bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-44. RAMAN SPECTROSCOPY AS A DIAGNOSTIC TOOL IN NEUROPATHOLOGY
Authors: Klamminger Gilbert Georg , Mombaerts Laurent , Klein Karoline , Jelke Finn , Mirizzi Giulia , Slimani Redouane , Gerardy Jean-Jacques , Husch Andreas , Hertel Frank , Mittelbronn Michel , Borgmann Felix Kleine
Published: November 2021

BACKGROUND

Although microscopic assessment is still the diagnostic gold standard in pathology, non-light microscopic methods such as new imaging methods and molecular pathology have considerably contributed to more precise diagnostics. As an upcoming method, Raman spectroscopy (RS) offers a "molecular fingerprint" which could be used to differentiate tissue heterogeneity or diagnostic entities. RS has so far been successfully applied on fresh and frozen tissue, however more aggressively, chemically treated tissue such as formalin-fixed, paraffin-embedded (FFPE) samples are challenging for RS.

METHODS

To address this issue, we examined FFPE samples of a broad range of intracranial tumors (e.g. glioblastoma and primary CNS lymphoma) and also different areas of morphologically highly heterogeneous glioblastoma tumor tissue. The latter in order to classify not only the tumor entity but also histologically defined GBM areas according to their spectral properties. We applied linear and nonlinear machine learning algorithms (Logistic Regression, Random Forest, Support Vector Machine) on our spectroscopic data and compared statistical performance of resulting classifiers.

RESULTS

We found that Random Forest classification distinguished between glioblastoma and primary CNS lymphoma with a balanced accuracy of 94%, only using Raman measurements on FFPE tissue. Furthermore, our established support vector machine-based classifier identified distinct histological areas in glioblastoma such as tumor core and necroses with an overall accuracy of 70.5% and showed a clear separation between the areas of necrosis and peritumoral zone.

CONCLUSIONS

This relatively cheap and easy-to-apply tool may serve useful to complement histopathological and molecular diagnostics. It provides an unbiased approach to tumor diagnostics with very little requirements (e.g. histopathological feature completeness of the tumor entity) to the sample. As a conclusion, we propose RS as a potential future additional method in the (neuro)-pathological toolbox for tumor diagnostics.
PATH-47. THE 2016 WHO CLASSIFICATION AND IT'S CLINICAL IMPACT: THE LEEDS TEACHING HOSPITALS NHS TRUST EXPERIENCE
Authors: Kalra Neeraj , Geng Zhuowen , Bailey Helen , Dony Alna , Chakrabarty Aruna , Roberts Paul , Mathew Ryan
Published: November 2021

INTRODUCTION

In 2016 the WHO Classification of Tumours of the Central Nervous System was updated to include molecular testing, in addition to the previous standard histological methods; producing a final integrated diagnosis. Although molecular information can guide treatment and aid in prognostication, it adds a significant workload to pathology and genetic testing services. Delayed diagnosis can also add anxiety to patients, at an already traumatic time. AIMS: To determine if final integrated diagnoses, for patients undergoing neurosurgery for CNS tumours, is being provided in an appropriate time frame, and whether it changes clinical management.

METHODS

All patients >16 years at the time of surgery with a histopathologically-confirmed CNS tumour were identified from 2016-2020. A retrospective analysis of the time taken to produce an integrated histological diagnosis took place, using the date of surgery and date of verified final integrated report being the first and last data points respectively. Data were collected by accessing electronic and paper health records, and local databases. Changes in clinical management between the initial histology result and the final integrated diagnosis were classified as no change or a major change.

RESULTS

1390 surgical procedures for CNS pathology were identified between 2016-2020, producing 361 final integrated diagnosis reports. 64 (18%) of these reports resulted in a major change in clinical management when compared to the initial histology report. The turn-around time for initial histology from date of surgery was a mean of 9 days and a mean of 34 days for the final integrated diagnosis.

CONCLUSIONS

The integrated diagnosis is essential for providing the gold standard of treatment for patients, although for the majority of patients it does not change their clinical management. Further study and discussion is required about the role of the final integrated diagnosis in the management of patients with CNS tumours.
PATH-48. RAPID-CNS2: RAPID COMPREHENSIVE ADAPTIVE NANOPORE-SEQUENCING OF CNS TUMORS, A PROOF OF CONCEPT STUDY
Authors: Patel Areeba , Dogan Helin , Payne Alexander , Sievers Philipp , Schoebe Natalie , Schrimpf Daniel , Stichel Damian , Holmes Nadine , Euskirchen Philipp , Hench Jürgen , Frank Stephan , Rosenstiel-Goidts Violaine , Dieterich Christoph , Herold-Mende Christel , Pfister Stefan , Wick Wolfgang , Schlesner Matthias , Loose Matthew , Jones David , von Deimling Andreas , Sill Martin , Sahm Felix
Published: November 2021

BACKGROUND

The WHO classification 2021 includes multiple molecular markers for routine diagnostics in addition to histology. Sequencing setup for complete molecular profiling requires considerable investment, while batching samples for sequencing and methylation profiling can delay turnaround time. We introduce RAPID-CNS2, a nanopore adaptive sequencing pipeline that enables comprehensive mutational, methylation and copy number profiling of CNS tumours with a single third generation sequencing assay. It can be run for single samples and offers highly flexible target selection requiring no additional library preparation.

METHODS

Utilising ReadFish, a toolkit enabling targeted nanopore sequencing, we sequenced DNA from 22 diffuse glioma patient samples on a MinION device. Target regions comprised our Heidelberg brain tumour NGS panel and pre-selected CpG sites for methylation classification by an adapted random forest classifier. Pathognomonic alterations, copy number profiles, and methylation classes were called using a custom bioinformatics pipeline. Results were compared to their corresponding NGS panel-seq and EPIC array outputs.

RESULTS

Complete concordance with the EPIC array was found for copy number profiles from RAPID-CNS2. 94% pathognomonic mutations were congruent with NGS panel-seq. MGMT promoter status was correctly identified in all samples. Methylation families were detected with 96% congruence. Among the alterations decisive for rendering a classification-compatible integrated diagnosis, 97% of the alterations were consistent over the entire cohort (completely congruent in 19/22 cases and sufficient for unequivocal diagnosis in all).

CONCLUSIONS

RAPID-CNS2 provides a swift and highly flexible alternative to conventional NGS and array- based methods for SNV/Indel analysis, detection of copy number alterations and methylation classification. The turnaround time of ~4 days can be further shortened to < 12h by altering target sizes. It offers a low-capital approach that would be cost-efficient for low throughput settings and invaluable in cases requiring immediate diagnoses.
NIMG-10. OPTIMIZING IMAGE QUALITY FOR MAGNETIC RESONANCE SIMULATION IN SPINE STEREOTACTIC BODY RADIATION THERAPY
Authors: Hammoudeh Lubna , Lee Ho Young , Kaza Evangelia , Guenette Jeffrey , Balboni Tracy
Published: November 2021

BACKGROUND

Currently, the standard MRI sequence for SC imaging in SBRT has been axial 2D T2-weighted Turbo Spin Echo (TSE). Even though 3D T2-weighted sequences such as SPACE (Sampling Perfection with Application optimized Contrasts using different flip angle Evolution) image a whole volume simultaneously and thus offer better reconstruction, they have not been clinically implemented due to their long acquisition times. However, the application of Compressed Sensing (CS) methods on SPACE sequences, achieving clinically acceptable time.

METHODS

A 3D T2 CS SPACE was obtained and evaluated against the standard 2D TSE for spine SBRT based on a MagPhan RT quality assurance phantom and patients data, analysis was done using the phantom manufacturer software ImageOwl that calculates image distortions by comparing the known position of phantom features to their detected position in the image.

RESULTS

Results of phantom comparison between 3D T2 and 2D T2 indicate that although the 3D sequence had lower signal-to-noise ratio (SNR) than the 2D sequence, it presented less geometric distortions caused by gradient non-linearities, particularly in the anterior-posterior (A/P) and head-feet (H/F) directions. Distortions caused by chemical shift are in theory smaller for the 3D T2 CS SPACE, amounting to 0.85mm compared to 1.62mm with 2D T2. Between 2D versus 3D MRI defined SC data among 4 patients, average deviation of the centroid point cord contours was 0.08cm. The volume of the cord showed 1cc larger 3D volumes compared to 2D T2. Finally, the mean voxel count overlap coefficient and DICE coefficient was 0.92 and 0.87 respectively.

CONCLUSIONS

Since 3D MRI is under consideration to replace 2D MRI, it is important to compare SC contours from 3D to 2D MRI and assess their impact on treatment plans. Positive results would pave the path for larger subject cohort evaluation.
NIMG-13. RESPONSE ASSESSMENT IN GLIOBLASTOMA PATIENTS TREATED WITH DENDRITIC CELL-BASED IMMUNOTHERAPY: A COMPARATIVE ANALYSIS OF MACDONALD, RANO, MRANO, IRANO AND VOLUMETRIC MEASUREMENTS
Authors: Heugenhauser Johanna , Galijasevic Malik , Mangesius Stephanie , Buchroithner Johanna , Erhart Friedrich , Pichler Josef , Widhalm Georg , Preusser Matthias , Stockhammer Guenther , Iglseder Sarah , Freyschlag Christian , Oberndorfer Stefan , Bordihn Karin , von Campe Gord , Czech Thomas , Surboeck Birgit , Purkart Tadeja Urbanic , Marosi Christine , Felzmann Thomas , Nowosielski Martha
Published: November 2021

INTRODUCTION

Response assessment in the treatment of glioblastoma (GB) based on MR-imaging is still challenging, in particular for immunotherapeutic strategies. Several assessment tools have been proposed. In this post-hoc analysis we compared response assessment criteria (MacDonald, RANO, mRANO, Vol.-mRANO, iRANO) in newly diagnosed GB patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression free survival (PFS) and overall survival (OS).

METHODS

76 patients with newly diagnosed GB enrolled in a multicenter randomized phase II trial receiving standard of care (SOC, n= 40) or SOC + Audencel vaccine (n= 36) were included. Tumor volumes were calculated by semiautomatic segmentation. To detect differences in PFS among the assessment criteria Kruskal-Wallis-test, for correlation analysis Spearman test was used.

RESULTS

There was a significant difference in median PFS based on the different assessments (mRANO 8.55 months [9.10-14.03], Vol.-mRANO 8.61 months [9.72-14.92] compared to MacDonald 4.04 months [5.21-8.75] and RANO 4.16 months [5.28-8.61]. For the vaccination arm only, median PFS by iRANO was 5.95 months [5.70-11.54]). There was no difference in PFS between SOC and SOC + Audencel using the different response criteria. The best correlation between PFS and OS was detected for mRANO (r= 0.65, p< 0.001) and Vol.-mRANO (r= 0.69, p< 0.001). At an 8-month landmark, the impact of progressive disease on median OS was best shown for mRANO (13.70 months [13.13-18.98], and Vol.-mRANO 12.03 months [12.51-17.94]) compared to MacDonald 17.97 months [15.45-20.92], RANO 17.97 months [15.92-20.95] and iRANO 17.34 months [14.99-22.73].

CONCLUSION

When comparing different response assessments in GB patients treated with dendritic cell-based immunotherapy the best correlation between PFS and OS was observed for mRANO and Vol.-mRANO. Overall, no difference in PFS and OS was seen between the two treatment arms. iRANO was not superior for predicting OS in patients treated with Audencel.
NIMG-30. PATHOLOGICAL VALIDATION OF CONTRAST ENHANCEMENT AT AUTOPSY BETWEEN PATIENTS TREATED AND UNTREATED WITH CHEMOTHERAPY AND RADIATION
Authors: Lowman Allison , Bobholz Samuel , Brehler Michael , Duenweg Savannah , Sherman John , Kyereme Fitzgerald , Connelly Jennifer , Cochran Elizabeth , Mueller Wade , Banerjee Anjishnu , LaViolette Peter
Published: November 2021

Tumor heterogeneity in glioblastoma complicates delineation of active tumor using standard MR imaging. Pseudo-progression following treatment with chemotherapy and radiation (chemoRT) further complicates how tumors appear. T1-weighted subtraction maps (T1S) have been used to better identify subtly enhancing regions containing infiltrative tumor. This study examines the differences in tumor appearance between patients treated with chemoRT compared to a cohort opting out at autopsy, to understand how chemoRT changes contrast enhancement on MRI. Ten patients diagnosed with glioblastoma were recruited for whole brain donation for this study. Three patients received no treatment (chemoRT-), and seven received a combination of chemoRT and additional treatments (chemoRT+), including but not limited to bevacizumab (Bev) and tumor treating fields (TTF). Large tissue samples were taken at autopsy from whole brain samples sliced axially to align with the last clinical MRI using patient-specific 3D-printed slicing jigs. All tissue samples were hematoxylin and eosin (HE) stained and digitized at 40X resolution (27 total samples). The whole slide images (WSI) were annotated to outline regions containing necrosis without pseudopalisading cells, tumor with pseudopalisading necrosis, and infiltrative tumor. T1S were created for each patient by subtracting intensity normalized T1-weighted images from T1 post-contrast images (T1C). The annotated WSIs were aligned and resampled into MRI space using a custom software. A mixed effect model was used to compare the T1S intensity between chemoRT +/- cohorts within each pathological annotation, incorporating a random effect for subject. Mean T1S intensity was greater in untreated subjects when compared to chemoRT-subjects within each pathological annotation, including necrosis without pseudopalisading cells, tumor with pseudopalisading necrosis, and infiltrative tumor (p< 0.001). We show that chemoRT reduces the contrast enhancement in all aspects of pathologically validated tumor compartments, including infiltrative tumor. Future research is needed to examine if other patterns are evident in additional MR sequences.
NIMG-34. DELAYED PSEUDOPROGRESSION IN GLIOBLASTOMA PATIENTS TREATED WITH TTFIELDS: A REPORT OF TWO CASES
Authors: Saito Norihiko , Hirai Nozomi , Yagihashi Akinori , Takahagi Shusaku , Kushida Naoki , Sato Sho , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Haya Morito , Sakurai Takatoshi , Iwabuchi Satoshi
Published: November 2021

INTRODUCTION: Tumor treating fields (TTFields) is an established treatment modality for glioblastoma (GBM) and is administered with the portable Optune system. Although the EF-14 phase 3 trial demonstrated the efficacy of TTFields for newly diagnosed GBM, uncertainty regarding the specific effects of this treatment has prevented its widespread clinical use. Pseudoprogression in response to chemoradiation is a known problem in GBM patients and most commonly occurs within 3 months after radiotherapy. We report 2 cases of TTFields delayed pseudoprogression. CASE REPORT: Two GBM patients being treated with TTFields showed signs of radiographic progression at 5 to 6 months after completing radiotherapy. Patient 1 was a 37-year-old woman with gliosarcoma in the right temporal lobe. Patient 2 was a 70-year-old man with wildtype-IDH GBM in the left temporal lobe. Both patients received TTFields in addition to maintenance temozolomide (TMZ) after radiotherapy (RT). Radiographic progression was noted at 5 and 6 months after RT in Patients 1 and 2, respectively. Second resections were performed, and pathology showed only the treatment effect, which ultimately led to diagnosis of pseudoprogression. DISCUSSION: Both patients had radiographic progression outside the typical pseudoprogression window. Recent studies reported that TTFields increased plasma cell membrane permeability, which could result in additional gadolinium leakage into the extracellular space. CONCLUSIONS: Better characterization of delayed pseudoprogression would improve treatment and could potentially reduce unnecessary surgeries and discontinuation of successful therapies.
NIMG-40. MRI-BASED ESTIMATION OF THE ABUNDANCE OF IMMUNOHISTOCHEMISTRY MARKERS IN GBM BRAIN USING DEEP LEARNING
Authors: Ranjbar Sara , Singleton Kyle , Boyett Deborah , Argenziano Michael , Grinband Jack , Canoll Peter , Swanson Kristin
Published: November 2021

Glioblastoma (GBM) is a devastating primary brain tumor known for its heterogeneity with a median survival of 15 months. Clinical imaging remains the primary modality to assess brain tumor response, but it is nearly impossible to distinguish between tumor growth and treatment response. Ki67 is a marker of active cell proliferation that shows inter- and intra-patient heterogeneity and should change under many therapies. In this work, we assessed the utility of a semi-supervised deep learning approach for regionally predicting high-vs-low Ki67 in GBM patients based on MRI. We used both labeled and unlabeled datasets to train the model. Labeled data included 114 MRI-localized biopsies from 43 unique GBM patients with available immunohistochemistry Ki67 labels. Unlabeled data included nine repeat routine pretreatment paired scans of newly-diagnosed GBM patients acquired within three days. Data augmentation techniques were utilized to enhance the size of our data and increase generalizability. Data was split between training, validation, and testing sets using 65-15-20 percent ratios. Model inputs were 16x16x3 patches around biopsies on T1Gd and T2 MRIs for labeled data, and around randomly selected patches inside the T2 abnormal region for unlabeled data. The network was a 4-conv layered VGG-inspired architecture. Training objective was accurate prediction of Ki67 in labeled patches and consistency in predictions across repeat unlabeled patches. We measured final model accuracy on held-out test samples. Our promising preliminary results suggest potential for deep learning in deconvolving the spatial heterogeneity of proliferative GBM subpopulations. If successful, this model can provide a non-invasive readout of cell proliferation and reveal the effectiveness of a given cytotoxic therapy dynamically during the patient's routine follow up. Further, the spatial resolution of our approach provides insights into the intra-tumoral heterogeneity of response which can be related to heterogeneity in localization of therapies (e.g. radiation therapy, drug dose heterogeneity).
NIMG-51. DEUTERIUM METABOLIC IMAGING OF BRAIN TUMOR IMMORTALITY USING 2H-PYRUVATE
Authors: Batsios Georgios , Taglang Céline , Tran Meryssa , Gillespie Anne Marie , Ronen Sabrina , Costello Joseph , Viswanath Pavithra
Published: November 2021

Telomere maintenance is essential for tumor immortality and sustained tumor proliferation. Most tumors, including high-grade glioblastomas and low-grade oligodendrogliomas achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. Due to this essential role, TERT is a therapeutic target and TERT inhibitors such as 6-thio-2’-deoxyguanosine are in clinical trials. Non-invasive methods of imaging TERT, therefore, have the potential to provide a readout of tumor proliferation and response to therapy. We previously showed that TERT expression is associated with elevated levels of NADH in gliomas. Since NADH is essential for the conversion of pyruvate to lactate, measuring pyruvate flux to lactate could be useful for imaging TERT expression. In this context, deuterium magnetic resonance spectroscopy (2H-MRS) recently emerged as a novel, clinically translatable method of monitoring metabolic fluxes. The goal of this study was to assess the potential of [U-2H]pyruvate for non-invasive imaging of TERT status in gliomas. Following intravenous injection of [U-2H]pyruvate, lactate production was significantly higher in mice bearing orthotopic oligodendroglioma (SF10417, BT88) or glioblastoma (GBM1, GBM6) tumors relative to tumor-free controls. 2D chemical shift imaging showed localization of lactate production to tumor vs. contralateral normal brain. Importantly, following treatment of mice bearing orthotopic GBM6 or BT88 tumors with the TERT inhibitor 6-thio-2’-deoxyguanosine, lactate production from [U-2H]pyruvate was significantly reduced at early timepoints when alterations in tumor volume could not be detected by anatomical imaging, pointing to the ability of [U-2H]pyruvate to report on pseudoprogression. Collectively, we have, for the first time, demonstrated the utility of [U-2H]pyruvate for metabolic imaging of brain tumor burden and treatment response in vivo. Importantly, since 2H-MRS can be implemented on clinical scanners, our results provide a novel, non-invasive method of integrating information regarding a fundamental tumor hallmark, i.e. TERT, into glioma patient management.
NIMG-54. RADIOMIC FEATURES FROM LESION HABITAT PREDICT RESPONSE TO COMBINATION OF NIVOLUMAB AND BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: A FEASIBILITY STUDY
Authors: Verma Ruchika , Rauf Yasmeen , Yadav Ipsa , Statsevych Volodymyr , Chen Jonathan , Evanoff Wendi , Ahluwalia Manmeet , Tiwari Pallavi
Published: November 2021

PURPOSE

The use of immunotherapy in glioblastoma management is under active investigation. Glioblastomas are “cold” tumors, meaning that they have inactivated or fewer tumor infiltrative lymphocytes in addition to substantial tumor necrosis, attributing to their poor response to immunotherapy. A significant challenge is the apriori identification of Glioblastoma patients who will respond favorably to immunotherapy. In this work, we evaluated the ability of computerized MRI-based quantitative features (radiomics) extracted from the lesion habitat (including enhancing lesion, necrosis, and peritumoral hyperintensities) to predict response and progression-free survival (PFS) in recurrent GBM patients treated with combination of Nivolumab and Bevacizumab.

METHODS

Immunotherapy response assessment in neuro-oncology (iRANO) criteria along with PFS were used to analyze n=50 patients enrolled in a randomized clinical trial where patients received Nivolumab with either standard or low dose Bevacizumab. These patients were assessed to see if they had complete response, partial response, stable disease (i.e. responders, n=31), or disease progression (i.e. non-responders, n=19). Lesion habitat constituting necrotic core, enhancing tumor, and edema were delineated by expert radiologist on Gd-T1w, T2w and FLAIR MRI scans. COLIAGE radiomic features from each of the delineated regions were selected using minimum redundancy maximum relevance (mRMR) via cross-validation, to segregate non-responder patients from responders. A multivariable cox proportional hazard model was used to predict survival (PFS).

RESULTS

CoLlAGe correlation, sum average, and sum variance features (capture local heterogeneity) from the lesion habitat, were found to segregate non-responder patients from responders with an accuracy of 86%, followed by 80% using features from peritumoral hyperintensities and 78% from enhancing tumor. In our survival analysis, C-index of 0.688 was obtained using features from the entire lesion habitat, followed by peritumoral hyperintensities (0.675) and enhancing tumor (0.656).

CONCLUSION

Radiomic features from the lesion habitat may predict response to combination of Nivolumab and Bevacizumab in recurrent Glioblastomas.
NIMG-60. PREDICTING OVERALL SURVIVAL IN GLIOBLASTOMA USING HISTOPATHOLOGY VIA AN END-TO-END DEEP LEARNING PIPELINE: A LARGE MULTI-COHORT STUDY
Authors: Verma Ruchika , Cohen Mark , Toro Paula , Mokhtari Mojgan , Tiwari Pallavi
Published: November 2021

PURPOSE

Glioblastoma is an aggressive and universally fatal tumor. Morphological information as captured from cellular regions on surgically resected histopathology slides has the ability to reveal the inherent heterogeneity in Glioblastoma and thus has prognostic implications. In this work, we hypothesized that capturing morphological attributes from high cellularity regions on Hematoxylin and Eosin (H&E)-stained digitized tissue slides using an end-to-end deep-learning pipeline will enable risk-stratification of GBM tumors based on overall survival.

METHODS

A large multi-cohort study consisting of N=514 H&E-stained digitized tissue slides along with overall-survival data (OS) was obtained from the Ivy Glioblastoma atlas project (Ivy-GAP (N=41)), TCGA (N=379), and CPTAC (N=94). Our deep-learning pipeline consisted of two stages. First stage involved segmenting cellular tumor (CT) from necrotic-regions and background using Resnet-18 model, while the second stage involved predicting OS, using only the segmented CT regions identified in the first stage. For the segmentation stage, we leveraged the Ivy-GAP cohort, where CT annotations confirmed by expert neuropathologists were available, to serve as the training set. Using this training model, the CT regions on the remaining cohort (TCGA, CPTAC) (i.e. test set) were identified. For the survival-prediction stage, the last layer of ResNet18 model was replaced with a cox layer (ResNet-Cox), and further fine-tuned using OS and censor information. Independent validation of ResNet-Cox was performed on two hold-out sites from TCGA and one from CPTAC.

RESULTS

Our segmentation model achieved an accuracy of 0.89 in reliably identifying CT regions on the validation data. The segmented CT regions on the test cohort were further confirmed by two experts. Our ResNet-Cox model achieved a concordance-index of 0.73 on MD Anderson Cancer Center (N=60), 0.71 on Henry Ford Hospital (N=96), and 0.68 on CPTAC data (N=41).

CONCLUSION

Deep-learning features captured from cellular tumor of H&E-stained histopathology images may predict survival in Glioblastoma.
NIMG-62. 68(GA)DOTATATE PET-BASED RADIATION CONTOURING CREATES SMALLER AND MORE PRECISE RADIATION VOLUMES FOR MENINGIOMA PATIENTS
Authors: Perlow Haley , Yang Michael , Siedow Michael , Gokun Yevgeniya , McElroy Joseph , Matsui Jennifer , Beyer Sasha , Arnett Andrea , Boulter Daniel , Fritz Joel , Miller Eric , Blakaj Dukagjin , Zoller Wesley , Cadieux Catherine , Eiler Daniel , Addington Mark , DiConstanzo Dominic , Grecula John , Raval Raju , Chakravarti Arnab , Palmer Joshua
Published: November 2021

PURPOSE

Radiation treatment planning for meningiomas conventionally involves MRI contrast enhanced images to define residual tumor. However, the gross tumor volume may be difficult to delineate for patients with a meningioma in the skull base, sagittal sinus, or post resection. Advanced PET imaging using 68(GA)DOTATATE PET, which has been shown to be more sensitive and specific than MRI imaging, can be used for target volume delineation in these circumstances. We hypothesize that 68(GA)DOTATATE PET scan-based treatment planning will lead to smaller radiation volumes and will detect additional areas of disease compared to standard MRI alone.

METHODS

Our data evaluated retrospective, deidentified, and blinded gross tumor volume (GTV) contour delineation with 7 CNS specialists (3 neuroradiologists, 4 CNS radiation oncologists) for 26 patients diagnosed with a meningioma who received both a 68(GA)DOTATATE PET and an MRI for radiation treatment planning. Both the MRI and the PET were non-sequentially contoured by each physician for each patient.

RESULTS

The mean MRI volume for each physician ranged from 24.14-35.52 ccs. The mean PET volume for each physician ranged from 10.59-20.54 ccs. The PET volumes were significantly smaller for 6 out of the 7 physicians. In addition, 7/26 (27%) patients had new non-adjacent areas contoured on PET by at least 6 of the 7 physicians that were not contoured by these physicians on the corresponding MRI. These new areas would not have been in the traditional MRI based volumes.

CONCLUSION

Our study supports that 68(GA)DOTATATE PET imaging can help radiation oncologist create smaller and more precise radiation treatment volumes. Utilization of 68(GA)DOTATATE PET may find undetected areas of disease which in turn can improve local control and progression free survival. 68(GA)DOTATATE PET guided treatment planning should be studied prospectively.
NIMG-64. TYPE OF BONY INVOLVEMENT PREDICTS GENOMIC SUBGROUP IN SPHENOID WING MENINGIOMAS
Authors: Jin Lan , Youngblood Mark , Gupte Trisha , Vetsa Shaurey , Nadar Arushii , Barak Tanyeri , Yalcin Kanat , Aguilera Stephanie , Mishra-Gorur Ketu , Blondin Nicholas , Omay S Bulent , Pointdujour-Lim Renelle , Judson Benjamin , Alperovich Michael , Aboian Mariam , McGuone Declan , Gunel Murat , Erson-Omay Zeynep , Fulbright Robert , Moliterno Jennifer
Published: November 2021

OBJECTIVE

As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature.

METHODS

Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as frank tumor invasion (TI), hyperostosis only (HOOs), or both (TI+HO). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Predictive logistic regression models were developed for genomic subgroups based on pre-operative clinical features.

RESULTS

Among 64 SWMs, 53% had HOO, 9% had TI, and 14% had TI+HO; nine SOMs were identified. Tumors with invasion (i.e., TI or TI+HO) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR: 27.6; p: 0.004), while hyperostosis only (without frank tumor invasion) were over 4 times more likely to have a TRAF7 mutation (OR: 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR: 10.21; p: 0.004).

CONCLUSIONS

SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers.
NIMG-65. RESTING-STATE FUNCTIONAL MRI DEMONSTRATES DAMAGE TO FUNCTIONAL CONNECTIVITY IN MENINGIOMA PATIENTS WITH PERIFOCAL EDEMA
Authors: Stoecklein Veit , Wunderlich Stephan , Papzov Boris , Liu Hesheng , Schmutzer Michael , Thon Niklas , Schichor Christian , Tonn Jörg-Christian , Stoecklein Sophia
Published: November 2021

BACKGROUND

Meningiomas are common intracranial tumors which usually carry a benign prognosis. Some meningiomas cause perifocal edema which might indicate that this subset could interfere with normal brain function. Resting-state functional MRI (rsfMRI) can be used to assess whole brain functional connectivity (fc) which can be used as a marker for disease severity in patients with intracranial tumors, as was recently shown by our group in a cohort of glioma patients. In this study, we investigated whether the presence of perifocal edema in preoperative patients with meningioma leads to fc.

METHODS

Patients with suspected meningioma were prospectively included and functional resting state MRI scans were obtained. The resulting data was processed according to our recently published method and abnormality of fc was quantified for each individual patient. Abnormality of fc was then correlated with tumor and edema volume as well as WHO grade.

RESULTS

26 patients (23 WHO grade I, 3 WHO grade II) were included. 13 patients had perifocal edema. There was a highly significant correlation between edema volume and higher abnormality of fc both in the lesional and the contra-lesional hemisphere (r=0.51, p=0.008 and r=0.61, p=0.001). Patients with no perifocal edema showed only very low abnormality of fc. Tumor volume was not correlated with abnormal fc in both the lesional and the contralesional hemispheres (r=0.23, p=0.27 and r=0.28, p=0.17). There was also no significant correlation between WHO grade and abnormality of fc.

CONCLUSION

RsfMRI showed significant abnormal fc in meningioma patients with perifocal edema in contrast to patients without edema, independent of tumor volume. This demonstrates that the presence of edema but not the tumor volume is relevant for disturbances of fc.
NIMG-66. USING 68GA-DOTATATE PET FOR POSTOPERATIVE GAMMA KNIFE RADIOSURGERY PLANNING IN PATIENTS WITH MENINGIOMA
Authors: Park David , Ma Daniel , Goenka Anuj , Schulder Michael
Published: November 2021

BACKGROUND

Patients with meningiomas are typically treated with maximal safe surgical resection. After subtotal resection or at the time of tumor recurrence, stereotactic radiosurgery (SRS) is often used as the treatment of choice. While magnetic resonance imaging (MRI) is typically used for SRS target delineation, differentiating tumor growth from postoperative change can be challenging. 68Ga-DOTATATE, a positron emission tomography (PET) radiotracer targeting the somatostatin receptor type 2 (SSTR2), has been shown to be a reliable biomarker of meningiomas.

METHODS

We present a consecutive case series of 13 patients with pathology-proven meningioma who received a 68Ga-DOTATATE PET prior to SRS between April 2019 and April 2021. Treatment planning was done at first using MRI only. The DOTATATE-PET images were then used to assess the accurate identification of tumor.

RESULTS

Ten of the patients had WHO grade 2 meningioma and three patients had WHO grade 1 tumor. Nine patients had recurrent meningiomas and four patients had newly diagnosed disease. Overall, the 68Ga-DOTATATE PET scan revealed additional tumor beyond what was seen on MRI in 5/13 patients. The SRS plan was changed to intensity-modulated radiation therapy (IMRT) for three patients and to octreotide injection in one patient. In one patient, after 68Ga-DOTATATE PET identified previously unrecognized recurrent meningioma in the resection cavity, SRS was performed. In three others, questionable tumor recurrence was seen on MRI, and then confirmed on 68Ga-DOTATATE-PET, but patient observation only was continued due to the small lesion size.

CONCLUSION

Incorporation of 68Ga-DOTATATE PET data changed SRS treatment in 5/13 our patients with meningioma after prior surgery. We have made this a routine part of our treatment planning and we recommend this method to optimize the use of SRS or RT in these patients. Further data collection is ongoing.
NCMP-04. BRAIN-UMAP: THE GENETIC INTERSECTION BETWEEN NEUROSCIENCE, NEUROLOGY, PSYCHIATRY, AND ONCOLOGY
Authors: Arora Sonali , Nuechterlein Nicholas , Pattwell Siobhan , Holland Eric
Published: November 2021

Whole transcriptome sequencing (RNA-seq) is an important tool for understanding genetic mechanisms underlying human diseases and gaining a better insight into complex human diseases. Several ground-breaking projects have uniformly processed RNASeq data from publicly available studies to enable cross-comparison. One noteworthy study is the recount2 pipeline, which in 2017, has reprocessed ~70,0000 samples from Short Read Archive(SRA), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx). This vast dataset also includes gene expression data for GTEx-defined brain regions, neurological and psychiatric disorders (such as Parkinson's, Alzheimer’s, Huntington’s) and gliomas (such as TCGA, Chinese Glioma Genome Atlas (CGGA)). We apply uniform manifold approximation and projection (UMAP), a non-linear dimension reduction tool, to bulk gene expression data from brain-related diseases to build a BRAIN-UMAP, which allows for visualization of gene expression profiles across datasets. This UMAP shows that while gliomas form a distinct cluster, the neurological and psychiatric diseases are similar to GTEX-defined normal brain regions which exhibit tissue-specific profiles and patterns. Incorporating gliomas from various publicly available datasets also allows for the ability to observe unique clustering of particular subtypes, which can increase our genetic understanding of the disease. We also present a resource where researchers interested in mechanisms, can easily compare, and contrast the expression of a given gene and/or pathway of interest across various diseases, gliomas, and normal brain regions. Our current study, focusing on brain related diseases, offers insight into what may be possible for the broader neuroscientific community if we continually reprocess newly available brain related RNASeq samples using recount2. Additionally, if we build similar uniformly processing pipelines for other kinds of next-generation sequencing data, we would be able to use multi-omic sequencing data to find novel associations between biological entities and increase our mechanistic knowledge of the disease.
NCMP-08. CHALLENGING DIAGNOSIS AND MANAGEMENT OF PCNSL IN AN IMMUNOSUPPRESSED PATIENT ON MYCOPHENOLATE MOFETIL FOR MYASTHENIA GRAVIS
Authors: Bricoune Ornella , Mokhtari Sepideh , Etame Arnold , Robinson Timothy , Pina yolanda , Macaulay Robert
Published: November 2021

INTRODUCTION

Primary CNS lymphoma (PCNSL) typically presents with non-focal neurologic symptoms including disorientation, poor balance and memory and singel or multifocal periventricular MRI lesions. Deviations in characteristic findings can delay diagnosis and require additional diagnostic tests.

OBSERVATION

A 68-year-old man with a recent zoster infection and acetylcholine receptor antibody positive myasthenia gravis (MG) on Mycophenolate Mofetil for 22 years presented at another institution with left eye vision changes, and focal neurological deficits. A brain MRI showed an enhancing lesion within his left medulla extending to the cerebellum. Cerebrospinal fluid (CSF) analysis was positive for EBV and negative for malignancy. He was diagnosed with VZV vasculopathy and discharged home on IV Acyclovir for 14 days and a 5-day course of oral prednisone 60 mg. Three months later, a repeat brain MRI showed multiple new enhancing lesions bilaterally along the periventricular white matter with involvement of the corpus callosum with several lesions in peripheral locations of the cerebrum, cerebellum, and brainstem. He presented to local ER with intermittent encephalopathy, acute left eye vision blurriness and was started on steroids. He was transferred to our institution and had CSF analysis which was positive for EBV and negative for malignancy. Due to rapid progression of his symptoms, he underwent gross total resection of the left frontal lesion which showed EBV-induced diffuse large B-cell lymphoma (DLBCL). His Mycophenolate Mofetil was discontinued and he had a dramatic improvement in his left eye vision and cognitive deficits within 24 hours after one dose of Rituximab IV 500 mg/m2.

DISCUSSION

In the setting of periventricular lesions and EBV positivity on CSF, EBV-induced DLBCL should be highly considered.

CONCLUSION

Misdiagnosis or delay in diagnosis of PCNSL due to the presence of atypical features in disease presentation and radiographic findings could lead to progression of PCNSL.
NCMP-10. DYSGRAPHIA AS THE EARLIEST PRESENTING SYMPTOM OF SEVERE CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY NEUROTOXICITY: A SINGLE CENTER EXPERIENCE
Authors: Yuen Carlen , Rezania Kourosh , Kelly Thomas , Bishop Michael
Published: November 2021

INTRODUCTION

Chimeric antigen receptor (CAR) T-cell therapy, including axicabtagene ciloleucel (axi-cel; Yescarta®) and tisagenlecleucel (tisa-cel; Kymriah®), are FDA approved for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Neurotoxicity (NT) associated with CAR T-cell therapy (immune effector cell-associated neurotoxicity syndrome [ICANS]) can be fatal. Timely data, in the form of an abbreviated bedside mini-mental status exam, is thought to lead to earlier identification of NT. However, existing literature validating this method is limited.

MATERIALS AND METHODS

In this retrospective study, patients with R/R DLBCL treated with commercial axi-cel or tisa-cel in our center from December 2017 to September 2018 were assessed for NT with the CTCAE v4 criteria and the CAR-T-cell-therapy-associated TOXicity (CARTOX-10) scoring system.

RESULTS

Twenty-six patients with R/R DLBCL were treated with CAR T-cell therapy (25 axi-cel/[Yescarta®] and 1 tisagenlecleucel [Kymriah®]). Twenty-three (88%) developed NT with 8 (31%) experiencing severe NT (Grade III-IV). Tremor and dysgraphia occurred in all patients with severe NT. Lower average CARTOX-10 score (p=< 0.01), dysgraphia (p< 0.01), inattention (p=.018), and disorientation (p=.01) were significantly associated in patients with severe NT. A trend towards significance was observed between tremor and severe NT (p=.08). All patients with severe NT had both dysgraphia and tremor 8/8 (100%) and 2/8 (25%) had concurrent dysnomia. Death occurred in 12/26 (46%) of patients due to disease progression (n=11) and cardiac failure due to myositis (n=1).

CONCLUSION

In our limited cohort, dysgraphia, inattention, and disorientation are heralding symptoms of severe NT in adult R/R DLBCL patients treated with commercial CAR T-cell therapy. Dysgraphia was the earliest presenting symptom in patients with severe CAR T-cell neurotoxicity and was likely a manifestation of motor dysfunction rather than a component of dysphasia. Further studies with a larger cohort are needed to validate our findings.
NCOG-01. RADIATION THERAPY MANAGEMENT FOR METASTATIC DISEASE TO THE BRAIN IN NSCLC PATIENTS – SURVIVAL OUTCOMES OF THE BRITISH COLUMBIA POPULATION 1996-2016
Authors: Stubbs Terry , DeVries Kimberly , Proulx Ryan , Ho Clement , Cheung Arthur , Nichol Alan , Krauze Andra
Published: November 2021

BACKGROUND

Radiation therapy (RT) for brain metastases in patients with non-small cell lung cancer (NSCLC) has undergone considerable evolution but remains controversial.

METHODS

Records for 2212 patients with NSCLC who received RT to the brain at one of six locations between 1996-2016 were retrospectively analyzed. Data were obtained from the institutional cancer registry following ethics approval. Overall survival (OS) was calculated from diagnosis of lung cancer to death, and Kaplan-Meier curves were compared by Log-rank and Cox regression.

RESULTS

Median OS was 11.8 months (95%CI 11-12.6 months). Median age was 65, and 1254 patients (57%) were female. ECOG performance status at diagnosis was 0 (12%), 1 (31%), 2 (17%), 3 (14%), 4 (2%), and unknown (24%). Younger age (HR=0.99, 95%CI 0.98-0.99), female sex (HR=0.80, 95%CI 0.74-0.88), and better ECOG performance status (p< 0.0001) were associated with superior OS. There was better OS in 932 patients (42%) that received chemotherapy (HR=0.63, 95%CI 0.58-0.69) and 603 (27%) that underwent surgery (HR=0.55, 95%CI 0.50-0.61). 2004 patients (91%) received 1 RT course, while 208 (9%) received multiple courses in various combinations of whole brain RT (WBRT) and stereotactic radiosurgery (SRS). SRS (HR=0.70, 95%CI 0.57-0.86) and multiple RT courses (HR=0.55, 95%CI 0.46-0.65) were associated with better OS. Median time from primary diagnosis to brain RT was 2.5 months, and from end of first brain RT to death was 3.5 months. A longer diagnosis to brain RT interval was associated with better OS (HR=0.95, 95%CI 0.95-96).

CONCLUSIONS

NSCLC patients with brain metastases continue to face poor prognosis, particularly when lung cancer diagnosis to first brain RT interval is short. Our analysis revealed younger age, female sex, and better ECOG performance status as predictors of superior survival. SRS and multiple RT courses also revealed superior survival, likely the result of patient selection and hence interpreted with caution.
NCOG-03. PREDICTORS OF NEUROLOGIC DEATH IN PATIENTS WITH BRAIN METASTASES
Authors: Reese Alexander , Lamba Nayan , Catalano Paul , Cagney Daniel , Wen Patrick , Aizer Ayal
Published: November 2021

BACKGROUND

Neurologic death (ND), defined as intracranial disease progression with accompanying neurologic symptoms in the absence of life-threatening systemic disease, is the most serious consequence of intracranial disease among patients with brain metastases (BMs). Data indicating which factors are predictive of this outcome remain limited, however. Determining which patients are at increased risk of ND will guide improved care and further research aimed at preventing ND.

METHODS

We identified 1,218 patients with newly diagnosed BMs managed at Brigham and Women’s Hospital from 2008-2015. Demographic and tumor characteristics for patients experiencing ND, non-neurologic death, and who were alive at last follow up were analyzed by univariable and multivariable Fine and Gray competing risks regression to identify predictors of ND, with non-neurologic death serving as a competing risk.

RESULTS

In multivariable analysis, ND was associated with number of BMs (hazard ratio [HR] 1.01 per 1 metastasis increase, 95% CI 1.01-1.02, p< 0.001) and three primary tumor sites (with non-small cell lung cancer as the reference): melanoma (HR 4.67, 95% CI 3.27-6.68, p< 0.001), small cell lung cancer (HR 2.33, 95% CI 1.47-3.68, p< 0.001), and gastrointestinal cancer (HR 2.21, 95% CI 1.28-3.82, p=0.005). Additionally, among patients with breast primaries, HER2+ tumors displayed increased risk of ND relative to the reference subtype (HR+/HER2-) in univariable analysis (HR 2.41, 95% CI 1.00-5.84, p=0.05). A reduced risk of ND was found in patients with Karnofsky performance status of 90-100 versus 30-80 (HR 0.67, 95% CI 0.48-0.95, p=0.03) and progressive extracranial disease (HR 0.50, 95% CI 0.38-0.67, p< 0.001).

CONCLUSION

Patients with melanoma, small cell lung cancer, gastrointestinal, and HER2+ breast cancer primaries, in addition to those with greater intracranial versus extracranial disease burdens, are at increased risk of ND. Future research into novel intracranial approaches should focus on these groups of patients.