Prevalence and Predictors of Inappropriate Antithrombotic Prescription in Patients Presenting With Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: A growing proportion of the US population is on antithrombotic therapy (AT), most significantly within the older subpopulation. Decision to use AT is a balance between the intended benefits and known bleeding risk, especially after traumatic brain injury (TBI). Preinjury inappropriate AT offers no benefit for the patient and also increases the risk of intracranial hemorrhage and worse outcome in the setting of TBI. Our objective was to examine the prevalence and predictors of inappropriate AT among patients presenting with TBI to a Level-1 Trauma Center. METHODS: A retrospective chart review was performed on all patients with TBI and preinjury AT who presented to our institution between January 2016 and September 2020. Demographic and clinical data were collected. Appropriateness of AT was determined through established clinical guidelines. Clinical predictors were determined by logistic regression. RESULTS: Of 141 included patients, 41.8% were female (n = 59) and the average age (mean ± SD) was 80.6 ± 9.9. The prescribed antithrombotic agents included aspirin (25.5%, n = 36), clopidogrel (22.7%, n = 32), warfarin (46.8%, n = 66), dabigatran (2.1%, n = 3), rivaroxaban (Janssen) (10.6%, n = 15), and apixaban (Bristol-Myers Squibb Co.) (18.4%, n = 26). The indications for AT were atrial fibrillation (66.7%, n = 94), venous thromboembolism (13.4%, n = 19), cardiac stent (8.5%, n = 12), and myocardial infarction/residual coronary disease (11.3%, n = 16). Inappropriate antithrombotic therapy use varied significantly by antithrombotic indication ( P < .001) with the highest rates seen with venous thromboembolism. Predictive factors also include age ( P = .005) with higher rates younger than 65 years and older than 85 years and female sex ( P = .049). Race and antithrombotic agent were not significant predictors. CONCLUSION: Overall, 1 in 10 patients presenting with TBI were found to be on inappropriate AT. Our study is the first to describe this problem and warrants investigation into possible workflow interventions to prevent post-TBI continuation of inappropriate AT.

CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future.

Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.

Genomic landscape of gliosarcoma: distinguishing features and targetable alterations.

Gliosarcoma is an aggressive brain tumor with histologic features of glioblastoma (GBM) and soft tissue sarcoma. Despite its poor prognosis, its rarity has precluded analysis of its underlying biology. We used a multi-center database to characterize the genomic landscape of gliosarcoma. Sequencing data was obtained from 35 gliosarcoma patients from Genomics Evidence Neoplasia Information Exchange (GENIE) 5.0, a database curated by the American Association of Cancer Research (AACR). We analyzed genomic alterations in gliosarcomas and compared them to GBM (n = 1,449) and soft tissue sarcoma (n = 1,042). 30 samples were included (37% female, median age 59 [IQR: 49-64]). Nineteen common genes were identified in gliosarcoma, defined as those altered in > 5% of samples, including TERT Promoter (92%), PTEN (66%), and TP53 (60%). Of the 19 common genes in gliosarcoma, 6 were also common in both GBM and soft tissue sarcoma, 4 in GBM alone, 0 in soft tissue sarcoma alone, and 9 were more distinct to gliosarcoma. Of these, BRAF harbored an OncoKB level 1 designation, indicating its status as a predictive biomarker of response to an FDA-approved drug in certain cancers. EGFR, CDKN2A, NF1, and PTEN harbored level 4 designations in solid tumors, indicating biological evidence of these biomarkers predicting a drug-response. Gliosarcoma contains molecular features that overlap GBM and soft tissue sarcoma, as well as its own distinct genomic signatures. This may play a role in disease classification and inclusion criteria for clinical trials. Gliosarcoma mutations with potential therapeutic indications include BRAF, EGFR, CDKN2A, NF1, and PTEN.

Incidence of Spontaneous Obliteration in Untreated Brain Arteriovenous Malformations.

BACKGROUND: Spontaneous obliteration (SpO) of untreated arteriovenous malformations (AVMs) is rare with fewer than 100 cases reported. The incidence and predisposing factors of SpO remain unclear, impeding our understanding of lesion progression in untreated patients. OBJECTIVE: To determine the incidence rate and predisposing factors of SpO in a North American cohort. METHODS: AVMs were retrospectively evaluated at our institution for over 25 yr. Untreated AVMs were divided into 2 groups: SpO-AVMs and non-SpO-AVMs. All statistical results were based on univariate analyses. Incidence was generated from counts of SpO over the untreated interval in patient years from birth until obliteration, treatment, or last follow-up. RESULTS: One hundred fifty-four patients had untreated AVMs; SpO was observed in 4. Average ages were 49.0 ± 23.6 and 48.7 ± 20.4 yr in the SpO-AVM and non-SpO-AVM group, respectively (P = .98). Average AVM sizes were 2.0 ± 1.8 cm (SpO-AVMs) and 3.7 ± 2.6 cm (non-SpO-AVMs, P = .25). All SpO-AVMs and 40 (27.0%) non-SpO-AVMs had a ruptured presentation (P = .006). A single draining vein was observed in all SpO-AVMs and 39 (32.8%) non-SpO-AVMs (P = .01). Deep venous drainage was not observed in any SpO-AVMs, but in 81 (57.9%) non-SpO-AVMs (P = .04). Mean follow-up time was 37.0 ± 42.6 and 75.6 ± 161.7 mo in SpO-AVM and non-SpO-AVMs patients, respectively. Of the 2 SpO-AVM patients with postobliteration follow-up, 1 experienced recanalization. From a 672-patient cohort, the incidence of SpO over 28 961 patient years was 0.014%. CONCLUSION: SpO-AVMs have an annual incidence rate of approximately 0.014% and tend to present with rupture, a single draining vein, and superficial venous drainage. Expectation of SpO for untreated AVMs is not justified, and patients should anticipate life-long hemorrhagic risk for untreated AVMs.

Absence of Ischemic Injury after Sacrificing the Superior Petrosal Vein during Microvascular Decompression.

BACKGROUND: Sacrificing the superior petrosal vein (SPV) is controversial during a microvascular decompression (MVD). There have been multiple reports of complications including life-threatening brainstem infarction and cerebellar edema. OBJECTIVE: To analyze the potential for vascular complications when the SPV is sacrificed during an MVD. METHODS: Retrospective chart review was performed to identify all MVDs for trigeminal neuralgia and hemifacial spasm from 2007 to 2018 at 1 institution. Cases with ≥1 mo of follow-up were included and SPV sacrifice was noted. The primary outcome was complications related to SPV sacrifice including sinus thrombosis, cerebellar edema, and midbrain or pontine infarction. Imaging was used to confirm all potential vascular complications noted in medical records. Fisher's exact test and unpaired t-tests were used to compare between groups. RESULTS: A total of 732 MVD cases were identified and 592 met inclusion criteria with an average follow-up of 11.8 ± 16.4 mo and a male-to-female ratio of 1:2.2. The SPV was sacrificed in 217 cases and retained in 375 cases. No SPV-related vascular complications were found in this study. Two unrelated cases of vascular complications were identified and both were in the nonsacrificed group. One case involved cerebellar bleeding while the other was an ipsilateral transverse sinus thrombosis that was present preoperatively. CONCLUSION: In MVDs, there is no difference in the rate of vascular complications when the SPV is sacrificed compared to preserved. To best visualize a cranial nerve and optimize safe decompression, surgeons should feel free to sacrifice the SPV.

Author Correction: Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20129-9.

Author Correction: Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Retrosigmoid approach for glycerin rhizotomy in the treatment of trigeminal neuralgia without overt arterial compression: updated case series.

OBJECTIVE: Trigeminal neuralgia (TN) is a neuropathic pain disorder characterized by severe, lancinating facial pain that is commonly treated with neuropathic medication, percutaneous rhizotomy, and/or microvascular decompression (MVD). Patients who are not found to have distinct arterial compression during MVD present a management challenge. In 2013, the authors reported on a small case series of such patients in whom glycerin was injected intraoperatively into the cisternal segment of the trigeminal nerve. The objective of the authors' present study was to report their updated experience with this technique to further validate this novel approach. METHODS: The authors performed a retrospective analysis of data obtained in patients in whom glycerin was directly injected into the inferior third of the cisternal portion of the trigeminal nerve. Seventy-four patients, including 14 patients from the authors' prior study, were identified, and demographic information, intraoperative findings, postoperative course, and complications were recorded. Fisher's exact test, unpaired t-tests, and Kaplan-Meier survival curves using Mantel log-rank test were used to compare the 74 patients with a cohort of 476 patients who received standard MVD by the same surgeon. RESULTS: The 74 patients who underwent MVD and glycerin injection had an average follow-up of 19.1 ± 18.0 months, and the male/female ratio was 1:2.9. In 33 patients (44.6%), a previous intervention for TN had failed. On average, patients had an improvement in the Barrow Neurological Institute Pain Intensity score from 4.1 ± 0.4 before surgery to 2.1 ± 1.2 after surgery. Pain improvement after the surgery was documented in 95.9% of patients. Thirteen patients (17.6%) developed burning pain following surgery. Five patients developed complications (6.7%), including incisional infection, facial palsy, CSF leak, and hearing deficit, all of which were minor. CONCLUSIONS: Intraoperative injection of glycerin into the trigeminal nerve is a generally safe and potentially effective treatment for TN when no distinct site of arterial compression is identified during surgery or when decompression of the nerve is deemed to be inadequate.

Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy.

Brain glioma treatment with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross blood-brain barrier (BBB). Here we describe targeted nanoscale immunoconjugates (NICs) on natural biopolymer scaffold, poly(ß-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) results in an increase of CD8+ T cells, NK cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with NIC combination is significantly longer compared to animals treated with single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of tumor-targeted polymer-conjugated checkpoint inhibitors as an effective GBM treatment via activation of both systemic and local privileged brain tumor immune response.

Adjuvant radiotherapy and outcomes of presumed hemorrhagic melanoma brain metastases without malignant cells.

BACKGROUND: Patients with melanoma can present with a hemorrhagic intracranial lesion. Upon resection, pathology reports may not detect any malignant cells. However, the hemorrhage may obscure their presence and so physicians may still decide whether adjuvant radiotherapy should be applied. Here, we report on the outcomes of a series of patients with melanoma with hemorrhagic brain lesions that returned with no tumor cells. METHODS: All melanoma patients who had craniotomies from 2008 to 2017 at a single institution for hemorrhagic brain lesions were identified through retrospective chart review. Those who had pathology reports with no malignant cells were analyzed. Recurrence at the former site of hemorrhage and resection was the primary outcome. RESULTS: Ten patients met inclusion criteria, and the median follow-up time was 8.5 (1.8-27.3) months. At the time of craniotomy, the median number of brain lesions was 3 (1-25). Two patients had prior craniotomies, eight had prior radiation, and six had prior immunotherapy to the lesion of interest. After surgery, one patient received stereotactic radiosurgery (SRS) to the resection bed. Only one patient developed subsequent melanoma at the resection site; this patient developed the lesion recurrence once and had not received postoperative SRS. CONCLUSION: Although small foci of metastatic disease as a source of bleeding for some patients cannot be excluded, melanoma patients with a suspected hemorrhagic brain metastasis that shows no tumor cells on pathology may benefit from close observation. The local recurrence risk in such cases appears to be low, even without adjuvant radiation.

Outcomes of Metastatic Brain Lesions Treated with Radioactive Cs-131 Seeds after Surgery: Experience from One Institution.

Introduction Brain metastases are common in patients with advanced systemic cancer and often recur despite treatment with surgical resection and radiotherapy. Whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) have significantly improved local control rates but are limited by complications including neurocognitive deficits and radiation necrosis. These risks can be higher in the re-irradiation setting. Brachytherapy may be an alternative method of additional targeted adjuvant radiotherapy with acceptable rates of toxicity. Methods A retrospective chart review of all patients undergoing resection for metastatic brain lesions and permanent low-dose rate Cs-131 brachytherapy was performed for one institution over a 10-year period. All patients had previous radiation therapy already and, after surgery, were followed with imaging every three months. Patient demographics, disease characteristics, intracranial disease, peri- and post-operative complications, and outcomes were recorded. The primary outcome of interest was local tumor recurrence at the site of brachytherapy while secondary outcomes included distant disease progression (within the brain) and complications such as radiation necrosis. Results During the study period, nine cases of individual patients met inclusion criteria. The median preoperative lesion diameter was 3 cm (0.8-4.1). The median overall survival after surgery and brachytherapy was 10.3 months, after excluding two patients who were lost to follow-up. Six of nine patients had no local recurrence, while three patients had development or progression of distant lesions. No patients experienced acute or delayed complications. Conclusion Cs-131 brachytherapy is a promising alternative method for controlling brain metastases after previous radiation interventions and surgical resection. In this case series, there were no incidences of local tumor recurrence or complications such as radiation necrosis.