBI), stroke, and other pathologies with elevated ICP. Most DCs are performed via a standard trauma flap shaped like a reverse question mark (RQM), which requires sacrificing the occipital and posterior auricular arteries and can be complicated by wound dehiscence and infections. The Ludwig Kempe hemispherectomy incision (Kempe) entails a T-shaped incision, one limb from the midline behind the hairline to the inion and the other limb from the root of the zygoma to the coronal suture. The authors' objective in this study was to define their implementation of the Kempe incision for DC and craniotomy, report clinical outcomes, and quantify the volume of bone removed compared with the RQM incision. METHODS: A retrospective review of a single-surgeon experience with DC in TBI and stroke was performed. Patient demographics, imaging, and outcomes were collected for all DCs from 2015 to 2020, and the incisions were categorized as either Kempe or RQM. Preoperative and postoperative CT scans were obtained and processed using a combination of automatic segmentation (in Python and SimpleITK) with manual cleanup and further subselection in ITK-SNAP. The volume of bone removed was quantified, and the primary outcome was percentage of hemicranium removed. Postoperative surgical wound infections, estimated blood loss (EBL), and length of surgery were compared between the two groups as secondary outcomes. Cranioplasty data were collected. RESULTS: One hundred thirty-six patients were included in the analysis; there were 57 patients in the craniotomy group (44 patients with RQM incisions and 13 with Kempe incisions) and 79 in the craniectomy group (41 patients with RQM incisions and 38 Kempe incisions). The mean follow-up for the entire cohort was 251 ± 368 days. There was a difference in the amount of decompression between approaches in multivariate modeling (39% ± 11% of the hemicranium was removed via the Kempe incision vs 34% ± 10% via the RQM incision, p = 0.047), although this did not achieve significance in multivariate modeling. Wound infection rates, EBL, and length of surgery were comparable between the two incision types. No wound infections in either cohort were due to wound dehiscence. Cranioplasty outcomes were comparable between the two incision types. CONCLUSIONS: The Kempe incision for craniectomy or craniotomy is a safe, feasible, and effective alternative to the RQM. The authors advocate the Kempe incision in cases in which contralateral operative pathology or subsequent craniofacial/skull base repair is anticipated.

Single-cell CUT&Tag analysis of chromatin modifications in differentiation and tumor progression.

Methods for quantifying gene expression1 and chromatin accessibility2 in single cells are well established, but single-cell analysis of chromatin regions with specific histone modifications has been technically challenging. In this study, we adapted the CUT&Tag method3 to scalable nanowell and droplet-based single-cell platforms to profile chromatin landscapes in single cells (scCUT&Tag) from complex tissues and during the differentiation of human embryonic stem cells. We focused on profiling polycomb group (PcG) silenced regions marked by histone H3 Lys27 trimethylation (H3K27me3) in single cells as an orthogonal approach to chromatin accessibility for identifying cell states. We show that scCUT&Tag profiling of H3K27me3 distinguishes cell types in human blood and allows the generation of cell-type-specific PcG landscapes from heterogeneous tissues. Furthermore, we used scCUT&Tag to profile H3K27me3 in a patient with a brain tumor before and after treatment, identifying cell types in the tumor microenvironment and heterogeneity in PcG activity in the primary sample and after treatment.

Endoscopic Spine Surgery in Athletes: Case Series and Review of Literature.

BACKGROUND: Degenerative spine disease is common in athletes and can progress to requiring surgical intervention. Traditional open surgical techniques necessitate prolonged recovery time and time away from play. Newly developed endoscopic surgical techniques may promote faster healing and recovery, and increased return to play. The goal of this paper is to summarize the current evidence in return to play after spine surgery and to present our series of 3 athletes who underwent endoscopic spine surgery. METHODS: A complete search of all PubMed indexed articles pertaining to spine surgery in athletes was conducted. This was supplemented by a 3-patient case series of our own endoscopic spine experience in athletes. RESULTS: There are no current widely accepted guidelines for return to play after spinal surgery. The best evidence available cites a return to play of 81% at 5.2-8.7 months after traditional open and minimally invasive surgery, and endoscopic surgery produces an average 88% return to play rate at 3 months. CONCLUSIONS: Although return to play can vary widely, case-based evidence as well as biomechanical principles support endoscopic spine surgery as a viable surgical modality for the treatment of spinal pathologies in athletes.

Pediatric functional hemispherectomy: operative techniques and complication avoidance.

Functional hemispherectomy/hemispherotomy is a disconnection procedure for severe medically refractory epilepsy where the seizure foci diffusely localize to one hemisphere. It is an improvement on anatomical hemispherectomy and was first performed by Rasmussen in 1974. Less invasive surgical approaches and refinements have been made to improve seizure freedom and minimize surgical morbidity and complications. Key anatomical structures that are disconnected include the 1) internal capsule and corona radiata, 2) mesial temporal structures, 3) insula, 4) corpus callosum, 5) parietooccipital connection, and 6) frontobasal connection. A stepwise approach is indicated to ensure adequate disconnection and prevent seizure persistence or recurrence. In young pediatric patients, careful patient selection and modern surgical techniques have resulted in > 80% seizure freedom and very good functional outcome. In this report, the authors summarize the history of hemispherectomy and its development and present a graphical guide for this anatomically challenging procedure. The use of the osteoplastic flap to improve outcome and the management of hydrocephalus are discussed.

Progress in diffuse intrinsic pontine glioma: advocating for stereotactic biopsy in the standard of care.

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor affecting approximately 300 children in the US annually. Median survival is less than 1 year, and radiation therapy has been the mainstay of treatment for decades. Recent advances in the biological understanding of the disease have identified the H3K27M mutation in nearly 80% of DIPGs, leading to the 2016 WHO classification of diffuse midline glioma H3K27M-mutant, a grade IV brainstem tumor. Developments in epigenetic targeting of transcriptional tendencies have yielded potential molecular targets for clinical trials. Chimeric antigen receptor T cell therapy has also shown preclinical promise. Recent clinical studies, including prospective trials, have demonstrated the safety and feasibility of pediatric brainstem biopsy in the setting of DIPG and other brainstem tumors. Given developments in the ability to analyze DIPG tumor tissue to deepen biological understanding of this disease and develop new therapies for treatment, together with the increased safety of stereotactic brainstem biopsy, the authors present a case for offering biopsy to all children with suspected DIPG. They also present their standard operative techniques for image-guided, frameless stereotactic biopsy.

Laser interstitial thermal therapy for pediatric atypical teratoid/rhabdoid tumor: case report.

Herein, the authors describe the successful use of laser interstitial thermal therapy (LITT) for management of metastatic craniospinal disease for biopsy-proven atypical teratoid/rhabdoid tumor in a 16-month-old boy presenting to their care. Specifically, LITT was administered to lesions of the right insula and left caudate. The patient tolerated 2 stages of LITT to the aforementioned lesions without complication and with evidence of radiographic improvement of lesions at the 2- and 6-month follow-up appointments. To the authors' knowledge, this represents the first such published report of LITT for management of atypical teratoid/rhabdoid tumor.

Predictors of preoperative endovascular embolization of meningiomas: subanalysis of anatomic location and arterial supply.

INTRODUCTION: Endovascular embolization of intracranial meningiomas is commonly used as an adjunct to surgical resection. We sought to describe the anatomic locations and vascular supplies of meningiomas to identify characteristics predictive of successful preoperative endovascular embolization. METHODS: We conducted a retrospective review of 139 meningioma cases receiving cerebral angiograms for possible preoperative endovascular embolization at our institution between December 2000 and March 2017. The extent of embolization, arterial supply, anatomic location, and procedural complications were recorded for each case. Univariate and multivariate analyses were performed to identify tumor characteristics that predicted successful embolization. RESULTS: Of the total meningioma patients undergoing preoperative angiography, 78% (108/139) were successfully embolized, with a 2.8% periprocedural complication rate (3/108). Within the subset of patients with successful embolization, 31% (33/108) achieved complete angiographic embolization. Significant multivariate predictors of embolization (either partial or complete) were convexity/parasagittal locations (OR 5.15, 95% CI 0.93 to 28.54, p=0.060), meningohypophyseal trunk (MHT, OR 4.65, 95% CI 1.63 to 13.23, p=0.004), middle meningeal artery (MMA, OR 10.89, 95% CI 3.43 to 34.64, p<0.001), and ascending pharyngeal artery supply (APA, OR 9.96, 95% CI 1.88 to 52.73, p=0.007). Significant predictors for complete embolization were convexity/parasagittal locations (OR 4.79, 95% CI 1.66 to 13.84, p=0.004) and embolized APA supply (OR 6.94, 95% CI 1.90 to 25.39, p=0.003). Multiple arterial supply was a negative predictor of complete embolization (OR 0.38, 95% CI 0.15 to 0.98, p=0.05). CONCLUSIONS: Tumor characteristics can be used to predict the likelihood of preoperative meningioma embolization. Parasagittal and convexity meningiomas, and those with APA supply, are most likely to achieve complete angiographic embolization.

Laser Ablation Therapy for Pediatric Patients with Intracranial Lesions in Eloquent Areas.

BACKGROUND: Laser interstitial thermal therapy (LITT) is an alternative, less-invasive, and, in some circumstances, effective treatment for patients with intracranial pathology including epilepsy and some tumors. For intracranial lesions in eloquent areas, resection by conventional craniotomy proves often to be a challenge, including in the care of pediatric patients. Herein, we reviewed our experience with magnetic resonance imaging (MRI)-guided LITT as treatment for pediatric patients with intracranial lesions in eloquent areas and evaluate neurologic function and clinical outcomes. METHODS: We retrospectively reviewed consecutive patients with intracranial lesions in eloquent speech and motor areas who underwent MRI-guided LITT. Clinical evaluation, including neurologic function and neuropsychological testing, was conducted according to clinical considerations. MRI pre- and postoperative imaging was reviewed to compare the change of lesion size. RESULTS: Five pediatric patients received MRI-guided LITT of intracranial lesions in eloquent cortex. One patient experienced complications secondary to MRI-guided LITT, but neither was discharged with a neurologic deficit. CONCLUSIONS: For intracranial lesions in the eloquent cortex, conventional craniotomy with surgical resection is a challenge for neurosurgeons, especially pediatric patients. MRI-guided LITT provides a less-invasive and potentially effective option for treatment in the management of pediatric epilepsy and tumors.

Diabetes Insipidus following Endoscopic Transsphenoidal Surgery for Pituitary Adenoma.

Objectives Pituitary adenoma (PA), among the most commonly encountered sellar pathologies, accounts for 10% of primary intracranial tumors. The reported incidence of postoperative diabetes insipidus (DI) is highly variable. In this study, we report our experience with DI following endoscopic transsphenoidal surgery (TSS) for PAs, elucidating the risk factors of postoperative DI, the likelihood of long-term DI, and the impact of DI on the length of stay (LOS). Methods The study included 178 patients who underwent endoscopic resection of PAs. Early DI was defined as that occurring within the first postoperative week. The mean follow-up was 36 months. Long-term DI was considered as DI apparent in the last follow-up visit. Results Of the 178 patients included in the study, 77% of the tumors were macroadenomas. Forty-seven patients (26%) developed early DI. Long-term DI was observed in 18 (10.1%) of the full cohort. Age younger than 50 years was significantly associated with a higher incidence of long-term DI ( p = 0.02). Macroadenoma and gross total resection were significantly associated with higher incidence of early DI ( p = 0.05 and p = 0.04, respectively). The mean LOS was 4 days for patients with early postoperative DI and 3 days for those without it. Conclusion The reported incidence of postoperative DI is significantly variable. We identified age younger than 50 years a risk factor for developing long-term postoperative DI. Gross total surgical resection and tumor size (> 1 cm) were associated with development of early DI. Early DI increased the LOS on average by 1 day.

Cavernous Sinus Involvement by Pituitary Adenomas: Clinical Implications and Outcomes of Endoscopic Endonasal Resection.

Background Parasellar invasion of pituitary adenomas (PAs) into the cavernous sinus (CS) is common. The management of the CS component of PA remains controversial. Objective The objective of this study was to analyze CS involvement in PA treated with endoscopic endonasal approaches, including incidence, surgical risks, surgical strategies, long-term outcomes, and our treatment algorithm. Methods We reviewed a series of 176 surgically treated PA with particular attention to CS involvement and whether the CS tumor was approached medial or lateral to the internal carotid artery. Results The median duration of follow-up was 36 months. Macroadenomas and nonfunctional adenomas represented 77 and 60% of cases, respectively. CS invasion was documented in 23% of cases. CS involvement was associated with a significantly diminished odds of gross total resection (47 vs. 86%, odds ratio [OR]: 5.2) and increased the need for subsequent intervention (4 vs. 40%, OR: 14.4). Hormonal remission was achieved in 15% of hormonally active tumors. Rates of surgical complication were similar regardless of CS involvement. Conclusion Our tailored strategy beginning with a medial approach and adding lateral exposure as needed resulted in good outcomes with low morbidity in nonfunctional adenomas. Functional adenomas involving the CS were associated with low rates of hormonal remission necessitating higher rates of additional treatment.

Leukotriene B4 antagonism ameliorates experimental lymphedema.

Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B4 (LTB4). LTB4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB4 was functionally bimodal: Lower LTB4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB4 stimulated, whereas high concentrations of LTB4 inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1-/- mice were refractory to the beneficial effects of LTB4 antagonism, suggesting that LTB4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB4 was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB4 is a promising drug target for the treatment of acquired lymphedema.

Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors.

Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.

Endovascular therapies for malignant gliomas: Challenges and the future.

Malignant gliomas are very difficult tumors to treat, with few effective therapies, early progression and high rates of recurrence. Here we review the literature on malignant gliomas treated with endovascular therapy. Endovascular therapy for malignant gliomas falls into one of three categories: (1) neoadjuvant embolization and devascularization; (2) direct intra-arterial drug delivery; and (3) disruption of the blood-brain barrier for improved intra-arterial drug delivery. There is a range of therapeutic benefits based on the endovascular intervention used. Challenges remain for those who aim to treat malignant gliomas with an endovascular approach. Specifically, embolization is difficult to accomplish in the small vessels that feed into malignant gliomas, and intra-arterial chemotherapy has yet to prove itself better than traditional intravenous chemotherapy. However, there exists promise in the therapeutic potential of intra-arterial chemotherapy paired with disruption of the blood-brain barrier at tumor-specific sites, and as such, continued research to optimize this approach is expected to yield benefit for patients with malignant gliomas.