bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-42. PROGNOSTIC FACTORS OF CNS GERM CELL TUMORS; MOLECULAR AND HISTOPATHOLOGICAL ANALYSES ON 154 CASES FROM THE IGCT CONSORTIUM
Authors: Satomi Kaishi , Nishikawa Ryo , Matsutani Masao , Ichimura Koichi , Takami Hirokazu 
Published: November 2021

Abstract

BACKGROUND
Germ cell tumors (GCTs) preferentially occurs in pediatric and young adult age groups. Chemo- and radiation therapies cause long-term sequelae in their later lives. We searched for clinical and histopathological features to predict the prognosis and affect treatment response, with a future goal of treatment stratification.

METHODS
A total of 154 GCT cases were included in the analysis. Total of 114 germinoma cases underwent measurement of tumor cell content on H-E specimen, and 82 GCT cases underwent 450K methylation analysis. 12p gain was determined on methylation-based copy number computation and FISH. Association with progression-free and overall survival (PFS/OS) was investigated.

RESULTS
The tumor cell content was widely distributed from &lt; 5% to 90% in the specimens, with a median value of 50%. Patients with a higher tumor cell content (≥50%) showed shorter PFS than those with a lower tumor cell content (&lt; 50 %) (p=0.03). In multivariate analysis with tumor location, tumor cell content was the sole statistically significant prognostic factor (p=0.04). 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs, particularly in cases with malignant components. The presence of 12p gain correlated with shorter PFS and OS, even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS. The 12p copy number status was shared among histological components in mixed GCTs. Whole-genome amplification was suggested by FISH.

CONCLUSIONS
We found that tumor cell content significantly affected the prognosis of germinomas. 12p gain predicts the presence of malignant components of NGGCTs, and poor prognosis of the patients. Furthermore, 12p is likely to be an early event in the tumorigenesis of GCT. These potentially open the possibility of leveraging these pathological and molecular factors in future clinical trials when stratifying the treatment intensity.
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

Abstract

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

Abstract

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 &gt;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

Abstract

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 &lt; 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

Abstract

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

Abstract

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&lt; 0.001) and Vol.-mRANO (r= 0.69, p&lt; 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

Abstract
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&lt; 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

Abstract
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

Abstract
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

Abstract
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.