RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Advancements in chimeric antigen receptor-expressing T-cell therapy for glioblastoma multiforme: Literature review and future directions.

Glioblastoma multiforme (GBM) is an aggressive cancer that has been difficult to treat and often requires multimodal therapy consisting of surgery, radiotherapy, and chemotherapy. Chimeric antigen receptor-expressing (CAR-T) cells have been efficacious in treating hematological malignancies, resulting in several FDA-approved therapies. CAR-T cells have been more recently studied for the treatment of GBM, with some promising preclinical and clinical results. The purpose of this literature review is to highlight the commonly targeted antigens, results of clinical trials, novel modifications, and potential solutions for challenges that exist for CAR-T cells to become more widely implemented and effective in eradicating GBM.

Developing a computable phenotype for glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor, and thus it is important to be able to identify patients with this diagnosis for population studies. However, this can be challenging as diagnostic codes are non-specific. The aim of this study was to create a computable phenotype (CP) for GBM from structured and unstructured data to identify patients with this condition in a large electronic health record (EHR). METHODS: We used the UF Health Integrated Data Repository, a centralized clinical data warehouse that stores clinical and research data from various sources within the UF Health system, including the EHR system. We performed multiple iterations to refine the GBM-relevant diagnosis codes, procedure codes, medication codes, and keywords through manual chart review of patient data. We then evaluated the performances of various possible proposed CPs constructed from the relevant codes and keywords. RESULTS: We underwent six rounds of manual chart reviews to refine the CP elements. The final CP algorithm for identifying GBM patients was selected based on the best F1-score. Overall, the CP rule "if the patient had at least 1 relevant diagnosis code and at least 1 relevant keyword" demonstrated the highest F1-score using both structured and unstructured data. Thus, it was selected as the best-performing CP rule. CONCLUSIONS: We developed a CP algorithm for identifying patients with GBM using both structured and unstructured EHR data from a large tertiary care center. The final algorithm achieved an F1-score of 0.817, indicating a high performance which minimizes possible biases from misclassification errors.

Ventriculo-inferior-venacaval shunt salvage via endovascular surgery.

INTRODUCTION: Hydrocephalus treatment can be very challenging. While some hydrocephalic patients can be treated endoscopically, many will require ventricular shunting. Frequent shunt issues over a lifetime is not uncommon. Although most shunt malfunctions are of the ventricular catheter or valve, distal failures occur as well. A subset of patients will accumulate non-functioning distal drainage sites. CASE DESCRIPTION: We present a 27-year-old male with developmental delay who was shunted perinatally for hydrocephalus from intraventricular hemorrhage of prematurity. After failure of the peritoneum, pleura, superior vena cava (SVC), gallbladder, and endoscopy, an inferior vena cava (IVC) shunt was placed minimally-invasively via the common femoral vein. We believe this is only the eighth reported ventriculo-inferior-venacaval shunt. IVC occlusion years later was successfully treated with endovascular angioplasty and stenting followed by anticoagulation. To our knowledge, a ventriculo-inferior-venacaval shunt salvaged by endovascular surgery has not been previously described in the literature. CONCLUSION: After failure of the peritoneum, pleura, SVC, gallbladder, and endoscopy, IVC shunt placement is an option. Subsequent IVC occlusion can be rescued by endovascular angioplasty and stenting. Anticoagulation after stenting (and potentially after initial IVC placement) is advised.

Impact of Low-Dose Computed Tomography and Physician Education on Referral for Head Shape.

Imaging before specialist evaluation of abnormal head shape is associated with a delay in evaluation and an increase in radiation exposure. A retrospective cohort study was performed to identify referral patterns before and after the implementation of a low-dose computed tomography (LDCT) protocol and physician education to examine the intervention's impact on time to evaluation and radiation exposure. Six hundred sixty-nine patients with an abnormal head shape diagnosis at a single academic medical center between July 1, 2014 and December 1, 2019 were reviewed. Demographics, referral information, diagnostic testing, diagnoses, and timeline of clinical evaluation were recorded. Before and after the LDCT and physician education intervention, the average ages at initial specialist appointments were 8.82 and 7.75 months, respectively ( P = 0.125). Children referred after our intervention were less likely to have prereferral imaging than children referred prior (odds ratio: 0.59, CI: 0.39-0.91, P = 0.015). Average radiation exposure per patient before referral decreased from 14.66 mGy to 8.17 mGy ( P = 0.021). Prereferral imaging, referral by a non-pediatrician, and non-Caucasian race were associated with older age at the initial specialist appointment. Widespread craniofacial center adoption of an LDCT protocol and improved clinician knowledge may lead to a reduction in late referrals and radiation exposure in pediatric patients with an abnormal head shape diagnosis.

What are we measuring? A refined look at the process of disrupted autoregulation and the limitations of cerebral perfusion pressure in preventing secondary injury after traumatic brain injury.

The cerebral perfusion pressure (CPP) and its relationship between intracranial pressure and mean arterial pressure is a concept ubiquitous in caring for the critically ill patient. CPP is often used as a surrogate measure for cerebral blood flow (CBF); however, this view fails to account for changes in cerebral vascular resistance (CVR). Changes in CVR occur due to cerebral autoregulation, which has classically been taught on a sigma shaped curve with a decline and increase at either end of a plateau. Historically, the conceptualized regulation maintains careful homeostatic levels despite external or internal dynamic changes; however, moderate and severe traumatic brain injury (TBI) has been postulated to bring about cerebral autoregulation dysfunction. We review the current application of CPP is limited by the dynamic changes in cerebral autoregulation after TBI. This review highlights CPP's role as a surrogate measure for CBF and the inherent limitations of current clinical management, due to the lack of monitoring capable of capture continuous variables to assist real-time decision making. This review evaluates the known literature and introduces topics for discussion that warrant further investigation via pre-clinical and clinical experimentation.

Clival Paraganglioma, Case Report and Literature Review.

Paragangliomas are rare tumors that may present with cranial neuropathies when located along the skull base. Supratentorial paragangliomas are less likely to secrete catecholamines but should be worked up, nonetheless. We highlight a case of a female in her fourth decade found to have a petroclival lesion following initial presentation that included one month of tooth pain, dysphagia, diplopia, hoarseness and right hemifacial hypoesthesia. Magnetic resonance imaging of the brain demonstrated a T2 hyperintense lesion favored to be a petroclival meningioma. Pre-operative angiography demonstrated a hypervascular tumor. She underwent a combined presigmoid craniotomy with posterior petrosectomy performed by both neurosurgery and neuro-otology. Pathology demonstrated paraganglioma. She had small volume residual tumor and is planned for continued outpatient radiotherapy. Paragangliomas should be on the differential for skull base lesions. Management paradigm involves multidisciplinary care and a combination of surgical resection and post-operative radiation. In this paper, we discuss underlying pathophysiology as well as appropriate workup and management.

Chiari I malformation and Noonan's syndrome: Shared manifestations of RASopathy.

Neurologic sequalae of Noonan syndrome have been postulated in the literature. A topic of significance is the role of RASopathy in the shared pathophysiology of Noonan Syndrome and Chiari I malformation. In this unique case report, we present a patient with concomitant Noonan Syndrome and Chiari I with 4th ventricular outflow obstruction. The case highlights the importance of close clinical suspicion in this patient population. We utilize the case to delve into intricacies of the known pathophysiology and encourage ongoing investigation.

Preoperative Radiographic Prediction Tool for Early Postoperative Segmental and Lumbar Lordosis Alignment After Transforaminal Lumbar Interbody Fusion.

Objective Transforaminal lumbar interbody fusion (TLIF) is a common approach and results in varying degrees of lordosis correction. The purpose of this study is to determine preoperative radiographic spinopelvic parameters that predict change in postoperative segmental and lumbar lordosis after TLIF. Materials & Methods This study is a single surgeon retrospective review of one-level and two-level TLIFs from L3-S1. All patients underwent bilateral facetectomies, 10 mm TLIF cage (non-lordotic) insertions, and bilateral pedicle screw-rod construct placements. Pre- and post-operative X-rays were assessed for preoperative segmental lordosis (SL), lumbar lordosis (LL), and pelvic incidence (PI). Univariate and multi-predictor linear regression analyses were performed to determine the relationships between preoperative radiographic findings and change in early postoperative segmental and lumbar lordosis. Results Ninety-seven patients contributing 128 intervertebral segments were examined. The mean change in SL after TLIF was 7.3 (range: 0.10-28.9°, SD 6.39°). The mean change in LL after TLIF was 5.5˚ (range: -14.8-39.2°, standard deviation (SD) 7.16°). Greater preoperative LL predicted less postoperative LL correction, while greater preoperative PI predicted more postoperative SL and LL correction. Greater anterior disk height was noted to be associated with a decreased change in SL (∆SL). An annular tear on preoperative magnetic resonance imaging (MRI) predicted a 2.7° decrease in ∆SL. A Schmorl's node on preoperative MRI predicted a 4.0° decrease in change in LL (∆LL). Conclusions A greater preoperative lordosis and a lower spinopelvic mismatch lessen the potential for an increase in the postoperative SL and LL after a TLIF, which is likely due to a 'ceiling' effect of an otherwise optimized spinal alignment. A greater anterior disk height and the presence of an annular tear are associated with decreased ∆SL.

Inflammatory myofibroblastic tumor masquerading as an anterior choroidal artery fusiform aneurysm.

BACKGROUND: Inflammatory myofibroblastic tumor is a rare, poorly understood tumor that has been found to occur in almost every organ tissue. Its location within the central nervous system is uncommon, and patients tend to present with nonspecific symptoms. CASE DESCRIPTION: A female in her eighth decade presented to neurosurgery clinic with complaints of headache and dizziness. Initial imaging was consistent with a low-grade, benign brain lesion in the region of the left choroidal fissure. She was recommended for observation but returned 1 month later with progressive symptoms and doubling of the lesion size. She underwent surgical resection and was found to have an IMT arising from the wall of the left anterior choroidal artery. CONCLUSION: Intracranial IMT remains a rare and poorly understood entity. The present case demonstrates a novel presentation of IMT in an adult patient and exemplifies the heterogeneity of the disease presentation.

Cysteine-rich domains of muc3 intestinal mucin promote cell migration, inhibit apoptosis, and accelerate wound healing.

BACKGROUND & AIMS: Muc3 intestinal mucin contains an extracellular cysteine-rich domain with 2 epidermal growth factor (EGF)-like motifs. The aim of this study was to determine the functional properties of Muc3 proteins. METHODS: Glutathione S-transferase-fusion proteins containing both Muc3 EGF-like domains (m3EGF1,2) or truncated versions (m3EGF1 and m3EGF2) were purified from Escherichia coli. Mouse colon (young adult mouse colon) and human A431 and LoVo cells were examined for migration and tyrosine phosphorylation in response to recombinant proteins. LoVo cells were transfected with a human MUC3A transmembrane-EGF1,2 construct and a stable clone was isolated (LhM3c14). Endogenous MUC3A in LoVo was inhibited by specific small interfering RNA transfection. Apoptosis was quantitated by nuclear morphology or terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling assay. Colitis was induced in mice by oral 5% dextran sodium sulfate or rectal 5% acetic acid, followed by enema treatments. RESULTS: m3EGF1,2 stimulated cell migration in all cell lines, but did not induce proliferation. Migration was inhibited by a tyrosine phosphorylation inhibitor, genistein, but not by the EGF receptor inhibitor, tyrphostin (AG1478). Inhibition of endogenous MUC3A in LoVo reduced baseline migration. Tyrosine phosphorylation of ErbB receptors was not observed after treatment of cells with m3EGF1,2. LoVo cells pretreated with m3EGF1,2 and transfected LhM3c14 cells showed reduced apoptosis in response to tumor necrosis factor alpha or Fas-receptor stimulation. Administration of m3EGF1,2 per rectum significantly reduced mucosal ulceration and apoptosis in experimental acute colitis. Truncated proteins m3EGF1 and m3EGF2 had no effect. CONCLUSIONS: The Muc3 mucin cysteine-rich domain plays an active role in epithelial restitution, and represents a potential novel therapeutic agent for intestinal wound healing.