Bendok, Bernard R.

Abstract High-grade gliomas represent the most common type of primary adult malignant brain tumor historically diagnosed and graded from histologic criteria alone. Gliomas harboring isocitrate dehydrogenase (IDH) 1 or 2 mutations, which are present in more than 80% of World Health Organization (WHO) grade 2 or 3 tumors, portend a favorable prognosis as compared to IDH-wildtype tumors. However, recent molecular profiling has identified the presence of additional alterations in these lower grade tumors that transform the biology toward an aggressive high-grade phenotype clinically that are independent of histologic grading and confer a worse clinical prognosis. Of these, the loss of CDKN2A/B is the strongest implicated alteration and is sufficient to define a grade 4 tumor in IDH-mutant astrocytomas regardless of histologic appearance. However, there remain no effective therapies targeted at molecular subgroups in aggressive gliomas to date. Here we have profiled the intratumoral heterogeneity via whole exome and RNA sequencing and copy number alteration analysis within a cohort of de-identified IDH-mutant astrocytoma patient tumors collected through the Mayo Clinic and Barrow Neurological Institute (BNI) biorepositories to determine the spatial evolution of aggressive molecular features. Within this cohort we have collected 42 image-localized intratumoral biopsy specimens representing 13 IDH-mutant patient tumors. We identified 11 biopsies from 3 tumors that harbored loss of CDKN2A/B which included 1 tumor that displayed intratumoral heterogeneity of CDKN2A/B expression across subclones. We performed an unsupervised cluster analysis to profile the transcriptional signatures in IDH-mutant astrocytomas across both differential CDKN2A/B status and tumor geographic location comparing contrast enhancing versus non-enhancing regions, and we analyzed the MRI features in IDH-mutant tumors across CDKN2A/B status. We found that tumors with CDKN2A/B alteration demonstrated lower signal intensity on delayed post-contrast T2*W images, which could represent lower pre-contrast T2*, unique contrast agent kinetics, or dissimilar diffusion properties related to increased cellular density and/or greater heterogeneity of cell size. Interestingly, we uncovered spatial heterogeneity of additional molecular drivers of high-grade glioma including KRAS, MYCN, and PDGFRA. While EGFR alterations are rarely reported in IDH-mutant tumors, we identified one treatment naïve patient tumor that harbored EGFR alteration only in the contrast non-enhancing region. Based on this work we propose there is early spatial evolution of aggressive tumor subclones prior to primary tumor diagnosis, and multiregional molecular profiling may better inform tumor biology and predict therapeutic strategies in IDH-mutant astrocytomas. Citation Format: Shannon P. Fortin Ensign, Fulvio D'Angelo, Francesca P. Caruso, Christopher Sereduk, Kyle Singleton, Jennifer Eschbacher, Gina Mazza, Maciej Mrugala, Alyx Porter, Bernard Bendok, Richard Zimmerman, Kris Smith, Peter Nakaji, Kamala Swanson, Junwen Wang, Nathenael Semmineh, Christopher Quarles, Anna Lasorella, Kristin Swanson, Michele Ceccarelli, Antonio Iavarone, Leland Hu, Nhan L. Tran. Multiregional imaging and genomic analysis in high-grade IDH-mutant astrocytoma identifies intratumor subclones with aggressive features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 770.

Abstract Background Magnetic Resonance Imaging (MRI) is the mainstay for neurosurgical oncology but not for informing us about glioma biology. An obstacle to developing MR-based glioma biomarkers is the absence of rigorous correlation between MRI features and glioma biology as assessed in multi-regional biopsies, within and across patients. Methods We directly addressed this obstacle by collating a unique cohort of 202 MRI-localized biopsies from 58 patients. We define a low-dimensional transcriptional pseudotime continuum along which heterogeneous high-grade glioma (HGG) samples organize both within and across patients. Results We observe three polarized transcriptional tissue states: infiltrated brain, immune/inflammatory, and proliferative associated with patterns of cohabitation of cellular subpopulations. The states and deconvolved populations show correlation with enhancement status on T1Gd MRI. Moreover, discrete MRI habitats, regions sharing common imaging features, defined as combinations of high or low signal intensity across multiparametric MRI revealed 14 MRI habitats. We order the MRI habitats according to the average pseudotime on the transcriptional continuum. We find that MRI habitats with low pseudotime (associated with early tumor development and diffusely invaded brain tissue) localized at the periphery of the tumor whilst high pseudotime either proliferative or immune/inflammatory states were towards the core of the lesion. We find that composition of MRI habitats are impacted by MGMT status and patient sex. Conclusion This suggests that ongoing aggregation of MRI-localized biopsies may augment our projection of biology onto MRI habitats to support tracking of the evolution of cellular ecologies within and across each patient’s tumor over time. Key Points Trajectory inference of HGG samples reveals a continuum connecting three polarized tissue states reflecting transitions in cellular population ecologies and gene set enrichment Combining multiparametric MRI features into regional MRI habitats reveal clinically-distinct patterns of cell co-habitation and tissue state MGMT methylation status shifts the cellular patterns of cohabitation within MRI habitats Importance of the Study Regional heterogeneity is a defining characteristic of high-grade glioma (HGG). Mapping the transcriptomic biology of multiregionally sampled MRI-localized biopsies from high-grade gliomas onto a low-dimensional space reveals a continuum between three primary tissue states: infiltrated brain, immune/inflammatory, and proliferative. Each state is associated with distinct cell cohabitation ecologies. Transitions between the tissue states coordinate with changes in tumor composition, revealing potential direct connections between tumor biology shifts and their manifestation on clinical imaging.

OBJECTIVE Improper embryological development of the clivus, a bony structure that comprises part of the skull base, can lead to a clival canal defect. Previously thought to be a benign condition, clival canals have been reported to be associated with meningitis and meningoceles. In this review, the authors sought to present an unpublished case of a patient with a clival canal defect associated with meningitis and to evaluate all other reported cases. METHODS In October 2020, a search of PubMed, Web of Science, and Scopus was conducted to identify all cases of clival canals reported from January 1, 1980, through October 31, 2020. RESULTS Including the case presented herein, 13 cases of clival canals, 11 in children (84.6%) and 2 in adults (15.4%), have been identified. Of the pediatric patients, 5 (45.5%) had an associated meningocele, and 8 (72.7%) had meningitis. Nine of the 13 patients (69.2%) had defects that were treated surgically, 5 (38.5%) by a transnasal approach and 4 (30.8%) by a transoral approach. Two patients (15.4%) were treated with drainage and antibiotics, 1 patient (7.7%) was treated solely with antibiotics, and 1 patient (7.7%) was not treated. In the literature review, 8 reports of clival canals were found to be associated with meningitis, further contributing to the notion that the clival canal may be an overlooked source of recurrent infection. In several of these cases, surgical repair of the lesion was curative, thus preventing continued episodes of meningitis. CONCLUSIONS When a patient has recurrent meningitis with no clear cause, taking a closer look at clival anatomy is recommended. In addition, if a clival canal defect has been identified, surgical repair should be considered a safe and effective primary treatment option.

BACKGROUND: Minimally invasive surgical techniques have reinvigorated the role of surgical options for spontaneous intracranial hematomas; however, they are limited by the lack of real-time feedback on the extent of hematoma evacuation. OBJECTIVE: To describe the development of a MRI-guided catheter-based aspiration system, the ClearPoint Pursuit Neuroaspiration Device (ClearPoint Neuro) and validation in phantom models. METHODS: In this preclinical experimental trial, 8 phantom brains with skull models were created to simulate an intracranial hematoma with 2 clot sizes, 30 cc (small clot) and 60 cc (large clot). After registration, the aspiration catheter (Pursuit device) was aligned to the desired planned trajectory. The aspiration of the clot was performed under real-time MRI scan in 3 orthogonal views. The primary end point was reduction of the clot volume to less than 15 cc or 70% of the original clot volume. RESULTS: Successful completion of clot evacuation was achieved in all models. The average postaspiration clot volume was 9.5 cc (8.7 cc for small clots and 10.2 cc for large clots). The average percentage reduction of clot volume was 76.3% (range 58.7%-85.2%). The average total procedure time (from frame registration to final postaspiration clot assessment) was 50 min. The average aspiration time was 6.9 min. CONCLUSION: This preclinical trial confirms the feasibility and efficacy of MRI-guided aspiration under real-time image guidance in simulation models for intracranial hematoma. Clinical use of the system in patients would further validate its efficacy and safety.

OBJECTIVE Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3) 2/3 × (6.106/[V T2 1/1 − V T1 1/1 ]) 2 , where V T2 and V T1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.

OBJECTIVE Available data on management of sacral arteriovenous fistulas (sAVFs) are limited to individual case reports and small series. Management includes observation, endovascular embolization, or surgical ligation, with no clear guidelines on the optimal treatment modality. The authors’ objective was to report their multiinstitutional experience with management of sAVF patients, including clinical and radiographic characteristics and postprocedural outcomes. METHODS The electronic medical records of patients with a diagnosis of spinal arteriovenous fistula treated from January 2004 to December 2019 at the authors’ institutions were reviewed, and data were summarized using descriptive statistics, including percentage and count for categorical data, median as a measure of central tendency for continuous variables, and interquartile range (IQR) as a measure of dispersion. RESULTS A total of 26 patients with sAVFs were included. The median (IQR) age was 65 (57–73) years, and 73% (n = 19) of patients were male. Lower-extremity weakness was the most common presenting symptom (n = 24 [92%]), and half the patients (n = 13 [50%]) reported bowel and bladder sphincter dysfunction. The median (IQR) time from symptom onset to treatment was 12 (5.25–26.25) months. Radiographically, all patients had T2 hyperintensity at the level of the conus medullaris (CM) (n = 26 [100%]). Intradural flow voids were identified in 85% (n = 22) of patients. The majority of the lesions had a single identifiable arterial feeder (n = 19 [73%]). The fistula was located most commonly at the S1 level (n = 13 [50%]). The site where the draining vein connects to the pial venous plexus was seen predominantly at the lumbar level (n = 16 [62%]). In total, 29 procedures were performed: 10 open surgeries and 19 endovascular embolization procedures. Complete occlusion was achieved in 90% (n = 9) of patients after open surgery and 79% (n = 15) after endovascular embolization. Motor improvement was seen in 68% of patients (n = 15), and bladder and bowel function improved in 9 patients (41%). At last follow-up, 73% (n = 16) of patients had either resolution or improvement of the pretreatment intramedullary T2 signal hyperintensity. CONCLUSIONS T2 hyperintensity of the CM and a dilated filum terminale vein are consistent radiographic signs of sAVF, and delayed presentation is common. Complete occlusion was achieved in almost all patients after surgery, and endovascular embolization was effective in 70% of the patients. Further studies are needed to determine the best treatment modality based on case-specific characteristics.

Abstract Arteriovenous malformations (AVMs) are highly complex vascular lesions characterized by abnormal connections between arteries and an intervening nidus. Definitive and safe treatment of AVMs may require the combination of multiple treatment modalities to address the various complex features of the AVM. 1 Endovascular embolization can be used as an adjuvant to surgery in order to control deep feeders, reduce flow, and address high-risk features such as aneurysms. In addition, by progressively reducing the AVM flow, staged embolization can lead to normalization of peri-AVM hemodynamics and therefore may decrease the risk of postresection hemorrhage. 2,3 In this operative video, we present a case of a 41-yr-old female who presented with progressively worsening left-sided hemiparesis. Magnetic resonance imaging (MRI) and angiography revealed a complex right fronto-parietal AVM with significant associated edema, likely due to the vascular steal phenomenon. The area of edema, which included the motor cortex, was thought to be at high risk for postoperative hemorrhage from normal perfusion pressure breakthrough. We therefore decided to proceed with staged presurgical embolization to gradually normalize the perilesional hemodynamics, and therefore possibly reduce the risk of postoperative morbidity. The patient underwent 3 embolization sessions at 6-wk intervals. An MRI after the last embolization showed near-complete resolution of the fluid-attenuated inversion-recovery (FLAIR) signal around the AVM. Microsurgical resection was performed on the day after the last embolization. The patient tolerated the procedure well and was discharged at her neurological baseline with mild contralateral hemiparesis, which has continued to improve at follow-up. Postoperative angiography showed complete resection of the AVM. The patient consented to the procedure as shown in this operative video and gave informed written consent for use of her images in publication.