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James G Shamul,1,2,* Sagar R Shah,1–3,* Jayoung Kim,1,2 Paula Schiapparelli,3 Carla A Vazquez-Ramos,3 Ben J Lee,1,2 Kisha K Patel,1,2 Alyssa Shin,1,2 Alfredo Quinones-Hinojosa,3 Jordan J Green1,2,4–6 1Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 2Translational Tissue Engineering Center and Institute for NanoBioTechnology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 3Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA; 4Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD 21231, USA; 5Department of Oncology, The Sidney Kimmel Comprehensive Cancer, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; 6Department of Ophthalmology, Department of Materials Science and Engineering, and Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21231, USA*These authors contributed equally to this workCorrespondence: Alfredo Quinones-Hinojosa; Jordan J Green Email Quinones-Hinojosa.Alfredo@mayo.edu; green@jhu.eduBackground: Nanomedicine can improve traditional therapies by enhancing the controlled release of drugs at targeted tissues in the body. However, there still exists disease- and therapy-specific barriers that limit the efficacy of such treatments. A major challenge in developing effective therapies for one of the most aggressive brain tumors, glioblastoma (GBM), is affecting brain cancer cells while avoiding damage to the surrounding healthy brain parenchyma. Here, we developed poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE) (PEG-PBAE)-based micelles encapsulating verteporfin (VP) to increase tumor-specific targeting.Methods: Biodegradable, pH-sensitive micelles of different shapes were synthesized via nanoprecipitation using two different triblock PEG-PBAE-PEG copolymers varying in their relative hydrophobicity. The anti-tumor efficacy of verteporfin loaded in these anisotropic and spherical micelles was evaluated in vitro using patient-derived primary GBM cells.Results: For anisotropic micelles, uptake efficiency was ∼100% in GBM cells (GBM1A and JHGBM612) while only 46% in normal human astrocytes (NHA) at 15.6 nM VP (p ≤ 0.0001). Cell killing of GBM1A and JHGBM612 vs NHA was 52% and 77% vs 29%, respectively, at 24 hrs post-treatment of 125 nM VP-encapsulated in anisotropic micelles (p ≤ 0.0001), demonstrating the tumor cell-specific selectivity of VP. Moreover, anisotropic micelles showed an approximately fivefold longer half-life in blood circulation than the analogous spherical micelles in a GBM xenograft model in mice. In this model, micelle accumulation to tumors was significantly greater for anisotropic micelle-treated mice compared to spherical micelle-treated mice at both 8 hrs (∼1.8-fold greater, p ≤ 0.001) and 24 hrs (∼2.1-fold greater, p ≤ 0.0001).Conclusion: Overall, this work highlights the promise of a biodegradable anisotropic micelle system to overcome multiple drug delivery challenges and enhance efficacy and safety for the treatment of brain cancer.Keywords: GBM, verteporfin, micelle, anisotropic, poly(ethylene glycol), PEG, poly(beta-amino ester), PBAE

Chimeric antigen receptor (CAR) T cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T cell therapies against solid tumors.

Objective: To describe the safety and feasibility of a fast-track pathway for neurosurgical craniotomy patients receiving care in a neurosciences progressive care unit (NPCU). Patients and Methods: Traditionally, most craniotomy patients are admitted to the neurosciences intensive care unit (NSICU) for postoperative follow-up. Decreased availability of NSICU beds during the coronavirus disease-2019 delta surge led our team to establish a de-novo NPCU to preserve capacity for patients requiring high level of care and would bypass routine NSICU admissions. Patients were selected a priori by treating neurosurgeons on the basis of the potential need for high-level ICU services. After operation, selected patients were transferred to the postoperative care unit, where suitability for NPCU transfer was reassessed with checklist-criteria. This process was continued after the delta surge. Results: From July 1, 2021 to September 30, 2022, 57 patients followed the NPCU protocol. Thirty-four (59.6%) were women, and the mean age was 56 years. Fifty-seven craniotomies for 34 intra-axial and 23 extra-axial lesions were performed. After assessment and application of the checklist-criteria, 55 (96.5%) were transferred to NPCU, and only 2 (3.5%) were transferred to ICU. All 55 patients followed in NPCU had good safety outcomes without requiring NSICU transfer. This saved $143,000 and led to 55 additional ICU beds for emergent admissions. Conclusion: This fast-track craniotomy protocol provides early experience that a surgeon-selected group of patients may be suitably monitored outside the traditional NSICU. This system has the potential to reduce overall health care expenses, increase capacity for NSICU bed availability, and change the paradigm of NSICU admission.

Early postoperative seizures (EPS) are a common complication of brain tumor surgery. EPS can lead to hemorrhage, cerebral hypoxia, increased intracranial pressure, longer hospitalization, reduced quality of life, decreased overall survival, and increased morbidity. However, there are no formal guidelines on perioperative antiseizure medication (ASM) management in patients with tumor-related epilepsy who are deemed high risk for EPS. In this study, we describe the case of a 38-year-old man with isocitrate dehydrogenase-mutant mixed glioma and two episodes of EPS manifesting with status epilepticus during prior tumor surgeries and who presented with tumor progression. The Tumor Board recommended awake craniotomy with direct electrical stimulation (DES). The patient was administered aggressive preoperative “prophylactic” ASMs by increasing the maintenance doses of lacosamide and levetiracetam by 25% 48 h before surgery. An intravenous load of fosphenytoin (20 mg/kg) was administered in the operating room before DES, followed by a maintenance dosing of 300 mg/day for 14 days. EPS did not occur, and he was discharged home on postoperative day 4. Our case illustrates that aggressive perioperative prophylactic ASM therapy beyond the maintenance ASM regimen can be considered in patients with tumor-related epilepsy at risk of EPS.

Introduction There have been several studies of Moyamoya disease (MMD) with concurrent autoimmune (AI) disease. It has been proposed that there may be a causal or synergistic effect of autoimmune and inflammatory conditions in patients with MMD. As such, in the present study we seek to characterizethe surgical outcomes of adults and children with MMD and coexisting AI conditions. Methods A systematic review was performed of published studies reporting patient level data of Moyamoya disease and concomitant autoimmune disease. Relevant studies were identified using Preferred reporting Items for Systematic Reviews and Meta‐Analysis criteria. Results A total of 149 studies were included, encompassing 257 patients. Of the 257 patients with concurrent AI and MMD, 107 (88 females, 19 males) underwent surgery. The average age was 31.3 years (Range 5–65; SD 12.5). Five cases presented with hemorrhagic symptoms, 87 ischemic, and 15 were unspecified. The most commonly associated AI conditions were Graves’ disease (71 cases, 66.4%), Lupus (17 cases, 15.9%), and T1DM (6 cases, 5.6%).Follow‐up was reported in 25 cases and was an average of 17.8 months. Surgical outcomes were reported in 82 cases; 63 (76.8%) improved, 7 (8.5%) were stable, 9 (10.9%) developed a new deficit, and 3 (3.7%) died at most recent follow up. Eight patients (7.5%) had disease progression. 63 (58.8%) patients were treated with additional autoimmune therapy although this therapy did not lead to any difference in outcomes. Twenty patients (18.7%) required additional supportive medical therapy (eg: aspirin, statins). Conclusions Moyamoya disease may be multifactorial. Patients with concomitant AI and Moyamoya disease may be at increased risk and warrant additional surveillance or intervention. The ideal therapy for these patients remains to be understood. These findings warrant further study into optimal diagnostic and therapeutic techniques for concomitant MMD and AI conditions.