Publications by authors named "Joshua D Bernstock"

86 Publications

Direct oral anticoagulants vs. low-molecular-weight heparin for pulmonary embolism in patients with glioblastoma.

Neurosurg Rev 2021 Apr 26. Epub 2021 Apr 26.

Department of Neurosurgery, University Hospital, Goethe University, Schleusenweg 2-16, 60598, Frankfurt, Germany.

Glioblastoma (GBM) is a cancer type with high thrombogenic potential and GBM patients are therefore at a particularly high risk for thrombotic events. To date, only limited data on anticoagulation management after pulmonary embolism (PE) in GBM is available and the sporadic use of DOACs remains off-label. A retrospective cohort analysis of patients with GBM and postoperative, thoracic CT scan confirmed PE was performed. Clinical course, follow-up at 6 and 12 months and the overall survival (OS) were evaluated using medical charts and neuroradiological data. Out of 584 GBM patients, 8% suffered from postoperative PE. Out of these, 30% received direct oral anticoagulants (DOACs) and 70% low-molecular-weight heparin (LMWH) for therapeutic anticoagulation. There was no significant difference in major intracranial hemorrhage (ICH), re-thrombosis, or re-embolism between the two cohorts. Although statistically non-significant, a tendency to reduced mRS at 6 and 12 months was observed in the LMWH cohort. Furthermore, patients receiving DOACs had a statistical benefit in OS. In our analysis, DOACs showed a satisfactory safety profile in terms of major ICH, re-thrombosis, and re-embolism compared to LMWH in GBM patients with postoperative PE. Prospective, randomized trials are urgent to evaluate DOACs for therapeutic anticoagulation in GBM patients with PE.
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http://dx.doi.org/10.1007/s10143-021-01539-9DOI Listing
April 2021

Association of Isocitrate Dehydrogenase (IDH) Status With Edema to Tumor Ratio and Its Correlation With Immune Infiltration in Glioblastoma.

Front Immunol 2021 25;12:627650. Epub 2021 Mar 25.

Department of Neurosurgery, Goethe University Hospital, Frankfurt, Germany.

Purpose: The extent of preoperative peritumoral edema in glioblastoma (GBM) has been negatively correlated with patient outcome. As several ongoing studies are investigating T-cell based immunotherapy in GBM, we conducted this study to assess whether peritumoral edema with potentially increased intracranial pressure, disrupted tissue homeostasis and reduced local blood flow has influence on immune infiltration and affects survival.

Methods: A volumetric analysis of preoperative imaging (gadolinium enhanced T1 weighted MRI sequences for tumor size and T2 weighted sequences for extent of edema (including the infiltrative zone, gliosis etc.) was conducted in 144 patients using the Brainlab® software. Immunohistochemical staining was analyzed for lymphocytic- (CD 3+) and myelocytic (CD15+) tumor infiltration. A retrospective analysis of patient-, surgical-, and molecular characteristics was performed using medical records.

Results: The edema to tumor ratio was neither associated with progression-free nor overall survival (p=0.90, p=0.74). However, GBM patients displaying IDH-1 wildtype had significantly higher edema to tumor ratio than patients displaying an IDH-1 mutation (p=0.01). Immunohistopathological analysis did not show significant differences in lymphocytic or myelocytic tumor infiltration (p=0.78, p=0.74) between these groups.

Conclusion: In our cohort, edema to tumor ratio had no significant correlation with immune infiltration and outcome. However, patients with an IDH-1wildtype GBM had a significantly higher edema to tumor ratio compared to their IDH-1 mutated peer group. Further studies are necessary to elucidate the underlying mechanisms.
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http://dx.doi.org/10.3389/fimmu.2021.627650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044904PMC
March 2021

Therapeutic cancer vaccines for pediatric malignancies: advances, challenges, and emerging technologies.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab027. Epub 2021 Feb 11.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Though outcomes for pediatric cancer patients have significantly improved over the past several decades, too many children still experience poor outcomes and survivors suffer lifelong, debilitating late effects after conventional chemotherapy, radiation, and surgical treatment. Consequently, there has been a renewed focus on developing novel targeted therapies to improve survival outcomes. Cancer vaccines are a promising type of immunotherapy that leverage the immune system to mediate targeted, tumor-specific killing through recognition of tumor antigens, thereby minimizing off-target toxicity. As such, cancer vaccines are orthogonal to conventional cancer treatments and can therefore be used alone or in combination with other therapeutic modalities to maximize efficacy. To date, cancer vaccination has remained largely understudied in the pediatric population. In this review, we discuss the different types of tumor antigens and vaccine technologies (dendritic cells, peptides, nucleic acids, and viral vectors) evaluated in clinical trials, with a focus on those used in children. We conclude with perspectives on how advances in combination therapies, tumor antigen (eg, neoantigen) selection, and vaccine platform optimization can be translated into clinical practice to improve outcomes for children with cancer.
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http://dx.doi.org/10.1093/noajnl/vdab027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034661PMC
February 2021

Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.

N Engl J Med 2021 04 10;384(17):1613-1622. Epub 2021 Apr 10.

From the Department of Pediatrics, Divisions of Pediatric Hematology-Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children's of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) - both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) - both in Tennessee; the Department of Neurosurgery, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center - both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children's Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) - both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.).

Background: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue.

Methods: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (10 or 10 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis.

Results: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes.

Conclusions: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).
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http://dx.doi.org/10.1056/NEJMoa2024947DOI Listing
April 2021

Neural stem cells traffic functional mitochondria via extracellular vesicles.

PLoS Biol 2021 Apr 7;19(4):e3001166. Epub 2021 Apr 7.

Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom.

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.
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http://dx.doi.org/10.1371/journal.pbio.3001166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055036PMC
April 2021

Case Report: Frontoparietal Metastasis From a Primary Fallopian Tube Carcinoma.

Front Surg 2021 17;8:594570. Epub 2021 Feb 17.

Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.

Metastatic brain tumors typically arise from primary malignancies of the lung, kidney, breast, skin, and colorectum. Brain metastases originating from malignancies of the female genital tract are extremely rare. We present a case of fallopian tube brain metastasis and in so doing review the pertinent literature. We describe a 59-year-old patient with a history of fallopian tube carcinoma who presented with an incidentally identified left frontal brain mass. MRI demonstrated an enhancing lesion in the left centrum semiovale with a second enhancing lesion noted in the cerebellar vermis. She underwent a left parietal craniotomy for resection of the dominant and clinically symptomatic lesion. Immunohistochemical stains were positive for PAX8 and p53, confirming fallopian tube origin. Fallopian tube cancer brain metastasis is extremely uncommon. We highlight the treatment and surgical resection of this patient's metastatic fallopian lesion and systematically review the literature regarding the pathogenesis, diagnosis, treatment, and histologic characteristics of the previously identified fallopian tube metastases to the central nervous system. The optimal course of treatment for brain metastasis of fallopian tube carcinoma has not been clearly defined due in part to the rarity of this condition. Consistent with neoplasms involving the breast and ovaries, the status of the patient's primary tumor likely increased the risk of central nervous system dissemination. This highlights a potential benefit of early screening of individuals with metastatic gynecologic malignancies associated with in the absence of any neurological symptoms.
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http://dx.doi.org/10.3389/fsurg.2021.594570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927667PMC
February 2021

Triage and Allocation of Neurocritical Care Resources During the COVID 19 Pandemic - A National Survey.

Front Neurol 2020 6;11:609227. Epub 2021 Jan 6.

Department of Neurosurgery, University Hospital Bonn, Bonn, Germany.

In light of the ongoing COVID-19 pandemic and the associated hospitalization of an overwhelming number of ventilator-dependent patients, medical and/or ethical patient triage paradigms have become essential. While guidelines on the allocation of scarce resources do exist, such work within the subdisciplines of intensive care (e.g., neurocritical care) remains limited. A 16-item questionnaire was developed that sought to explore/quantify the expert opinions of German neurointensivists with regard to triage decisions. The anonymous survey was conducted via a web-based platform and in total, 96 members of the Initiative of German Neurointensive Trial Engagement (IGNITE)-study group were contacted via e-mail. The IGNITE consortium consists of an interdisciplinary panel of specialists with expertise in neuro-critical care (i.e., anesthetists, neurologists and neurosurgeons). Fifty members of the IGNITE consortium responded to the questionnaire; in total the respondents were in charge of more than 500 Neuro ICU beds throughout Germany. Common determinants reported which affected triage decisions included known patient wishes (98%), the state of health before admission (96%), SOFA-score (85%) and patient age (69%). Interestingly, other principles of allocation, such as a treatment of "youngest first" (61%) and members of the healthcare sector (50%) were also noted. While these were the most accepted parameters affecting the triage of patients, a "first-come, first-served" principle appeared to be more accepted than a lottery for the allocation of ICU beds which contradicts much of what has been reported within the literature. The respondents also felt that at least one neurointensivist should serve on any interdisciplinary triage team. The data gathered in the context of this survey reveal the estimation/perception of triage algorithms among neurointensive care specialists facing COVID-19. Further, it is apparent that German neurointensivists strongly feel that they should be involved in any triage decisions at an institutional level given the unique resources needed to treat patients within the Neuro ICU.
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http://dx.doi.org/10.3389/fneur.2020.609227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874200PMC
January 2021

Radiation-induced intracranial osteosarcoma of the anterior skull base after treatment of esthesioneuroblastoma.

BMJ Case Rep 2021 Jan 18;14(1). Epub 2021 Jan 18.

Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.

Esthesioneuroblastoma (ENB) is an uncommon sinonasal cancer of the olfactory neuroepithelium that is typically treated with surgical resection followed by radiation therapy. Radiation-induced intracranial osteosarcoma of the skull base is a rare but devastating long-term complication of radiation therapy in this region. Here, we present a case of an 82-year-old patient who developed radiation-induced osteosarcoma of the anterior skull base and paranasal sinuses 10 years after radiation therapy following resection of an ENB. Older patients may be at risk of developing this complication earlier and with a worse prognosis relative to younger patients. Treating physicians/surgeons should be aware of this devastating complication. Patients who are treated with high-dose radiation therapy in this region should be followed for many years.
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http://dx.doi.org/10.1136/bcr-2020-238928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813314PMC
January 2021

Glioma stem cells and their roles within the hypoxic tumor microenvironment.

Theranostics 2021 1;11(2):665-683. Epub 2021 Jan 1.

Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL.

Tumor microenvironments are the result of cellular alterations in cancer that support unrestricted growth and proliferation and result in further modifications in cell behavior, which are critical for tumor progression. Angiogenesis and therapeutic resistance are known to be modulated by hypoxia and other tumor microenvironments, such as acidic stress, both of which are core features of the glioblastoma microenvironment. Hypoxia has also been shown to promote a stem-like state in both non-neoplastic and tumor cells. In glial tumors, glioma stem cells (GSCs) are central in tumor growth, angiogenesis, and therapeutic resistance, and further investigation of the interplay between tumor microenvironments and GSCs is critical to the search for better treatment options for glioblastoma. Accordingly, we summarize the impact of hypoxia and acidic stress on GSC signaling and biologic phenotypes, and potential methods to inhibit these pathways.
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http://dx.doi.org/10.7150/thno.41692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738846PMC
January 2021

Direct oral anticoagulants for therapeutic anticoagulation in postoperative pulmonary embolism after meningioma resection.

J Clin Neurosci 2020 Nov 16;81:265-269. Epub 2020 Oct 16.

Department of Neurosurgery, University Medicine of Rostock, Rostock, Germany.

Background: Acute postoperative pulmonary embolism (PE) is a dreaded complication with severe mortality rates. Brain tumor patients are at the highest risk for postoperative PE. The juxtaposition of low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA) and direct oral anticoagulation (DOAC) in the treatment of postoperative PE in meningioma patients is largely unexplored.

Patients/methods: This is a single center observational analysis of meningioma patients who underwent neurosurgical resection with a thoracic CT scan confirmation of postoperative PE. The treatment modality, clinical course and outcome were investigated.

Results: Of 538 meningioma patients operated, 30 (6%) developed acute postoperative PE. After diagnosis, these patients received different long-term anticoagulation regimes. No significant difference in postoperative hemorrhage (p < 0.56), re-operation rate (p < 0.70) or Karnofsky performance scale (KPS) at 3 (p < 0.34) and 12 months (p = 1) were identified, when compared according to the different anticoagulation regimes.

Conclusion: DOACs were not associated with elevated risk for hemorrhage, recurrent thrombosis or poor outcome when compared with traditional anticoagulation regimes. Prospective randomized trials are necessary to verify the non-inferiority of DOACs for long-term anticoagulation in postoperative pulmonary embolism after meningioma resection.
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http://dx.doi.org/10.1016/j.jocn.2020.09.059DOI Listing
November 2020

Supervised Valsalva Maneuver after Burr Hole Evacuation of Chronic Subdural Hematomas: A Prospective Cohort Study.

J Neurotrauma 2021 Apr 14;38(7):911-917. Epub 2020 Dec 14.

Department of Neurosurgery, University Hospital, and Goethe University, Frankfurt, Germany.

Research on chronic subdural hematoma (cSDH) management has primarily focused on potential recurrence after surgical evacuation. Herein, we present a novel postoperative/non-invasive treatment that includes a supervised Valsalva maneuver (SVM), which may serve to reduce SDH recurrence. Accordingly, the aims of the study were to investigate the effects of SVM on SDH recurrence rates and functional outcomes. A prospective study was conducted from December 2016 until December 2019 at the Goethe University Hospital Frankfurt. Of the 204 adult patients with surgically treated cSDH who had subdural drains placed, 94 patients were assigned to the SVM group and 82 patients were assigned to the control group. The SVM was performed by having patients blow into a self-made SVM device at least two times/h for 12 h/day. The primary end-point was SDH recurrence rate, while secondary outcomes were morbidity and functional outcomes at 3 months of follow-up. SDH recurrence was observed in 16 of 94 patients (17%) in the SVM group, which was a significant reduction as compared with the control group, which had 24 of 82 patients (29.3%;  = 0.05) develop recurrent SDHs. Further, the infection rate (e.g., pneumonia) was significantly lower in the SVM group (1.1%) than in the control group (13.4%;  < 0.001; odds ratio [OR] 0.1). At the 3-month follow-up, 85 of 94 patients (90.4%) achieved favorable outcomes in the SVM group compared with 62 of 82 patients (75.6%) in the control group ( = 0.008; OR 3.0). Independent predictors for favorable outcome at follow-up were age (OR 0.9) and infection (OR 0.2). SVM appears to be safe and effective in the post-operative management of cSDHs, reducing both recurrence rates and infections after surgical evacuation, thereby resulting in favorable outcomes at follow-up.
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http://dx.doi.org/10.1089/neu.2020.7391DOI Listing
April 2021

Concussion in soccer: a comprehensive review of the literature.

Concussion 2020 Jul 1;5(3):CNC76. Epub 2020 Jul 1.

Department of Neurosurgery, University of Alabama at Birmingham, 1813 6th Ave S #516, Birmingham, AL 35233, USA.

Sports-related concussion has been examined extensively in collision sports such as football and hockey. However, historically, lower-risk contact sports such as soccer have only more recently garnered increased attention. Here, we review articles examining the epidemiology, injury mechanisms, sex differences, as well as the neurochemical, neurostructural and neurocognitive changes associated with soccer-related concussion. From 436 titles and abstracts, 121 full texts were reviewed with a total of 64 articles identified for inclusion. Concussion rates are higher during competitions and in female athletes with purposeful heading rarely resulting in concussion. Given a lack of high-level studies examining sports-related concussion in soccer, clinicians and scientists must focus research efforts on large-scale data gathering and development of improved technologies to better detect and understand concussion.
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http://dx.doi.org/10.2217/cnc-2020-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506470PMC
July 2020

Intraventricular metastatic melanoma: A case report and review of the literature.

Clin Case Rep 2020 Sep 3;8(9):1757-1764. Epub 2020 Jul 3.

Department of Neurosurgery The University of Alabama at Birmingham Birmingham AL USA.

Intraventricular melanoma is a very rare and highly malignant disease. Safe resection is the mainstay of treatment, but no standard guidelines exist for adjuvant therapy. Early histologic and molecular diagnosis is key for improved survival.
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http://dx.doi.org/10.1002/ccr3.2983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495808PMC
September 2020

Rapid Evolution and Rupture of an Incidental Aneurysm During Hyperdynamic Therapy for Cerebral Vasospasm.

World Neurosurg 2021 Jan 18;145:205-209. Epub 2020 Sep 18.

Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Among the most common sequelae of aSAH is delayed cerebral ischemia. Hyperdynamic therapy (fluid supplementation and hypertension) is used to increase cerebral perfusion. However, the safety of hyperdynamic therapy in patients with separate unruptured, unsecured intracranial aneurysms is not well-established. Herein, a rare case demonstrating the rapid evolution and rupture of an incidental unsecured aneurysm in the setting of hyperdynamic therapy is presented.

Case Description: A 56-year-old woman without significant medical history presented with aSAH secondary to rupture of a 3-mm left posterior inferior cerebellar artery aneurysm. After endovascular treatment of this aneurysm, she developed symptomatic vasospasm prompting initiation of hyperdynamic therapy. Seven days after initiation of hyperdynamic therapy, she experienced rupture of an incidental pericallosal artery aneurysm that was found to have increased in size during the hyperdynamic therapy. She ultimately survived and was functionally independent approximately 1 year after her initial ictus.

Conclusions: This case demonstrates that enlargement and rupture of an incidental, previously unruptured aneurysm may occur during hyperdynamic therapy.
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http://dx.doi.org/10.1016/j.wneu.2020.09.078DOI Listing
January 2021

Small ubiquitin-like modifier 2 (SUMO2) is critical for memory processes in mice.

FASEB J 2020 11 10;34(11):14750-14767. Epub 2020 Sep 10.

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

Small ubiquitin-like modifier (SUMO1-3) conjugation (SUMOylation), a posttranslational modification, modulates almost all major cellular processes. Mounting evidence indicates that SUMOylation plays a crucial role in maintaining and regulating neural function, and importantly its dysfunction is implicated in cognitive impairment in humans. We have previously shown that simultaneously silencing SUMO1-3 expression in neurons negatively affects cognitive function. However, the roles of the individual SUMOs in modulating cognition and the mechanisms that link SUMOylation to cognitive processes remain unknown. To address these questions, in this study, we have focused on SUMO2 and generated a new conditional Sumo2 knockout mouse line. We found that conditional deletion of Sumo2 predominantly in forebrain neurons resulted in marked impairments in various cognitive tests, including episodic and fear memory. Our data further suggest that these abnormalities are attributable neither to constitutive changes in gene expression nor to alterations in neuronal morphology, but they involve impairment in dynamic SUMOylation processes associated with synaptic plasticity. Finally, we provide evidence that dysfunction on hippocampal-based cognitive tasks was associated with a significant deficit in the maintenance of hippocampal long-term potentiation in Sumo2 knockout mice. Collectively, these data demonstrate that protein conjugation by SUMO2 is critically involved in cognitive processes.
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http://dx.doi.org/10.1096/fj.202000850RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606628PMC
November 2020

Checkpoint inhibitor immunotherapy for glioblastoma: current progress, challenges and future outlook.

Expert Rev Clin Pharmacol 2020 Oct 11;13(10):1147-1158. Epub 2020 Sep 11.

Department of Neurosurgery, Duke University Medical Center , Durham, NC, USA.

Introduction: Despite maximal surgical resection and chemoradiation, glioblastoma (GBM) continues to be associated with significant morbidity and mortality. Novel therapeutic strategies are urgently needed. Given success in treating multiple other forms of cancer, checkpoint inhibitor immunotherapy remains foremost amongst novel therapeutic strategies that are currently under investigation.

Areas Covered: Through a systematic review of both published literature and the latest preliminary data available from ongoing clinical studies, we provide an up-to-date discussion on the immune system in the CNS, a detailed mechanistic evaluation of checkpoint biology in the CNS along with evidence for disruption of these pathways in GBM, and a summary of available preclinical and clinical data for checkpoint blockade in GBM. We also include a discussion of novel, emerging targets for checkpoint blockade which may play an important role in GBM immunotherapy.

Expert Opinion: Evidence indicates that while clinical success of checkpoint blockade for the treatment of GBM has been limited to date, through improved preclinical models, optimization in the context of standard of care therapies, assay standardization and harmonization, and combinatorial approaches which may include novel targets for checkpoint blockade, checkpoint inhibitor immunotherapy may yield a safe and effective therapeutic option for the treatment of GBM.
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http://dx.doi.org/10.1080/17512433.2020.1817737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658017PMC
October 2020

DNMT1 and DNMT3B regulate tumorigenicity of human prostate cancer cells by controlling RAD9 expression through targeted methylation.

Carcinogenesis 2021 Feb;42(2):220-231

Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Prostate cancer is the second most common type of cancer and the second leading cause of cancer death in American men. RAD9 stabilizes the genome, but prostate cancer cells and tumors often have high quantities of the protein. Reduction of RAD9 level within prostate cancer cells decreases tumorigenicity of nude mouse xenographs and metastasis phenotypes in culture, indicating that RAD9 overproduction is essential for the disease. In prostate cancer DU145 cells, CpG hypermethylation in a transcription suppressor site of RAD9 intron 2 causes high-level gene expression. Herein, we demonstrate that DNA methyltransferases DNMT1 and DNMT3B are highly abundant in prostate cancer cells DU145, CWR22, LNCaP and PC-3; yet, these DNMTs bind primarily to the transcription suppressor in DU145, the only cells where methylation is critical for RAD9 regulation. For DU145 cells, DNMT1 or DNMT3B shRNA reduced RAD9 level and tumorigenicity, and RAD9 ectopic expression restored this latter activity in the DNMT knockdown cells. High levels of RAD9, DNMT1, DNMT3B and RAD9 transcription suppressor hypermethylation were significantly correlated in prostate tumors, and not in normal prostate tissues. Based on these results, we propose a novel model where RAD9 is regulated epigenetically by DNMT1 and DNMT3B, via targeted hypermethylation, and that consequent RAD9 overproduction promotes prostate tumorigenesis.
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http://dx.doi.org/10.1093/carcin/bgaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905840PMC
February 2021

Incidence and risk factors for seizures associated with deep brain stimulation surgery.

J Neurosurg 2020 Aug 7:1-5. Epub 2020 Aug 7.

Departments of1Neurosurgery and.

Objective: The objective of this study was to determine the incidence of seizures following deep brain stimulation (DBS) electrode implantation and to evaluate factors associated with postoperative seizures.

Methods: The authors performed a single-center retrospective case-control study. The outcome of interest was seizure associated with DBS implantation. Univariate analyses were performed using the Student t-test for parametric continuous outcomes. The authors used the Kruskal-Wallis test or Wilcoxon rank-sum test for nonparametric continuous outcomes, chi-square statistics for categorical outcomes, and multivariate logistic regression for binomial variables.

Results: A total of 814 DBS electrode implantations were performed in 645 patients (478 [58.7%] in men and 520 [63.9%] in patients with Parkinson's disease). In total, 22 (3.4%) patients who had undergone 23 (2.8%) placements experienced seizure. Of the 23 DBS implantation-related seizures, 21 were new-onset seizures (3.3% of 645 patients) and 2 were recurrence or worsening of a prior seizure disorder. Among the 23 cases with postimplantation-related seizure, epilepsy developed in 4 (17.4%) postoperatively; the risk of DBS-associated epilepsy was 0.50% per DBS electrode placement and 0.63% per patient. Nine (39.1%) implantation-related seizures had associated postoperative radiographic abnormalities. Multivariate analyses suggested that age at surgery conferred a modest increased risk for postoperative seizures (OR 1.06, 95% CI 1.02-1.10). Sex, primary diagnosis, electrode location and sidedness, and the number of trajectories were not significantly associated with seizures after DBS surgery.

Conclusions: Seizures associated with DBS electrode placement are uncommon, typically occur early within the postoperative period, and seldom lead to epilepsy. This study suggests that patient characteristics, such as age, may play a greater role than perioperative variables in determining seizure risk. Multiinstitutional studies may help better define and mitigate the risk of seizures after DBS surgery.
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http://dx.doi.org/10.3171/2020.5.JNS20125DOI Listing
August 2020

Intracranial anaplastic solitary fibrous tumor/hemangiopericytoma: immunohistochemical markers for definitive diagnosis.

Neurosurg Rev 2020 Jul 15. Epub 2020 Jul 15.

Department of Neurosurgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.

Intracranial anaplastic hemangiopericytoma (AHPC) is a rare and malignant subset of solitary fibrous tumor/hemangiopericytoma (SFT/HPC) as per the WHO 2016 Classification of Tumors of the Central Nervous System. AHPC portends a poor prognosis and is associated with higher rates of recurrence/metastasis in comparison with SFT/HPC. Accordingly, it is critical to continue to define the clinical course of patients with AHPC and in so doing further refine clinicopathologic/immunohistochemical (IHC) criteria needed for definitive diagnosis. Herein, we describe clinical/histological characteristics of six patients with AHPC. In addition, we reviewed and analyzed the expression of various IHC markers reported within the literature (i.e., a total of 354 intracranial SFT/HPCs and 460 meningiomas). Histologically, tumors from our six patients were characterized by a staghorn-like vascular pattern, mitotic cells, and strong nuclear atypia. Immunohistochemically, all tumors displayed positive nuclear staining for STAT6; other markers, including CD34 and Bcl-2, were expressed only in three patients. Analysis of IHC expression patterns for SFT/HPC and meningioma within the literature revealed that nuclear expression of STAT6 had the highest specificity (100%) for SFT/HPC, followed by ALDH1 (97.2%) and CD34 (93.6%). Of note, SSTR2A (95.2%) and EMA (85%) displayed a high specificity for meningioma. Anaplastic SFT/HPC is a tumor with poor prognosis that is associated with higher rates of recurrence and metastasis in comparison with SFT/HPC. Given that anaplastic SFT/HPC requires more aggressive treatment than meningioma despite of a similar presentation on imaging, it is crucial to be able to distinguish between these tumors.
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http://dx.doi.org/10.1007/s10143-020-01348-6DOI Listing
July 2020

Design and Rationale for First-in-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic HSV G207 to Treat Malignant Pediatric Cerebellar Brain Tumors.

Hum Gene Ther 2020 10 17;31(19-20):1132-1139. Epub 2020 Aug 17.

Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.
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http://dx.doi.org/10.1089/hum.2020.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585605PMC
October 2020

Impact of insurance on hospital course and readmission after resection of benign meningioma.

J Neurooncol 2020 Aug 11;149(1):131-140. Epub 2020 Jul 11.

Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, USA.

Introduction: Surgical outcomes and healthcare utilization have been shown to vary based on patient insurance status. We analyzed whether patients' insurance affects case urgency for and readmission after craniotomy for meningioma resection, using benign meningioma as a model system to minimize confounding from the disease-related characteristics of other neurosurgical pathologies.

Methods: We analyzed 90-day readmission for patients who underwent resection of a benign meningioma in the Nationwide Readmission Database from 2014-2015.

Results: A total of 9783 meningioma patients with private insurance (46%), Medicare (39%), Medicaid (10%), self-pay (2%), or another scheme (3%) were analyzed. 72% of all cases were elective; with 78% of cases in privately insured patients being elective compared to 71% of Medicare (p > 0.05), 59% of Medicaid patients (OR 2.3, p < 0.001), and 49% of self-pay patients (OR 3.4, p < 0.001). Medicare (OR 1.5, p = 0.002) and Medicaid (OR 1.4, p = 0.035) were both associated with higher likelihood of 90-day readmission compared to private insurance. In comparison, 30-day analyses did not unveil this discrepancy between Medicaid and privately insured, highlighting the merit for longer-term outcomes analyses in value-based care. Patients readmitted within 30 days versus those with later readmissions possessed different characteristics.

Conclusions: Compared to patients with private insurance coverage, Medicaid and self-pay patients were significantly more likely to undergo non-elective resection of benign meningioma. Medicaid and Medicare insurance were associated with a higher likelihood of 90-day readmission; only Medicare was significant at 30 days. Both 30 and 90-day outcomes merit consideration given differences in readmitted populations.
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http://dx.doi.org/10.1007/s11060-020-03581-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484429PMC
August 2020

Corpus Callosotomy for Refractory Epilepsy in Aicardi Syndrome: Case Report and Focused Review of the Literature.

World Neurosurg 2020 10 9;142:450-455. Epub 2020 Jul 9.

Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Aicardi syndrome is a severe neurodevelopmental disorder that occurs primarily in females and is characterized by seizures, agenesis of the corpus callosum, and chorioretinal lacunae, which occur together in the majority of affected individuals. Seizures begin in infancy and tend to progress in intensity and are often refractory to standard multimodal medication treatments.

Case Description: We present here a unique case of a 12-year-old girl with partial agenesis of the corpus callosum who underwent a corpus callosotomy for treatment of medically refractory epilepsy. In so doing, we also review the literature with regard to the neurosurgical management of these unique patients.

Conclusions: For the subset of children who present with partial, rather than complete, agenesis of the corpus callosum, corpus callosotomy should be considered as a treatment option to reduce seizure burden.
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http://dx.doi.org/10.1016/j.wneu.2020.06.230DOI Listing
October 2020

The diagnosis and management of primary and iatrogenic soft tissue sarcomas of the sella.

Pituitary 2020 Oct;23(5):558-572

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

Purpose: Soft tissue sarcoma (STS) of the sella is exceptionally rare. We conducted a case series, literature review, and nationwide analysis of primary and iatrogenic (radiation-associated) STS of the sella to define the clinical course of this entity.

Methods: This study employed a multi-institutional retrospective case review, literature review, and nationwide analysis using the National Cancer Database (NCDB).

Results: We report five patients who were diagnosed at three institutions with malignant STS of the sella. All patients presented with symptoms related to mass effect in the sellar region. All tumors extended to the suprasellar space, with the majority displaying extension into the cavernous sinus. All patients underwent an operation via a transsphenoidal approach with a goal of maximal safe tumor resection in four patients and biopsy for 1 patient. Histopathologic evaluation demonstrated STS in all patients. Post-operative adjuvant radiotherapy and chemotherapy were given to 2 and 1 out of 4 patients with known post-operative clinical course, respectively. The 1-year and 5-year overall survival rates were 100% (5/5) and 25% (1/4). Twenty-two additional reports of primary, non-iatrogenic STS of the sella were identified in the literature. Including the three cases from our series, treatment included resection in all cases, and adjuvant radiotherapy and chemotherapy were utilized in 50% (12/24) and 17% (4/24) of cases, respectively. The national prevalence of malignant STS is estimated to be 0.01% among all pituitary and sellar tumors within the NCDB.

Conclusions: We report the prevalence and survival rates of STS of the sella. Multimodal therapy, including maximal safe resection, chemotherapy, and radiotherapy are necessary to optimize outcomes for this uncommon pathology.
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http://dx.doi.org/10.1007/s11102-020-01062-yDOI Listing
October 2020

Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits.

Acta Neuropathol Commun 2020 06 9;8(1):84. Epub 2020 Jun 9.

Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA.

Multiple Sclerosis (MS) causes neurologic disability due to inflammation, demyelination, and neurodegeneration. Immunosuppressive treatments can modify the disease course but do not effectively promote remyelination or prevent long term neurodegeneration. As a novel approach to mitigate chronic stage pathology, we tested transplantation of mouse induced neural stem cells (iNSCs) into the chronically demyelinated corpus callosum (CC) in adult mice. Male C57BL/6 mice fed 0.3% cuprizone for 12 weeks exhibited CC atrophy with chronic demyelination, astrogliosis, and microglial activation. Syngeneic iNSCs were transplanted into the CC after ending cuprizone and perfused for neuropathology 2 weeks later. Magnetic resonance imaging (MRI) sequences for magnetization transfer ratio (MTR), diffusion-weighted imaging (T2), and diffusion tensor imaging (DTI) quantified CC pathology in live mice before and after iNSC transplantation. Each MRI technique detected progressive CC pathology. Mice that received iNSCs had normalized DTI radial diffusivity, and reduced astrogliosis post-imaging. A motor skill task that engages the CC is Miss-step wheel running, which demonstrated functional deficits from cuprizone demyelination. Transplantation of iNSCs resulted in marked recovery of running velocity. Neuropathology after wheel running showed that iNSC grafts significantly increased host oligodendrocytes and proliferating oligodendrocyte progenitors, while modulating axon damage. Transplanted iNSCs differentiated along astrocyte and oligodendrocyte lineages, without myelinating, and many remained neural stem cells. Our findings demonstrate the applicability of neuroimaging and functional assessments for pre-clinical interventional trials during chronic demyelination and detect improved function from iNSC transplantation. Directly reprogramming fibroblasts into iNSCs facilitates the future translation towards exogenous autologous cell therapies.
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http://dx.doi.org/10.1186/s40478-020-00960-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285785PMC
June 2020

Complex Management of Hydrocephalus Secondary To Choroid Plexus Hyperplasia.

World Neurosurg 2020 09 1;141:101-109. Epub 2020 Jun 1.

Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Background: Hyperplasia of the choroid plexus represents a rare cause of communicating hydrocephalus in children. Recent work has associated such disease with genetic abnormalities (such as perturbations in chromosome 9). Given such extensive cerebrospinal fluid (CSF) overproduction, patients with choroid plexus hyperplasia often fail CSF diversion and therefore require adjuvant interventions.

Case Description: We present the case of a male infant with a ventriculoperitoneal shunt and radiographic choroid hyperplasia who presented to our institution with a massive abdominal hydrocele caused by an inability to absorb the significant amount of CSF drainage into the abdomen.

Conclusion: The child was treated with an endoscopic third ventriculostomy and choroid plexus coagulation; however, he still required CSF diversion via a ventriculoatrial shunt. A genetic workup showed tetraploidy of chromosome 9. We discuss criteria for selection of treatment strategies, including endoscopic third ventriculostomy with choroid plexus coagulation and/or CSF diversion, that may prevent the need for re-operation in select patients with hydrocephalus due to choroid plexus hyperplasia.
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http://dx.doi.org/10.1016/j.wneu.2020.05.211DOI Listing
September 2020

Risk factors for wound-related complications after microvascular decompression.

Neurosurg Rev 2021 Apr 18;44(2):1093-1101. Epub 2020 Apr 18.

Department of Neurological Surgery, University of Alabama at Birmingham, 1057 Faculty Office Tower, 510 20th Street South, Birmingham, AL, 35294-3410, USA.

Retrosigmoid craniotomy for microvascular decompression (MVD) has been traditionally performed via craniectomy. Various closure techniques have been described, yet factors associated with wound-related complications remain undetermined. Accordingly, herein, we sought to identify risk factors associated with wound-related complications after such procedures. An institutional retrospective case-control study was performed; outcomes of interest were cerebrospinal fluid (CSF) leak, wound dehiscence, wound infection, and pseudomeningocele. Univariate analysis was performed using Wilcoxon rank sum test for non-parametric continuous outcomes and chi-square test for categorical outcomes. Multivariate logistic regression was performed on binomial outcome variables. The study population included 197 patients who underwent MVD for trigeminal neuralgia (83.2%), hemifacial spasm (12.2%), vestibular nerve section (3.0%), and glossopharyngeal neuralgia (1.5%). The overall wound-related complication rate was 14.2% (n = 28), including twelve patients (6.1%) with CSF leak, ten patients (5.1%) with wound infection, ten patients (5.1%) with pseudomeningocele, and nine (4.6%) patients with wound dehiscence. Using multivariate logistic regression, preoperative anemia and current tobacco use were associated with significantly higher rates of complications (OR 6.01 and 4.58, respectively; p < 0.05), including CSF leak (OR 12.83 and 12.40, respectively, p < 0.05). Of note, use of synthetic bone substitute for cranioplasty was associated with a significantly lower rate of complications (OR 0.13, p < 0.01). Preoperative anemia and current tobacco use significantly increased, while synthetic bone substitute cranioplasty significantly decreased, odds of wound-related complications, the need for treatment, and CSF leaks. Additionally, higher BMI, longer operative duration, and prior radiosurgery may increase risk for wound-related complications.
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http://dx.doi.org/10.1007/s10143-020-01296-1DOI Listing
April 2021

Central Nervous System-Invading Eccrine Gland Carcinoma: A Clinicopathologic Case Series and Literature Review.

World Neurosurg 2020 06 3;138:e17-e25. Epub 2020 Mar 3.

Computational Neurosciences Outcomes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Eccrine carcinoma involvement of the central nervous system (CNS) is exceedingly rare. The prognosis and response to treatment of this pathology remain poorly characterized.

Methods: A retrospective case series and literature review were conducted.

Results: CNS-invading eccrine carcinoma was diagnosed in 3 patients (2 male and 1 female; age range, 60-79 years), including 2 cases of brain metastases and 1 case of brain-invading skull metastasis with subsequent spinal metastasis. The interval from primary tumor to CNS invasion was 18-51 months. All patients received multimodal therapy following diagnosis of CNS involvement. One patient who harbored a NOTCH1 mutation demonstrated a durable oncologic response after treatment with the immune checkpoint inhibitor pembrolizumab and lived 39 months after CNS invasion. The other 2 patients were discharged to hospice care within 1 month after the diagnosis of eccrine carcinoma brain metastasis. Including this case series, 23 cases of eccrine carcinoma invasion or metastasis to the CNS have been reported, with survival after diagnosis of CNS involvement ranging from a few weeks to 4 years.

Conclusions: We present 3 cases of eccrine carcinoma metastatic to the CNS, including the first reported case to our knowledge of eccrine carcinoma treated with immunotherapy. This case, harboring a NOTCH1 mutation, demonstrated the longest durable oncologic response reported in this rare disease. Genomic and molecular testing may play increasingly important roles in the evaluation of these metastases.
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http://dx.doi.org/10.1016/j.wneu.2020.01.111DOI Listing
June 2020

Identification of ALDH1A3 as a Viable Therapeutic Target in Breast Cancer Metastasis-Initiating Cells.

Mol Cancer Ther 2020 05 3;19(5):1134-1147. Epub 2020 Mar 3.

Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.

The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates; however, this has failed to positively affect the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial-mesenchymal transition (EMT) gene signature (mesenchymal markers, CD44 or Vimentin) were compared in tumors derived from BM, lung metastases (LM), or bone metastases (BoM) of patients as well as mice after injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small-molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716183PMC
May 2020

Medullary Infarction Leading to Locked-In Syndrome Following Lumbar Puncture in a Patient with Basilar Invagination.

World Neurosurg 2020 05 14;137:292-295. Epub 2020 Feb 14.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Background: Lumbar puncture is a common procedure that can be safely performed in most patients. Certain populations may have increased risk for complications following lumbar puncture, but the significance of basilar invagination is often underappreciated.

Case Description: A 45-year-old woman with basilar invagination received multiple lumbar punctures in the workup of acute meningitis. Preprocedural computed tomography was obtained. Following lumbar puncture, the patient developed locked-in syndrome. Magnetic resonance imaging obtained several days later demonstrated severe compression and infarction of the medulla and inferior cerebellum by the odontoid process and ectopic cerebellar tonsils. The patient was transferred but at this point, surgical decompression was not possible. She did not regain significant neurologic function.

Conclusions: Basilar invagination is a risk factor for devastating neurologic complications following lumbar puncture. Awareness of this complication and prompt recognition of its occurrence may prevent future morbidity of lumbar puncture in patients with basilar invagination.
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http://dx.doi.org/10.1016/j.wneu.2020.02.040DOI Listing
May 2020

Targeting glioma-initiating cells via the tyrosine metabolic pathway.

J Neurosurg 2020 Feb 14:1-12. Epub 2020 Feb 14.

Departments of1Neurosurgery and.

Objective: Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism.

Methods: Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry.

Results: Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core.

Conclusions: Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.
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http://dx.doi.org/10.3171/2019.11.JNS192028DOI Listing
February 2020