Clinical trial links oncolytic immunoactivation to survival in glioblastoma.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).

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

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 (107 or 108 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.).

Neural stem cells traffic functional mitochondria via extracellular vesicles.

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.

Elevated risk of recurrence and retreatment for silent pituitary adenomas.

PURPOSE: Pituitary adenomas are the most common tumor of the pituitary gland and comprise nearly 15% of all intracranial masses. These tumors are stratified into functional or silent categories based on their pattern of hormone expression and secretion. Preliminary evidence supports differential clinical outcomes between some functional pituitary adenoma (FPA) subtypes and silent pituitary adenoma (SPA) subtypes. METHODS: We collected and analyzed the medical records of all patients undergoing resection of SPAs or FPAs from a single high-volume neurosurgeon between 2007 and 2018 at Brigham and Women's Hospital. Descriptive statistics and the Mantel-Cox log-rank test were used to identify differences in outcomes between these cohorts, and multivariate logistic regression was used to identify predictors of radiographic recurrence for SPAs. RESULTS: Our cohort included 88 SPAs and 200 FPAs. The majority of patients in both cohorts were female (48.9% of SPAs and 63.5% of FPAs). SPAs were larger in median diameter than FPAs (2.1 cm vs. 1.2 cm, p < 0.001). The most frequent subtypes of SPA were gonadotrophs (55.7%) and corticotrophs (30.7%). Gross total resection (GTR) was achieved in 70.1% of SPA resections and 86.0% of FPA resections (p < 0.001). SPAs had a higher likelihood of recurring (hazard ratio [HR] 3.2, 95% confidence interval [95%CI] 1.6-7.2) and a higher likelihood of requiring retreatment for recurrence (HR 2.5; 95%CI 1.0-6.1). Subset analyses revealed that recurrence and retreatment were more both likely for subtotally resected SPAs than subtotally resected FPAs, but this pattern was not observed in SPAs and FPAs after GTR. Among SPAs, recurrence was associated with STR (odds ratio [OR] 9.3; 95%CI 1.4-64.0) and younger age (OR 0.92 per year; 95%CI 0.88-0.98) in multivariable analysis. Of SPAs that recurred, 12 of 19 (63.2%) were retreated with repeat surgery (n = 11) or radiosurgery (n = 1), while the remainder were observed (n = 7).There were similar rates of recurrence across different SPA subtypes. CONCLUSION: Patients undergoing resection of SPAs should be closely monitored for disease recurrence through more frequent clinical follow-up and diagnostic imaging than other adenomas, particularly among patients with STR and younger patients. Several patients can be observed after radiographic recurrence, and the decision to retreat should be individualized. Longitudinal clinical follow-up of SPAs, including an assessment of symptoms, endocrine function, and imaging remains critical.

Leveraging artificial intelligence in neurosurgery-unveiling ChatGPT for neurosurgical discharge summaries and operative reports.

PURPOSE: Chat generative pre-trained transformer (GPT) is a novel large pre-trained natural language processing software that can enable scientific writing amongst a litany of other features. Given this, there is a growing interest in exploring the use of ChatGPT models as a modality to facilitate/assist in the provision of clinical care. METHODS: We investigated the time taken for the composition of neurosurgical discharge summaries and operative reports at a major University hospital. In so doing, we compared currently employed speech recognition software (i.e., SpeaKING) vs novel ChatGPT for three distinct neurosurgical diseases: chronic subdural hematoma, spinal decompression, and craniotomy. Furthermore, factual correctness was analyzed for the abovementioned diseases. RESULTS: The composition of neurosurgical discharge summaries and operative reports with the assistance of ChatGPT leads to a statistically significant time reduction across all three diseases/report types: p < 0.001 for chronic subdural hematoma, p < 0.001 for decompression of spinal stenosis, and p < 0.001 for craniotomy and tumor resection. However, despite a high degree of factual correctness, the preparation of a surgical report for craniotomy proved to be significantly lower (p = 0.002). CONCLUSION: ChatGPT assisted in the writing of discharge summaries and operative reports as evidenced by an impressive reduction in time spent as compared to standard speech recognition software. While promising, the optimal use cases and ethics of AI-generated medical writing remain to be fully elucidated and must be further explored in future studies.

Recurrent Glioblastoma-Molecular Underpinnings and Evolving Treatment Paradigms.

Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

Global, Regional, and National Economic Consequences of Stroke.

BACKGROUND: An understanding of global, regional, and national macroeconomic losses caused by stroke is important for allocation of clinical and research resources. The authors investigated the macroeconomic consequences of stroke disease burden in the year 2019 in 173 countries. METHODS: Disability-adjusted life year data for overall stroke and its subtypes (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) were collected from the GBD study (Global Burden of Disease) 2019 database. Gross domestic product (GDP, adjusted for purchasing power parity [PPP]) data were collected from the World Bank; GDP and disability-adjusted life year data were combined to estimate macroeconomic losses using a value of lost welfare (VLW) approach. All results are presented in 2017 international US dollars adjusted for PPP. RESULTS: Globally, in 2019, VLW due to stroke was $2059.67 billion or 1.66% of the global GDP. Global VLW/GDP for stroke subtypes was 0.78% (VLW=$964.51 billion) for ischemic stroke, 0.71% (VLW=$882.81 billion) for intracerebral hemorrhage, and 0.17% (VLW=$212.36 billion) for subarachnoid hemorrhage. The Central European, Eastern European, and Central Asian GBD super-region reported the highest VLW/GDP for stroke overall (3.01%), ischemic stroke (1.86%), and for subarachnoid hemorrhage (0.26%). The Southeast Asian, East Asian, and Oceanian GBD super-region reported the highest VLW/GDP for intracerebral hemorrhage (1.48%). CONCLUSIONS: The global macroeconomic consequences related to stroke are vast even when considering stroke subtypes. The present quantification may be leveraged to help justify increased spending of finite resources on stroke in an effort to improve outcomes for patients with stroke globally.

Cerebellar Stroke Score and Grading Scale for the Prediction of Mortality and Outcomes in Ischemic Cerebellar Stroke.

BACKGROUND: Several individual predictors for outcomes in patients with cerebellar stroke (CS) have been previously identified. There is, however, no established clinical score for CS. Therefore, the aim of this study was to develop simple and accurate grading scales for patients with CS in an effort to better estimate mortality and outcomes. METHODS: This multicentric retrospective study included 531 patients with ischemic CS presenting to 5 different academic neurosurgical and neurological departments throughout Germany between 2008 and 2021. Logistic regression analysis was performed to determine independent predictors related to 30-day mortality and unfavorable outcome (modified Rankin Scale score of 4-6). By weighing each parameter via calculation of regression coefficients, an ischemic CS-score and CS-grading scale (CS-GS) were developed and internally validated. RESULTS: Independent predictors for 30-day mortality were aged ≥70 years (odds ratio, 5.2), Glasgow Coma Scale score 3 to 4 at admission (odds ratio, 2.6), stroke volume ≥25 cm3 (odds ratio, 2.7), and involvement of the brain stem (odds ratio, 3.9). When integrating each parameter into the CS-score, age≥70 years and brain stem stroke were assigned 2 points, Glasgow Coma Scale score 3 to 4, and stroke volume≥25 cm3 1 point resulting in a score ranging from 0 to 6. CS-score of 0, 1, 2, 3, 4, 5, and 6 points resulted in 30-day mortality of 1%, 6%, 6%, 17%, 21%, 55%, and 67%, respectively. Independent predictors for 30-day unfavorable outcomes consisted of all components of the CS-score with an additional variable focused on comorbidities (CS-GS). Except for Glasgow Coma Scale score 3 to 4 at admission, which was assigned 3 points, all other parameters were assigned 1 point resulting in an overall score ranging from 0 to 7. CS-GS of 0, 1, 2, 3, 4, 5, 6, and 7 points resulted in 30-day unfavorable outcome of 1%, 17%, 33%, 40%, 50%, 80%, 77%, and 100%, respectively. Both 30-day mortality and unfavorable outcomes increased with increasing CS-score and CS-GS (P<0.001). CONCLUSIONS: The CS-score and CS-GS are simple and accurate grading scales for the prediction of 30-day mortality and unfavorable outcome in patients with CS. While the score systems proposed here may not directly impact treatment decisions, it may help discuss mortality and outcome with patients and caregivers.

Metastatic pituitary tumors: an institutional case series.

PURPOSE: Pituitary carcinomas are a rare entity that respond poorly to multimodal therapy. Patients follow a variable disease course that remains ill-defined. METHODS: We present an institutional case series of patients treated for pituitary carcinomas over a 30-year period from 1992 to 2022. A systematic review was conducted to identify prior case series of patients with pituitary carcinomas. RESULTS: Fourteen patients with a mean age at pituitary carcinoma diagnosis of 52.5 years (standard deviation [SD] 19.4) met inclusion criteria. All 14 patients had tumor subtypes confirmed by immunohistochemistry and hormone testing, with the most common being ACTH-producing pituitary adenomas (n = 12). Patients had a median progression-free survival (PFS) of 1.4 years (range 0.7-10.0) and a median overall survival (OS) of 8.4 years (range 2.3-24.0) from pituitary adenoma diagnosis. Median PFS and OS were 0.6 years (range 0.0-2.2) and 1.5 years (range 0.1-9.6) respectively upon development of metastases. Most patients (n = 12) had locally invasive disease to the cavernous sinus, dorsum sellae dura, or sphenoid sinus prior to metastasis. Common sites of metastasis included the central nervous system, liver, lung, and bone. In a pooled analysis including additional cases from the literature, treatment of metastases with chemotherapy or a combination of radiation therapy and chemotherapy significantly prolonged PFS (p = 0.02), while failing to significantly improve OS (p = 0.14). CONCLUSION: Pituitary carcinomas are highly recurrent, heterogenous tumors with variable responses to treatment. Multidisciplinary management with an experienced neuro-endocrine and neuro-oncology team is needed given the unrelenting nature of this disease.

Syndrome of anterior neural stalk, vertebral abnormality, enteric duplication cyst, and diaphragmatic hernia related to persistent ventral neurenteric canal: report of two cases.

PURPOSE: Abnormalities in notochordal development can cause a range of developmental malformations, including the split notochord syndrome and split cord malformations. We describe two cases that appear related to unusual notochordal malformations, in a female and a male infant diagnosed in the early postnatal and prenatal periods, which were treated at our institution. These cases were unusual from prior cases given a shared constellation of an anterior cervicothoracic meningocele with a prominent "neural stalk," which coursed ventrally from the spinal cord into the thorax in proximity to a foregut duplication cyst. METHODS: Two patients with this unusual spinal cord anomaly were assessed clinically, and with neuroimaging and genetics studies. RESULTS: We describe common anatomical features (anterior neural stalk arising from the spinal cord, vertebral abnormality, enteric duplication cyst, and diaphragmatic hernia) that support a common etiopathogenesis and distinguish these cases. In both cases, we opted for conservative neurosurgical management in regards to the spinal cord anomaly. We proposed a preliminary theory of the embryogenesis that explains these findings related to a persistence of the ventral portion of the neurenteric canal. CONCLUSION: These cases may represent a form of spinal cord malformation due to a persistent neurenteric canal and affecting notochord development that has rarely been described. Over more than 1 year of follow-up while managed conservatively, there was no evidence of neurologic dysfunction, so far supporting a treatment strategy of observation.

Development of an educational method to rethink and learn oncological brain surgery in an "a la carte" connectome-based perspective.

BACKGROUND: Understanding the structural connectivity of white matter tracts (WMT) and their related functions is a prerequisite to implementing an "a la carte" "connectomic approach" to glioma surgery. However, accessible resources facilitating such an approach are lacking. Here we present an educational method that is readily accessible, simple, and reproducible that enables the visualization of WMTs on individual patient images via an atlas-based approach. METHODS: Our method uses the patient's own magnetic resonance imaging (MRI) images and consists of three main steps: data conversion, normalization, and visualization; these are accomplished using accessible software packages and WMT atlases. We implement our method on three common cases encountered in glioma surgery: a right supplementary motor area tumor, a left insular tumor, and a left temporal tumor. RESULTS: Using patient-specific perioperative MRIs with open-sourced and co-registered atlas-derived WMTs, we highlight the critical subnetworks requiring specific surgical monitoring identified intraoperatively using direct electrostimulation mapping with cognitive monitoring. The aim of this didactic method is to provide the neurosurgical oncology community with an accessible and ready-to-use educational tool, enabling neurosurgeons to improve their knowledge of WMTs and to better learn their oncologic cases, especially in glioma surgery using awake mapping. CONCLUSIONS: Taking no more than 3-5 min per patient and irrespective of their resource settings, we believe that this method will enable junior surgeons to develop an intuition, and a robust 3-dimensional imagery of WMT by regularly applying it to their cases both before and after surgery to develop an "a la carte" connectome-based perspective to glioma surgery.

Spontaneous intramedullary abscesses caused by Streptococcus anginosus: two case reports and review of the literature.

BACKGROUND: Intramedullary abscesses are rare infections of the spinal cord. Intramedullary abscesses often have a complex presentation, making a high index of suspicion essential for prompt diagnosis and management. CASE PRESENTATION: We present two cases of intramedullary abscesses referred to and ultimately managed at our institution. Delayed diagnosis occurred in both instances due to the rarity of intramedullary abscesses and their propensity to mimic other pathologies. For both patients, prompt surgical management and the rapid institution of broad-spectrum antibiotics were critical in preventing further neurological decline. CONCLUSIONS: Although rare, it is critical to consider intramedullary abscesses on the differential for any MRI lesions that are hyperintense on T2 and peripherally enhancing on T1 post-contrast sequences, as even short delays in treatment can lead to severe neurological damage.

Transcranial MR-Guided Focused Ultrasound and Hyperostosis Calvariae Diffusa: Case Report and Systematic Review of the Literature.

We describe a 74-year-old male with intractable essential tremor (ET) and hyperostosis calvariae diffusa who was unsuccessfully treated with magnetic resonance-guided focused ultrasound (MRgFUS). A computed tomography performed prior to the procedure demonstrated a skull density ratio (SDR) of 0.37 and tricortical hyperostosis calvariae diffusa. No lesion was evident on post-MRgFUS MRI, and no improvement in the patient's hand tremor was noted clinically. We systematically reviewed the literature to understand outcomes for those patients with hyperostosis who have undergone MRgFUS. A comprehensive literature search using the PubMed, Cochrane, and Google Scholar databases identified 3 ET patients with hyperostosis who failed treatment with MRgFUS. Clinical findings, skull characteristics, treatment parameters, and outcomes were summarized, demonstrating different patterns/degrees of bicortical hyperostosis and variable SDRs (i.e., from 0.38 to ≥0.45). Although we have successfully treated patients with bicortical hyperostosis frontalis interna (n = 50), tricortical hyperostosis calvariae diffusa appears to be a contraindication for MRgFUS despite acceptable SDRs.

Intracranial pressure monitoring in posterior fossa lesions-systematic review and meta-analysis.

Elevated intracranial pressure (ICP) with reduced cerebral perfusion pressure is a well-known cause of secondary brain injury. Previously, there have been some reports describing different supra- and infratentorial ICP measurements depending on the location of the mass effect. Therefore, we aimed to perform a systematic review and meta-analysis to clarify the issue of optimal ICP monitoring in the infratentorial mass lesion. A literature search of electronic databases (PUBMED, EMBASE) was performed from January 1969 until February 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. Two assessors are independently screened for eligible studies reporting the use of simultaneous ICP monitoring in the supra- and infratentorial compartments. For quality assessment of those studies, the New Castle Ottawa Scale was used. The primary outcome was to evaluate the value of supra- and infratentorial ICP measurement, and the secondary outcome was to determine the time threshold until equalization of both values. Current evidence surrounding infratentorial ICP measurement was found to be low to very low quality according to New Castle Ottawa Scale. Eight studies were included in the systematic review, four of them containing human subjects encompassing 27 patients with infratentorial pathology. The pooled data demonstrated significantly higher infratentorial ICP values than supratentorial ICP values 12 h after onset (p < 0.05, 95% CI 3.82-5.38) up to 24 h after onset (p < 0.05; CI 1.14-3.98). After 48-72 h, both ICP measurements equilibrated showing no significant difference. Further, four studies containing 26 pigs and eight dogs showed a simultaneous increase of supra- and infratentorial ICP value according to the increase of supratentorial mass volume; however, there was a significant difference towards lower ICP in the infratentorial compartment compared to the supratentorial compartment. The transtentorial gradient leads to a significant discrepancy between supra- and infratentorial ICP monitoring. Therefore, infratentorial ICP monitoring is warranted in case of posterior fossa lesions for at least 48 h.

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

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.

"Recycling" A Failed Superficial Temporal Artery Indirect Bypass into a Double Barrel Direct Bypass in Moyamoya Disease.

OBJECTIVES: Moyamoya disease is an idiopathic cerebrovascular disorder in which patients experience recurrent transient ischemic attacks, ischemic or hemorrhagic strokes, headaches, and seizures from progressive stenosis of the vessels of the anterior circulation. The mainstay of treatment in symptomatic patients is surgical revascularization. Here, we present the case of a moyamoya patient in which a failed encephaloduroarteriosynangiosis, after new strokes, is recycled and converted into a combined "double barrel" direct superficial temporal artery to middle cerebral artery bypass with included video. CASE REPORT/RESULTS: We describe a 37-year-old woman with a history of hypertension, obstructive sleep apnea, celiac disease, and moyamoya disease complicated by multiple ischemic strokes who presented with progressive dysarthria, dysphagia, and new left-sided ischemic infarcts. The patient had previously undergone right-sided direct bypass and left-sided encephaloduroarteriosynangiosis in the setting of multiple ischemic strokes. After more strokes, the patient underwent a left-sided frontotemporoparietal craniotomy for conversion of the failed indirect bypass into a "double barrel" direct bypass. CONCLUSIONS: The literature is divided over which revascularization procedure should be preferred. Irrespectively, most failed bypass grafts are repaired via direct bypasses, to good effect. We highlight a case in which a failed indirect bypass is directly incorporated into a combined direct bypass with resulting restoration of blood flow. In the case of a failed indirect bypass in an adult patient with moyamoya disease, this method provides the operator with an additional option for restoration of perfusion, especially in patients without other viable vessels available for anastomosis.

Tumor-Associated Macrophages/Microglia in Glioblastoma Oncolytic Virotherapy: A Double-Edged Sword.

Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some favorable clinical results in glioblastoma (GBM) trials, durable increases in overall survival have remained elusive. Recent evidence has emerged that tumor-associated macrophage/microglia (TAM) involvement is likely an important factor contributing to OV treatment failure. It is prudent to note that the relationship between TAMs and OV therapy failures is complex. Canonically activated TAMs (i.e., M1) drive an antitumor response while also inhibiting OV replication and spread. Meanwhile, M2 activated TAMs facilitate an immunosuppressive microenvironment thereby indirectly promoting tumor growth. In this focused review, we discuss the complicated interplay between TAMs and OV therapies in GBM. We review past studies that aimed to maximize effectiveness through immune system modulation-both immunostimulatory and immunosuppressant-and suggest future directions to maximize OV efficacy.

Leveraging artificial intelligence in ischemic stroke imaging.

Artificial intelligence (AI) is having a disruptive and transformative effect on clinical medicine. Prompt clinical diagnosis and imaging are critical for minimizing the morbidity and mortality associated with ischemic strokes. Clinicians must understand the current strengths and limitations of AI to provide optimal patient care. Ischemic stroke is one of the medical fields that have been extensively evaluated by artificial intelligence. Presented herein is a review of artificial intelligence applied to clinical management of stroke, geared toward clinicians. In this review, we explain the basic concept of AI and machine learning. This review is without coding and mathematical details and targets the clinicians involved in stroke management without any computer or mathematics' background. Here the AI application in ischemic stroke is summarized and classified into stroke imaging (automated diagnosis of brain infarction, automated ASPECT score calculation, infarction segmentation), prognosis prediction, and patients' selection for treatment.

Treatment-Limiting Decisions in Patients with Spontaneous Intracerebral Hemorrhage.

Background and Objectives: Treatment-limiting decisions (TLDs) are employed to actively withhold treatment/invasive interventions from patients in whom clinicians feel they would derive little to no benefit and/or suffer detrimental effects. Data regarding the employment of TLDs in patients with spontaneous intracerebral hemorrhage (ICH) remain sparse. Accordingly, this study sought to investigate both the prevalence of TLDs and factors driving TLDs in patients suffering from spontaneous ICH. Materials and Methods: This was a retrospective study of 249 consecutive patients with ICH treated from 2018−2019 at the Neurovascular Center of the University Hospital Bonn. Reasons deemed critical in the decision-making process with regard to TLD were ultimately extracted/examined via chart review of qualifying patients. Results: A total of 249 patients with ICH were included within the final analyses. During the time period examined, 49 patients (20%) had advanced directives in place, whereas in 53 patients (21%) consultation with relatives or acquaintances was employed before further treatment decisions. Overall, TLD ultimately manifested in 104 patients (42%). TLD was reached within 6 h after admission in 52 patients (50%). Congruent with severity of injury and expected outcomes, TLDs were more likely in patients with signs of cerebral herniation and an ICH score > 3 (p < 0.001). Conclusions: The present study examines details associated with TLDs in patients with spontaneous ICH. These data provide insight into key decisional processes and reinforce the need for further structured investigations in an effort to help guide patients and their families.

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

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.