Intracranial Sites Research Articles

Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach.

Simple SummaryThis manuscript investigates the latest proton and photon radiation delivery techniques and the delivered dose distribution dependence on age and brain tumour location for simulated paediatric patients. Brain tumors are the leading cause of cancer-related burden in childhood cancer survivors. Standard treatment regimens include radiotherapy, and whilst photon therapy is commonly prescribed, proton particles (where available) have been proven to reduce the risk of long-term illness and morbidities. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Ependymoma proton plans demonstrated greater dose reduction for the 9 vs. 13-year-old patients (pituitary gland p < 0.001). Whilst medulloblastoma proton plans achieved greater maximum dose sparing to optic structures (4.8–12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Understanding these differences may help clinicians estimate the benefit and improve referral across available centres.Background: Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) radiation doses for select paediatric intracranial tumours. Methods: IMPT and IMRT dose distributions for gender-matched paediatric cranial CT-datasets (ages 5, 9 and 13 years) were retrospectively calculated to simulate irradiation of supratentorial (ependymoma) and infratentorial (medulloblastoma) target volumes diameters (1–3 cm) and position (central and 1–2 cm shifts). Results: Clinical dosimetric objectives were achieved for all 216 treatment plans. Whilst infratentorial IMPT plans achieved greater maximum dose sparing to optic structures (4.8–12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Mean dose difference for optic chiasm was associated with medulloblastoma target position (p < 0.0197). Supratentorial IMPT plans demonstrated greater dose reduction for the youngest patients (pituitary gland p < 0.001). Conclusions: Normal tissue sparing was achieved regardless of patient age for infratentorial tumours. However, for supratentorial tumours, there was a dosimetric advantage of IMPT across 9 vs. 13-year-old patients.

Primary intracranial Ewing sarcoma/ peripheral primitive neuroectodermal tumor, an entity of unacquaintance: a series of 8 cases.

The purpose is to highlight the primary intracranial (meningeal-based) occurrence of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET). This report is a collation of clinicopathological features of eight cases of molecularly and clinicoradiologically confirmed primary (non-metastatic) intracranial (non-osseous) meningeal ES/PNET. The age range was 1 to 33 years with a median age of 9 years. Male to female ratio was 0.6:1. All patients were diagnosed on the debulking surgical material (gross total resection, 2 cases; subtotal resection, 6 cases) and showed primitive embryonal histomorphology with diffuse membranous CD99 immunoexpression and EWSR1 gene rearrangement by fluorescence in situ hybridization. Seven of them showed a typical FISH pattern of split signals with break-apart probe, while one showed an unusual signal pattern of loss of green signals. EFT-2001 adjuvant protocol was followed along with focal radiotherapy (RT) in all cases (except case 8, full course of chemotherapy could not be completed). Two cases had local recurrence-one of them died of disease recurrence before the administration of further treatment. This series adds non-osseous intracranial site to the list of uncommon sites of occurrence for ES/PNET and more importantly emphasizes the need to be considered in a differential list of primary intracranial primitive embryonal tumors before embarking as primary central nervous system (CNS) embryonal tumor, NOS.

CIMPACT-NOW update 7: advancing the molecular classification of ependymal tumors.

Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO) classification of CNS tumors (2016) have prompted the cIMPACT-NOW group to recommend a new classification. Separation of ependymal tumors by anatomic site is an important principle of the new classification and was prompted by methylome profiling data to indicate that molecular groups of ependymal tumors in the posterior fossa and supratentorial and spinal compartments are distinct. Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group, PFA and PFB. A recently described type of aggressive spinal ependymoma with MYCN amplification has also been included. Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma. While the cIMPACT-NOW group considered that data to inform assignment of grade to molecularly defined ependymomas are insufficiently mature, it recommends assigning WHO grade 2 to myxopapillary ependymoma and allows grade 2 or grade 3 to be assigned to ependymomas not defined by molecular status.

Craniospinal irradiation in patients diagnosed with glioblastoma with primitive neuronal component prevents distant intracranial and leptomeningeal recurrences.

e14540 Background: Glioblastoma (GBM) is the most common primary central nervous system (CNS) malignancy. In recent years, molecular and histological analyses have identified GBM with primitive neuronal component (GBM-PNC) as a distinct entity with poor regional control and worse overall prognosis. GBM-PNCs are more prone to CNS dissemination and leptomeningeal (LM) metastasis, occurring in up to 40% of patients. Given the concern for distal CNS spread, we hypothesized that craniospinal irradiation (CSI) may be an effective treatment option for GBM-PNC. Methods: We performed a retrospective chart review of patients diagnosed with GBM-PNC treated at a large academic center with institutional review board approval. Clinical, histologic and treatment characteristics, as well as disease outcomes were obtained from the electronic medical record. Results: Ten patients diagnosed with GBM-PNC were identified in the period of 2005-2019. Median follow-up was 17 months. Overall, 80% of patients were men, median age was 49 years (range 20-64) and ECOG 0-1. Fifty percent of patients received CSI as opposed to involved field radiation therapy (IFRT). Four of five patients receiving CSI were treated with proton therapy. All patients, but one received concurrent Temozolomide. Both IFRT and CSI were tolerated well with minimal grade 3-4 toxicities. Patients treated with CSI were more likely to experience transient grade 3-4 lymphopenia (60% vs 0%). Eighty percent of patients experienced a recurrence after treatment with median progression free survival (PFS) of 13 months (range 8-26). PFS did not differ between patients receiving IFRT and CSI (14 vs 12.5 months, p = 0.9). Median overall survival (OS) was 30 months for patients who received IFRT, and median OS was not reached in the CSI group. Of the patients who received CSI as part of their treatment, all recurrences were within the high dose radiation area. On the contrary, 75% of patients who received IFRT experienced multiple recurrences at new intracranial sites and later in the leptomeninges or the spine, requiring multiple treatment courses. Conclusions: This hypothesis generating study demonstrates that CSI may prevent distant intracranial metastasis and LM disease progression. CSI delivered with proton therapy was well tolerated with minimal additional toxicity. A larger study is needed to guide the optimal treatment of patients diagnosed with glioblastoma with primitive neuronal component.

An investigation into the robustness of dynamically collimated proton therapy treatments.

To investigate the dosimetric robustness of dynamically collimated proton therapy (DCPT) treatment plans delivered using a dynamic collimation system (DCS) with respect to random uncertainties in beam spot and collimator position as well as systematic offsets in the DCS mounting alignment. This work also demonstrates a technique that can increase plan robustness while preserving target conformity. Variability in beam spot and collimator positioning can result in changes to a beamlet's dose distribution and incident fluence. The robustness of the DCPT treatment plans was evaluated for three intracranial treatment sites by modeling treatment variability as normally distributed random variables with standard deviations reflecting a clinical system. The simulated treatment plans were then recalculated and compared against their nominal, idealized dose distribution among several trials. It was hypothesized that a plan's robustness to these delivery variables could be reduced by restricting a trimmer's placement toward a beamlet's central axis during collimation. By introducing a minimum trimmer offset of 1.5mm, the variation of the planning target volume (PTV) D95% coverage was reduced to within 2% of the prescribed dose. The treatment plans with trimmers that were placed within 0.5mm of a collimated beamlet's central axis resulted in the greatest healthy tissue sparing but deviations as high as 11.4% to the PTV D95% were observed. The nominal conformity of these treatment plans utilizing the 1.5 mm trimmer offset was also well maintained. For each treatment plan studied, the 90% conformity index remained within 6.25% of the conformity index achieved without a minimum trimmer offset, and the D50% of surrounding healthy tissue increased by no more than 3.1Gy relative to a plan without a trimmer offset. While DCPT can offer a significant reduction in healthy tissue irradiation, the results from this work indicate that special care must be taken to ensure proper PTV coverage amid uncertainties associated with this new treatment modality. A simple approach utilizing a minimum trimmer offset was able to preserve the majority of the target conformity and healthy tissue sparing the DCS technology affords while minimizing the uncertainties in this treatment approach.

First line transradial access for posterior circulation stroke intervention; initial 12-month experience at a high volume thrombectomy center

BackgroundThe Neurointerventional Surgery Standards and Guidelines Committee has advocated the use of transradial access in the setting of posterior circulation stroke intervention, however there is a paucity of published data on this approach. The purpose of this study is to present 12-months of prospectively collected data from a high volume thrombectomy center following the adoption of a first line transradial approach for posterior circulation stroke intervention. MethodsA range of data on patient characteristics, procedural metrics, complications and outcomes was prospectively collected between August 2018 - August 2019 following the adoption of first line transradial access for posterior circulation stroke intervention at a high volume thrombectomy center. ResultsTransradial access was successful in 22/23 cases (96%), median arteriotomy to reperfusion time was 24 min (IQR 18–40), good angiographic outcome (mTICI 2b-3) was achieved in all cases and good clinical outcome (mRs 0–2) was achieved in 61% of cases. No intracranial or radial artery access site complications occurred. ConclusionThe fast procedure times, excellent outcomes and low complication rates achieved in this prospective 12-month study indicate that transradial access is a viable first line strategy in posterior circulation stroke intervention.

Vertebral Artery Stenoses Contribute to the Development of Diffuse Plaques in the Basilar Artery.

Vertebral artery (VA) stenosis is relevant to a high early risk of recurrent stroke and basilar artery (BA) is the most common intracranial site of atherosclerotic lesions. It is important to show predictive risk factors for transient ischemic attack (TIA) or posterior infarctions. The aim of the study is to investigate morphometry and hemodynamics in intracranial vertebral and basilar arteries of health and diseased patients to enhance the risk assessment. Based on the geometrical model reconstructed from CTA images in 343 patients, a transient three-dimensional computational model was used to determine the hemodynamics. Patients were classified in symmetric, asymmetric, hypoplastic, and stenotic groups while patients in the stenotic group were divided into unilateral, bilateral, bifurcation, and tandem stenotic sub-groups. Patients in bilateral, bifurcation, and tandem stenotic sub-groups had significantly lower basilar artery diameters than other groups. Patients in the stenotic group had significantly higher surface area ratio (SAR) of high time-averaged wall shear stress gradient (TAWSSG) and higher incidence of TIAs or posterior infarctions than other groups while patients in the tandem stenotic sub-group had the highest values (SAR-TAWSSG of 57 ± 22% and TIAs or posterior infarction incidence of 54%). The high SAR-TAWSSG is predisposed to induce TIAs or posterior infarction.

Bevacizumab treatment of meningeal melanoma metastases

BackgroundMelanoma patients with metastatic growth in the meninges have poor prognosis and few treatment options. Although treatment with BRAF inhibitors or immune checkpoint inhibitors has provided promising results, most patients with advanced melanoma are resistant to these treatments and develop severe side effects. Novel treatment strategies are needed for patients with meningeal melanoma metastases, and the potential of antiangiogenic therapy was investigated in this preclinical study.MethodsTwo GFP-transfected melanoma models (A-07 and D-12) differing substantially in VEGF-A expression were included in the study, and the anti-VEGF-A antibody bevacizumab was used as therapeutic agent. Meningeal metastases were initiated in BALB/c nu/nu mice by intracranial inoculation of melanoma cells, and bevacizumab treatment was given twice a week in i.p. doses of 10 mg/kg until the mice became moribund. Therapeutic effects were evaluated by determining tumor host survival time, assessing tumor growth and angiogenic activity by quantitative analyses of histological preparations, and measuring the expression of angiogenesis-related genes by quantitative PCR.ResultsMeningeal A-07 melanomas showed higher expression of VEGF-A than meningeal D-12 melanomas, whereas the expression of ANGPT2 and IL8, two important angiogenesis drivers in melanoma, was much higher in D-12 than in A-07 tumors. Bevacizumab treatment inhibited tumor angiogenesis and prolonged host survival in mice with A-07 tumors but not in mice with D-12 tumors. Meningeal A-07 tumors in bevacizumab-treated mice compensated for the reduced VEGF-A activity by up-regulating a large number of angiogenesis-related genes, including ANGPT2 and its receptors TIE1 and TIE2. Melanoma cells migrated from meningeal tumors into the cerebrum, where they initiated metastatic growth by vessel co-option. In the A-07 model, the density of cerebral micrometastases was higher in bevacizumab-treated than in untreated mice, either because bevacizumab treatment increased mouse survival or induced increased tumor gene expression.ConclusionsThe development of antiangiogenic strategies for the treatment of meningeal melanoma metastases is a challenging task because the outcome of treatment will depend on the angiogenic signature of the tumor tissue, treatment-induced alterations of the angiogenic signature, and the treatment sensitivity of metastatic lesions in other intracranial sites.

Clinical utility of circulating miR-371a-3p for the management of patients with intracranial malignant germ cell tumors.

BackgroundThe current biomarkers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) have limited sensitivity/specificity for diagnosing malignant germ cell tumors (GCTs) and “marker-negative” patients require histological confirmation for diagnosis. However, GCTs at intracranial sites are surgically relatively inaccessible and biopsy carries risks. MicroRNAs from the miR-371~373 and miR-302/367 clusters are over-expressed in all malignant GCTs and, in particular, miR-371a-3p shows elevated serum levels at diagnosis for testicular disease.MethodsUsing our robust preamplified qRT-PCR methodology, we quantified miR-371a-3p levels in serum and cerebrospinal fluid (CSF) in a series of 4 representative clinical cases, 3 with intracranial malignant GCT and 1 with Langerhans cell histiocytosis (LCH), compared with appropriate control cases.ResultsSerum and/or CSF miR-371a-3p levels distinguished those with intracranial malignant GCTs from LCH and, if known in real time, could have helped clinical management. The benefits would have included (1) the only confirmatory evidence of an intracranial malignant GCT in 1 case, supporting clinical decision making; (2) early detection of intracranial malignant GCT in another, where an elevated CSF miR-371a-3p level preceded the histologically confirmed diagnosis by 2 years; and (3) confirmation of an intracranial malignant GCT relapse with an elevated serum miR-371a-3p level, where serum and CSF AFP and HCG levels were below thresholds for such a diagnosis.ConclusionsThis series highlights the potential for microRNA quantification to assist the noninvasive diagnosis, prognostication, and management for patients with intracranial malignant GCTs. Serum and CSF should be collected routinely as part of future studies to facilitate the extension of these findings to larger patient cohorts.

Benign Tumors of the Anterior Cranial Base.

Benign tumors of the anterior cranial base may originate from intracranial, cranial, or extracranial sites. Intracranial tumors such as meningiomas may secondarily involve the cranial base and extend into the sinuses or nasal cavity. Bony tumors arising from the cranium include benign fibro-osseous lesions such as osteoma, fibrous dysplasia, and ossifying fibroma. The most common extracranial tumors that may extend to the skull base include angiofibroma and inverted papilloma. Symptoms are nonspecific and diagnosis is often delayed. In most cases, a diagnosis can be established based on the clinical presentation and radiographic features. Some small asymptomatic tumors may be observed for growth (meningioma, osteoma), whereas others should be treated due to continued destructive growth (angiofibromas) or potential for malignancy (inverted papilloma). Surgery remains the predominant treatment modality for benign tumors of the anterior cranial base. The major advance in recent decades has been the adoption of endoscopic techniques. Advances in endoscopic transnasal surgery have dramatically altered the surgical landscape, enabling the removal of tumors of the anterior cranial base with minimal morbidity. Due to decreased morbidity in comparison to transfacial or transcranial approaches, endoscopic transnasal surgery has lowered the threshold for surgery for benign tumors and can be applied to adult as well as pediatric populations. Anatomical limits include the anterior cranial base from the frontal sinus to the sella and optic canals and laterally to the mid-plane of the orbital roofs. Large dural defects can be reliably reconstructed using local (nasoseptal) and regional (extracranial pericranial) vascularized flaps.

Clinical Profile and Outcome of Brain Abscess in Children from a Tertiary Care Hospital in Eastern Uttar Pradesh.

Background and Aims:Brain abscess is a serious and dreadful disease presenting at tertiary centre. The objective of this study was to look into the clinical profile, predisposing conditions, microbiology and outcome of children suffering from brain abscess.Methods:30 children up to 18 years with clinical and imaging evidence of brain abscess were taken for study. Patients were stabilized as per unit protocol. Necessary investigations were carried out. Neuroimaging (CT or MRI) was used to confirm the diagnosis. All parameters (clinical, investigation, outcome) were recorded in predesigned performa. Neurosurgery consultation was sought in patients with multiple abscesses, posterior fossa abscesses, abscess with air-fluid level and causing midline shift.Results:There were 16 males with 13 patients in age group (5-10 years). Mean duration of stay in hospital was 14.8 days. Most common predisposing factor was chronic suppurative otitis media (n-15). Typically, patients presented with fever, headache and seizures. On examination, motor deficits were the most common followed by signs of meningitis. Computerized tomography confirmed the diagnosis in most cases. Temporal lobe (n-11) was the commonest intracranial site for the abscess. Methicillin resistant staphylococcus and proteus mirabilis were the common pathogen isolated from blood and pus. Blood culture positivity rate was 16.7% and pus culture positivity rate was 25%. All cases were managed with intravenous antibiotics and aspiration (n-10) and excision (n-6). There were 5 deaths. There was complete immediate recovery in 13 cases with residual motor deficit in 12 cases.Conclusion:Brain abscess is a rare but serious entity in children. Late diagnosis and improper management leads to poor outcome. Early surgical intervention is helpful. Threshold for diagnosis should be low in children with chronic ear infection and congenital heart diseases.

Extracellular-Matrix-Anchored Click Motifs for Specific Tissue Targeting.

Local presentation of cancer drugs by injectable drug-eluting depots reduces systemic side effects and improves efficacy. However, local depots deplete their drug stores and are difficult to introduce into stiff tissues, or organs, such as the brain, that cannot accommodate increased pressure. We present a method for introducing targetable depots through injection of activated ester molecules into target tissues that react with and anchor themselves to the local extracellular matrix (ECM) and subsequently capture systemically administered small molecules through bioorthogonal click chemistry. A computational model of tissue-anchoring depot formation and distribution was verified by histological analysis and confocal imaging of cleared tissues. ECM-anchored click groups do not elicit any noticeable local or systemic toxicity or immune response and specifically capture systemically circulating molecules at intradermal, intratumoral, and intracranial sites for multiple months. Taken together, ECM anchoring of click chemistry motifs is a promising approach to specific targeting of both small and large therapeutics, enabling repeated local presentation for cancer therapy and other diseases.

PD-L1, PD-1, LAG-3, and TIM-3 in Melanoma: Expression in Brain Metastases Compared to Corresponding Extracranial Tumors.

BackgroundMetastatic melanoma to the brain carries a particularly poor prognosis that may be associated with an attenuated antitumor response in the presence of central nervous system malignancies. Thus, the development of brain metastases could theoretically accelerate cancer progression both locally and systemically. Although dysregulation of checkpoint markers, such as programmed death-ligand 1 (PD-L1), programmed cell death receptor 1 (PD-1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), have been implicated in immune dysfunction, the exact relationship between these markers and brain tumor-mediated immune suppression remains unclear. Thus, the objective of this study was to explore whether there exists a differential expression of the above checkpoint markers in the intracranial milieu as compared to tumors in the periphery, which may shed light on the mechanism behind the diminished antitumor response.MethodsWe identified nine patients with extracranial melanomas and matched intracranial metastases. Formalin-fixed, paraffin-embedded slides were stained for PD-L1, PD-1, LAG-3, and TIM-3 via immunohistochemistry. Qualitative analysis was performed to assess the staining of the markers in the neoplastic and lymphocytic cells, which were the two cell lineages in each biopsy. ResultsExpression of PD-1 and TIM-3 between extracranial and intracranial tumoral sites was conserved. Specifically, in lymphocytes, PD-1 expression was observed in 100% of extracranial and 100% of intracranial slides, whereas TIM-3 expression was seen in 33.33% of extracranial and 33.33% of intracranial slides. Neither marker stained tumor cells, as expected. PD-L1 showed a slight variation in staining between sites, with lymphocyte staining in 100% of extracranial and 88.89% of intracranial slides, and the same percentages per site for tumor cells. The greatest variability was observed in LAG-3 lymphocyte staining, with staining in 77.78% of extracranial and 33.33% of intracranial slides. No LAG-3 staining of tumor cells was noted, as expected.ConclusionPreliminary analysis revealed the conservation of PD-L1, PD-1, LAG-3, and TIM-3 expression intra- and extracranially. This could suggest that these markers are important in maintaining an immunosuppressive phenotype at both sites. Another possibility is that this pattern of expression is associated with patients who develop brain metastasis, as this was the only subset of patients included in this study. Interestingly, LAG-3 staining of lymphocytes appeared more prominent in extracranial over intracranial tumors. Future studies should include more samples to draw out potential patterns masked by the small sample size, as well as to compare checkpoint expression in other patient groups, such as those with non-brain metastasis or those with no metastasis at all.

Classification of orbitocranial wooden foreign body penetration injuries: what to do when they violate the intracranial space? A systematic review.

Orbitocranial wooden foreign body (OWF) penetrations are rare but challenging occurrences that may violate the intracranial space resulting in brain damage and hemorrhagic, as well as infectious, complications. Moreover, there is a specific subset of cases of OWF penetrations that are particularly challenging to treat. Although there are well-defined management guidelines for pure intraorbital localization, there is not yet a defined treatment protocol for foreign bodies reaching the intracranial space. However, their removal performed either directly or through craniotomy, is often easily attainable given the condition that all necessary precautions are accounted for. After having treated a 48-year-old man with a transorbital OWF penetration injury at our neurosurgical department, we systematically reviewed the last 15 years of literature to define and summarize the best management strategy. Multiple databases were searched for case reports and case series involving patients with intraorbital and transorbital OWF penetration injuries. For each study, we extracted data on age, sex, imaging modality, type of wood (processed vs. unprocessed), location of periorbital and intracranial entry site, treatment type ("pull and see" or "open and see"), antibiotic therapy, and complications. We classified transorbital OWFs into two categories: transorbital with only cavernous sinus involvement and transorbital with more extensive intracranial involvement. We described what we believed was the most appropriate management conduct in each case. Grounded on our experience and on the review of the literature, we suggest, based on the anatomical localization of the OWF, a classification system for OWFs which is coupled with a tailored treatment strategy for each case. These suggestions are made to provide surgeons with direction on the correct management of such rare but challenging occurrences.

DDIS-03. DEVELOPMENT OF A NOVEL CLASS OF cGAS AGONISTS TO TRIGGER STING PATHWAY-DEPENDENT INNATE IMMUNE RESPONSES AGAINST GLIOBLASTOMA

Abstract The Stimulator of Interferon Genes (STING) pathway represents a major innate immune sensing mechanism for tumor-derived DNA. Modified cyclic dinucleotides (CDNs) that mimic the endogenous STING ligand cGAMP are currently being explored in patients with solid tumors that amenable to intratumoral delivery. Inadequate bioavailability and insufficient lipophilicity are limiting factors for clinical CDN development, in particular when consideration is given to systemic administration approaches. We have shown that the formulation of oligonucleotides into Spherical Nucleic Acid (SNA) nanostructures, i.e., the presentation of oligonucleotides at high density on the surface of nanoparticle cores, lead to biochemical and biological properties that are radically different from those of linear oligonucleotides. First-generation SNAs conjugated with TLR9-agonsitic DNA oligonculeotides (NCT03086278; solid cancers) and intravenously administered, brain-penetrant siRNA-based SNAs (NCT03020017, recurrent GBM) have recently entered clinical trials. Here, we report the development of a STING-agonistic immunotherapy by targeting cGAS, the sensor of cytosolic dsDNA upstream of STING, with SNAs presenting dsDNA at high surface density. The strategy of using SNAs exploits the ability of cGAS to raise STING responses by delivering dsDNA and inducing the catalytic production of endogenous CDNs. SNA nanostructures carrying a 45bp IFN-simulating dsDNA oligonucleotide, the most commonly used and widely characterized cGAS activator, potently activated the cGAS-STING pathway, as evidenced by increased IRF responses, elevated protein marker expression indicative of the activated M1 macrophage state, and enhanced expression of pro-inflammatory cytokines in macrophage cultures in vitro, and in intracranial isogenic GBM explants in vivo. Our use of SNAs addresses the challenges of nucleic acid delivery to intracranial tumor sites, exploits the binding of closely-spaced, neighboring dsDNA molecules on the SNA surface to enhance the formation of a dimeric cGAS:DNA complex, and establishes cGAS-agonistic SNAs as a novel class of immune-stimulatory modalities for triggering innate immune responses against tumor.

The impact of targeted therapies and immunotherapy in melanoma brain metastases: A systematic review and meta‐analysis

Targeted therapies (TT), combination immunotherapy (CMI), and monoimmunotherapy (MI) in combination with radiotherapy (CRI) or not are commonly used in patients with melanoma brain metastases, but studies that directly compare these strategies are lacking. The current meta-analysis aimed to better elucidate their activity and efficacy. A systematic search of MEDLINE, Embase, and conference proceedings up to January 2019 was performed to identify trials investigating combination TT, monotargeted TT (mono TT), MI, CMI, and CRI in melanoma brain metastases. The outcomes considered were progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR) as evaluated at both intracranial and extracranial sites. Random effects models were used to compare the different therapeutic strategies. A total of 15 trials were included that provided 1132 patients for analyses. CMI demonstrated a statistically significant better OS compared with MI (P=.03, P=.05, and P=.03, respectively, at 6months, 18months, and 24months) and combination TT (P=.04 and P=.03, respectively, at 18months and 24months). CMI demonstrated a statistically significant better PFS compared with combination TT (P<.001 at 12months and 18months), MI (P=.02, P<.02, and P=.05, respectively, at 6months, 12months, and 18months), and mono TT (P<.001 at 6months, 12months, and 18months). The intracranial objective response rate was higher with CMI compared with mono TT (P<.001) and MI (P<.001), whereas there was no difference between CMI and combination TT. The results of the current meta-analysis suggested that CMI increases long-term PFS and OS compared with MI and combination TT. Combination TT and CMI are associated with a similar intracranial response rate. The role of systemic therapy in combination with radiotherapy remains to be better elucidated.

Coagulation Factor Xa (Recombinant), Inactivated-Zhzo (Andexanet Alfa) Hemostatic Outcomes and Thrombotic Event Incidence at an Academic Medical Center.

Andexanet alfa is approved for the reversal of factor Xa inhibitors in patients with major bleeding events. We aimed to review the incidence of effective hemostasis with andexanet alfa in a real-world environment. This retrospective cohort included patients hospitalized for a major bleed that resulted in andexanet alfa administration. The primary outcome was effective hemostasis at 12 hours after andexanet alfa treatment. Thromboembolic events and mortality within 30 days were also assessed. Over a 14-month period, 13 patients received andexanet alfa with a mean age of 69 ± 10 years, 54% male, 69% exposed to apixaban (31% rivaroxaban), and had intracranial (46%) and nonintracranial (54%) bleeding sites. Effective hemostasis was observed in 10 (77%) patients. Four (31%) patients experienced 5 thromboembolic events with a median time to event of 6.5 days (range: 0.5-29). Four thrombotic events occurred during the period in which anticoagulation (prophylaxis or therapeutic) was not restarted. Mortality rate was 15%. Andexanet alfa was effective in obtaining hemostasis in a majority of patients. However, the incidence of thromboembolic events was high and may be attributed to a delay in restarting anticoagulation.

Patterns of Local Extension and Nodal Involvement From 1300 Nasopharyngeal Carcinoma Patients Based on Magnetic Resonance Imaging

To clarify the biological behavior of nasopharyngeal carcinoma by exploring patterns of local extension and nodal involvement. To offer our suggestions for clinical target volume delineation. We retrospectively reviewed the imaging documents of 1300 consecutive cases of newly diagnosed nasopharyngeal carcinoma between January 2012 and December 2016. According to the incidence rates of tumor invasion, the anatomic sites were classified into three groups: high-risk group (≥50%), medium-risk group (≥10%∼<50%), low-risk group (<10%). The location of lymph nodes was determined based on the 2013 updated guidelines for neck node levels. Furthermore, we proposed a novel clinical classification according to patterns of local extension and nodal metastasis.Abstract MO_6_2508; Table 1Local TypeSuperior TypeInferior TypeMix Typeskull base and/or intracranial extension-+-+lymph nodes metastasis--++ Open table in a new tab The incidence rates of tumor invasion were between 0.2% and 91.2%. Local extension invaded across the midline in 95.2% cases. If anatomic sites in high-risk group or median-risk group were involved, the incidence rates of tumor invasion in adjacent medium-risk sites or low-risk group were increased. On the contrary, the incidence rates were decreased when the adjacent high-risk sites or median-risk group were not involved. 85.9% cases had involved lymph nodes. The frequency of skip metastases was only 3.9%. The necrosis rate of lymph nodes was 37.8% and the rate of extracapsular spread was 46.5%. The incidence rates of nodal involvement were increased when adjacent upper nodal level was involved. Among four clinical types, the mix type has the highest rate, reaching 40.5%. No significant correlation was found between T stage and nodal involvement (χ2=14.469，P=0.107). In patients presenting with nasopharyngeal carcinoma, local disease spreads stepwise from proximal sites to more distal sites. The invasion rates of medium-risk sites and low-risk sites are related to the involvement of adjacent high-risk and median-risk sites. The frequency of metastases in the jugular lymph node chains decreased in the cranio-caudal direction. Both solitary metastases and skip metastases are rare. The incidence rates of nodal metastasis are related to the involvement of adjacent upper nodal level. The most common clinical type of NPC is the invasion of skull bone, intracranial sites, along with neck node metastasis.

Association of Clinical, Imaging, and Thrombus Characteristics With Recanalization of Visible Intracranial Occlusion in Patients With Acute Ischemic Stroke

Recanalization of intracranial thrombus is associated with improved clinical outcome in patients with acute ischemic stroke. The association of intravenous alteplase treatment and thrombus characteristics with recanalization over time is important for stroke triage and future trial design. To examine recanalization over time across a range of intracranial thrombus occlusion sites and clinical and imaging characteristics in patients with ischemic stroke treated with intravenous alteplase or not treated with alteplase. Multicenter prospective cohort study of 575 patients from 12 centers (in Canada, Spain, South Korea, the Czech Republic, and Turkey) with acute ischemic stroke and intracranial arterial occlusion demonstrated on computed tomographic angiography (CTA). Demographics, clinical characteristics, time from alteplase to recanalization, and intracranial thrombus characteristics (location and permeability) defined on CTA. Recanalization on repeat CTA or on first angiographic acquisition of affected intracranial circulation obtained within 6 hours of baseline CTA, defined using the revised arterial occlusion scale (rAOL) (scores from 0 [primary occlusive lesion remains the same] to 3 [complete revascularization of primary occlusion]). Among 575 patients (median age, 72 years [IQR, 63-80]; 51.5% men; median time from patient last known well to baseline CTA of 114 minutes [IQR, 74-180]), 275 patients (47.8%) received intravenous alteplase only, 195 (33.9%) received intravenous alteplase plus endovascular thrombectomy, 48 (8.3%) received endovascular thrombectomy alone, and 57 (9.9%) received conservative treatment. Median time from baseline CTA to recanalization assessment was 158 minutes (IQR, 79-268); median time from intravenous alteplase start to recanalization assessment was 132.5 minutes (IQR, 62-238). Successful recanalization occurred at an unadjusted rate of 27.3% (157/575) overall, including in 30.4% (143/470) of patients who received intravenous alteplase and 13.3% (14/105) who did not (difference, 17.1% [95% CI, 10.2%-25.8%]). Among patients receiving alteplase, the following factors were associated with recanalization: time from treatment start to recanalization assessment (OR, 1.28 for every 30-minute increase in time [95% CI, 1.18-1.38]), more distal thrombus location, eg, distal M1 middle cerebral artery (39/84 [46.4%]) vs internal carotid artery (10/92 [10.9%]) (OR, 5.61 [95% CI, 2.38-13.26]), and higher residual flow (thrombus permeability) grade, eg, hairline streak (30/45 [66.7%]) vs none (91/377 [24.1%]) (OR, 7.03 [95% CI, 3.32-14.87]). In patients with acute ischemic stroke, more distal thrombus location, greater thrombus permeability, and longer time to recanalization assessment were associated with recanalization of arterial occlusion after administration of intravenous alteplase; among patients who did not receive alteplase, rates of arterial recanalization were low. These findings may help inform treatment and triage decisions in patients with acute ischemic stroke.

Phase‐amplitude coupling between interictal high‐frequency activity and slow waves in epilepsy surgery

We hypothesized that the modulation index (MI), a summary measure of the strength of phase-amplitude coupling between high-frequency activity (>150Hz) and the phase of slow waves (3-4Hz), would serve as a useful interictal biomarker for epilepsy presurgical evaluation. We investigated 123 patients who underwent focal cortical resection following extraoperative electrocorticography recording and had at least 1 year of postoperative follow-up. We examined whether consideration of MI would improve the prediction of postoperative seizure outcome. MI was measured at each intracranial electrode site during interictal slow-wave sleep. We compared the accuracy of prediction of patients achieving International League Against Epilepsy class 1 outcome between the full multivariate logistic regression model incorporating MI in addition to conventional clinical, seizure onset zone (SOZ), and neuroimaging variables, and the reduced logistic regression model incorporating all variables other than MI. Ninety patients had class 1 outcome at the time of most recent follow-up (mean follow-up = 5.7years). The full model had a noteworthy outcome predictive ability, as reflected by regression model fit R2 of 0.409 and area under the curve (AUC) of receiver operating characteristic plot of 0.838. Incomplete resection of SOZ (P<0.001), larger number of antiepileptic drugs at the time of surgery (P=0.007), and larger MI in nonresected tissues relative to that in resected tissue (P=0.020) were independently associated with a reduced probability of class 1 outcome. The reduced model had a lower predictive ability as reflected by R2 of 0.266 and AUC of 0.767. Anatomical variability in MI existed among nonepileptic electrode sites, defined as those unaffected by magnetic resonance imaging lesion, SOZ, or interictal spike discharges. With MI adjusted for anatomical variability, the full model yielded the outcome predictive ability of R2 of 0.422, AUC of 0.844, and sensitivity/specificity of 0.86/0.76. MI during interictal recording may provide useful information for the prediction of postoperative seizure outcome.