bluuebunny/crossref_metadata_2025 huggingface dataset:
INNV-19. THE DETECTION OF DISSEMINATED PINEAL PARENCHYMAL TUMOR OF INTERMEDIATE DIFFERENTIATION (PPTID) IN CEREBROSPINAL FLUID (CSF) USING CELL CAPTURE AND IMMUNOCYTOCHEMISTRY
Authors: Armijo Kaitlyn , Sweed Nathan , Hsiao Steven , Pircher Tony , Marrin Mikayla , Cho Leslie , Kreitzburg Kelly , Blouw Barbara , Fisher Deanna , Dugan Michael , Kesari Santosh
Published: November 2022

BACKGROUND

Pineal parenchymal tumors of intermediate differentiation (PPTID) account for 21% to 54% of pineal parenchymal tumors and may be complicated by cerebrospinal dissemination (most commonly at time of reoccurrence; up to 4-10 years post resection). The integral membrane protein synaptophysin is expressed in neuroendocrine cells and virtually all neuraxial neurons that contribute to synaptic transmission. PPTID frequently demonstrates synaptophysin independently of other neural differentiation markers. Cerebrospinal fluid (CSF) cell capture assays have demonstrated utility for assessing disseminated intracranial neoplasms, thus we explore this technology for monitoring a patient with PPTID.

METHODS

A 30-year-old female patient with PPTID diagnosed two years prior was suspected for intracranial dissemination and underwent five CSF collections over the course of 64 days. Per collection, approximately 7 mL of CSF was submitted for each cytology and cell capture. Cytology was performed at Providence Saint John’s Health Center. The CNSide™ platform (Biocept, Inc.) was used to capture and stain cells for DAPI, synaptophysin, and CD45. Multiple capture antibody cocktails (termed 1986, 1822, and gTP1—originally developed for use in carcinoma, melanoma, and glioma) were tested. Cells of interest (COI) were defined by positive immunoreactivity for both DAPI and synaptophysin and no immunoreactivity for CD45. Results were quantified and compared longitudinally.

RESULTS

CSF analysis on days 0, 9, 21, 36, and 64 demonstrated negative results by cytology and 51, 96, 170, 130, and 43 COI/mL by the CNSide platform, respectively. Cumulative mean capture rates for cocktails 1986, 1822, and gTP1 were 47, 14, and 36 COI/mL/sample, respectively.

DISCUSSION

A significant amount of PPTID patients will develop cerebrospinal dissemination. The importance of craniospinal control in this setting has been previously demonstrated. Our work suggests that cell capture assays paired with immunocytochemistry can be used as sensitive means to monitor disseminated PPTID and may impact treatment decisions.
INNV-24. PATIENT SATISFACTION AND COST ANALYSIS OF THE TELEMEDICINE PROGRAM WITHIN A NEURO-ONCOLOGY PROGRAM
Authors: Bilenkin Arkady , Kang Richard , Prorok Rachel , Rogers Andrea , Naso Cristina , Patel Krupal , Beer-Furlan Andre , Liu James
Published: November 2022

Unique challenges exist in the utilization of telemedicine for neurological and surgical specialties. We examined the differences in patient satisfaction for telemedicine versus in-person Press Ganey survey reports within an integrated Neuro-Oncology Department to assess whether there was a difference between surgical and medical specialties. We also examined the potential cost savings benefits of utilizing telemedicine. 1189 Press Ganey surveys in the Department of Neuro-Oncology (982 in-person and 207 telemedicine) submitted by neurosurgical and neuro-oncology patients between 04/01/2020 and 06/30/2021 were analyzed. Survey results were divided into 4 categories (Access, Provider, Technology (for telemedicine only), and Overall Satisfaction). Results were compared between telemedicine and in-person visits, and by gender, age, insurance, and specialty. Potential time and cost savings were estimated by calculating lost productivity based on census income data with motor vehicle expenses, and round-trip distances with mean visit durations, respectively. The survey results demonstrated that, among telemedicine patients, there were no differences in satisfaction based on gender, age, or insurance. Surgical specialties scored higher in Access, Technology, and Overall. Among in-person patients, patients older than 65 had higher satisfaction for Provider (p=0.0368) and Overall (p=0.0010). Medicare patients returned higher scores compared to non-private insurance for Overall (p=0.0172). Surgical patients scored higher for Access (p=0.0002). When comparing Telemedicine to In-Person scores, In-person satisfaction was higher for Provider for all patients combined. For surgical patients only, Telemedicine scored higher only in Access (p=0.0252). Cost analysis demonstrated that patients saved an average of 155.4 to 175.1 miles and 3.1 to 3.4 hours of travel per visit and average cost savings were $117.84 to $185.00. We conclude that telemedicine lessens the financial and time burden on neuro-oncology patients and yields non-inferior patient-satisfaction when employed in neurosurgery as compared to medicine, despite potential limitations of the technology in neurological and surgical specialties.
INNV-25. ASSESSING SLEEP AND CIRCADIAN RHYTHMS IN PRIMARY BRAIN TUMORS PATIENTS: AN OBSERVATIONAL STUDY
Authors: Wollet Alex , Leeper Heather , Vera Elizabeth , Mentges Kelly , King Amanda , Rogers James , Sass Dilorom (Delia) , Acquaye Alvina , Adegbesan Kendra , Boris Lisa , Burton Eric , Celiku Orieta , Chambers Claudia , Choi Anna , Christ Alexa , De Le Minyety Julianie Cruz , Evans Karen , Grajkowska Ewa , Komlodi-Pasztor Edina , Levine Jason , Lindsley Matthew , Lollo Nicole , Mendoza Tito , Miller Hope , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Polskin Lily , Reyes Jennifer , Roche Kayla , Sahebjam Solmaz , Stockdill Macy , Theeler Brett , Wall Kathleen , Wu Jing , Gilbert Mark , Armstrong Terri , Shuboni-Mulligan Dorela
Published: November 2022

Sleep-wake disturbances are among the most common and severe symptoms in primary brain tumor (PBT) patients. Currently, no studies have quantified their physiological sleep measurements or compared these assessments to established patient reported outcome measures (PROs). Smart wearable devices, such as Fitbits, continuously monitor patient behaviors at home and provide detailed physiological measurements of sleep, activity, and heart rate. We hypothesized that smart wearable devices can accurately determine physiological sleep disturbances and circadian disruptions and will complement established PROs in a PBT patient population. This observational, cross-sectional trial monitors sleep and circadian rhythm variables using Fitbit smart wearable devices worn for 1 month. Additionally, participants will answer PROs questionnaires (PROMIS Sleep Disturbance and Sleep Related Impairment-Short Forms, Sleep Hygiene Index, Morningness-Eveningness questionnaire, and Consensus Sleep Diary) at study entry and during the last week on-study. The present study is a planned interim analysis of 54 patients to assess feasibility, including evaluation of enrollment, attrition, study parameter completion and data missingness. 73 PBT patients were screened and approached. Of these patients, 54 (74%) were enrolled on study and 19 (26%) declined participation (8 lacked interest, 3 discomfort wearing watches, 3 lacked smart phone, 2 unable to wear device at work, 2 unable to attend consent calls, 1 pregnancy and 1 cognitive complication). The accrued patients were 56% male, 56%³ 50 years of age, and 81% had a KPS³ 90. Patients represented different stages of treatment: 6% of patients were newly diagnosed, 24% on active treatment (11% 1st recurrence, 13% 2nd recurrence), and 70% were on imaging surveillance. Feasibility was confirmed as there were no deviations reported and 100% of PROs and study timepoints completed. Quantified Fitbit data including percent time worn and physiologic sleep parameters will be reported. Study enrollment for efficacy measures continues.
INNV-27. SAFETY OF DIRECT ORAL ANTICOAGULANTS AS COMPARED TO LOW MOLECULAR WEIGHT HEPARIN IN TREATING VENOUS THROMBOEMBOLISM IN PATIENTS WITH PRIMARY BRAIN TUMORS AND BRAIN METASTASES
Authors: Ali Assad , Shah Nirja , Santiago Raphael Bastianon , Mandel Mauricio , Obrzut Michal , Borghei-Razavi Hamid , Adada Badih , Ranjan Surabhi
Published: November 2022

INTRODUCTION

Patients with brain tumors (PBTs) have a 20 to 30% incidence of venous thromboembolism (VTE) Recently, new direct oral anticoagulants (DOACs) such as rivaroxaban, apixaban, dabigatran and edoxaban, have gained popularity in treating VTE in cancer patients due to ease of administration and favorable safety profile. DOACs are also being used in treating VTE in in PBTs. While clinical trials have established the safety of DOAC use in systemic cancers, there is only limited literature on safety of DOAC in PBTs. In this review, we explore all prospective and retrospective studies to evaluate the safety of DOAC in comparison to LMWH in treating VTEs in PBTs.

METHODS

A search on PubMed database using keywords “Direct Oral Anticoagulant,” OR “Oral Anticoagulant,” AND “Cancer,” AND “Clinical Trial” was performed for clinical trials. Another search using keywords “Direct Oral Anticoagulants,” OR “Oral Anticoagulant,” AND “Brain Tumor,” AND “Retrospective.” was performed for retrospective studies.

RESULTS

Of 359 clinical trials in cancer patients, only 4 evaluating DOAC versus LMWH, included PBTs– Hokusai, Select D, ADAM VTE and EINSTEIN-DVT/PE. Four retrospective studies (Lee 2021, Carney 2019, Schwartz 2021 and Leader 2021) were identified.These four clinical trials enrolled a very limited number of PBTs (0.7, 1.5%, 2.7% and 6.8% of all patients). The risk of ICH with DOAC as compared to LMWH was low in Hokusai trial (OR = 0.93; CI=0.14-5.9) and uninformative in other 3 trials (0 episodes of ICH in either/both groups). All four retrospective studies showed no increase in incidence of ICH in the DOAC versus LMWH group in PBTs.

CONCLUSION

In the small number of prospective and retrospective studies which have evaluated the safety of DOAC in comparison to LMWH in brain tumors, the use of DOAC appears to be safe with no increase in the risk of ICH over LMWH.
INNV-28. A PILOT STUDY EVALUATING THE FEASIBILITY OF USING AN ULTRA-FAST DIGITAL CONFOCAL MICROSCOPY SCANNER FOR REAL-TIME INTRA-OPERATIVE BRAIN TUMOUR DIAGNOSIS
Authors: Bolton William , Ramakrishnan Piravin , Reveendran Dharsshini , Chakrabarty Arundhati , Mathew Ryan
Published: November 2022

INTRODUCTION

Real-time intra-operative brain tumour tissue analysis in the operating room (OR) can shorten turnaround times and facilitate repeated sampling; the latter can improve diagnostic accuracy and guide resection to maximise extent. We evaluated the feasibility of using an ultra-fast confocal microscopy scanner (Histolog®, SamanTree Medical SA) in the OR for real-time intra-operative brain tumour tissue diagnosis. This study is the first use of Histolog® on primary human brain tissue globally.

METHODS

An observational pilot study with varying brain tumour types was conducted in a tertiary UK brain tumour centre. Multiple, freshly excised tissue samples were stained with Acridine Orange, and images captured within 60 seconds on Histolog® in the OR in parallel to current diagnostic pathways. A Consultant Neuropathologist performed a blinded correspondence assessment between Histolog® and current gold standard histopathology. Qualitative logging of diagnostic features was performed.

RESULTS

Cases studied (n=12) included glioma, metastasis, meningioma, schwannoma, and pituitary adenoma. Concordance between Histolog® and traditional (frozen section) intra-operative histopathological diagnosis was 83% (10/12 cases). One Histolog® case demonstrated superior diagnostic accuracy to frozen section. Histolog® images demonstrated specific diagnostic features such as clusters of cohesive epithelioid cells (metastatic carcinoma), sheet-like variably cellular and pleomorphic cells (gliomas), diffuse sheet-like monomorphic round nuclei (pituitary adenoma), elongated spindle cells (schwannoma), and nodular architecture and oval nuclei (meningioma).

DISCUSSION

Ultra-fast confocal microscopy scanning with Histolog® is feasible in the OR and Histolog® image resolution is adequate to identify histopathological features necessary for intra-operative brain tumour diagnosis. Training and clinico-radiological details are important in minimising discordance. A larger study with greater numbers and tumour types will now be performed to define an optimal scanning protocol and determine the strengths and limitations of the technology. Future studies should investigate the effect of real-time margin zone analysis on extending resection.
INNV-30. RETROSPECTIVE ANALYSIS OF TTFIELDS IN PATIENTS WITH HGG BASED ON THE CRITERIA OF 2021 WHO CNS5
Authors: Yang Xiaoyan , Zhang Li , Ren Yanming , Mao Qing , Liu Yanhui , Wang Xiang , Chen Ni , Yue Qiang , Wu Xin , Liu Lei , Wang Feng
Published: November 2022

PURPOSE

High-grade glioblastoma (HGG) was highly malignant and had a poor prognosis, with an overall median survival time of only 15 months. Tumor-Treating Fields (TTFields) has been approved for the newly diagnosed glioblastoma (GBM), and more clinical evidence is needed for its use in HGG. The aim of this study was to analyze the efficacy and safety of TTFields in patients with HGG in our center.

METHODS

We analyzed baseline characteristics, efficacy, and safety data of 27 newly diagnosed HGG patients treated with TTFields for at least four weeks from January 2020 to February 2022 at West China Hospital of Sichuan University. All the pathological grades were diagnosed based on the 2021 World Health Organization Classification of Tumors of the Central Nervous System (2021 WHO CNS5) criteria.

RESULTS

Twenty-one patients (77.78%) were diagnosed as grade 4. Among them, the percentage of gross total resection was 81.48%, and MGMT promoter methylation was 51.85%. The median interval from surgery to TTFields initiation of treatment was 2.47 months (95% CI, 1.47-10.37). The median follow-up time was 12.47 months (95% CI, 8.6-15.03). The 12-month PFS rate and 12-month OS rate were 70.73% and 90.24%, respectively. Median PFS and OS have not been reached. The median compliance of patients wearing TTFields was as high as 95%, and their associated adverse events were patch-induced rash and ulcers, all of which were grade 1 ~ 2.

CONCLUSIONS

This study is the first to define HGG patients with the 2021WHO CNS5. TTFields were observed in this retrospective analysis to improve patients’ 12-month PFS rate and OS rate. Adherence was much higher than that reported in clinical studies, and safety remained good. More extended Survival data would be updated by further follow-up.
PATH-05. SEX-SPECIFIC HISTOLOGICAL FEATURES RELATED TO THE SPATIAL ORGANIZATION OF TUMOR-INFILTRATING LYMPHOCYTES PREDICT OVERALL SURVIVAL IN FEMALE GLIOBLASTOMA PATIENTS
Authors: Krebs Olivia , Corredor German , Tiwari Pallavi
Published: November 2022

PURPOSE

Epidemiological studies suggest that biological sex influences overall survival (OS) in Glioblastoma (GBM), possibly due to immunological variances between the sexes. Further, while prognostic in other cancers, the association of tumor-infiltrating lymphocytes (TILs) to OS in GBM requires additional exploration. We hypothesize that histological features corresponding to spatial organization of TILs from within the GBM microenvironment, when evaluated in a sex-specific manner, will be associated with OS.

METHODS

Digitized Hematoxylin-and-Eosin (H&E) slides of resected GBM tumors were collected to establish a multi-site cohort of Nf435 patients. The training set included Nf201 patients from eleven contributing sites of the Cancer Genome Atlas (TCGA). The validation set included Nf234 patients consisting of cases from two hold-out TCGA sites and the Clinical Proteomic Tumor Analysis Consortium. Each digitized H&E slide was assessed for quality, followed by employing a pre-trained classifier to label TIL and non-TIL cells. Spatial features related to the connectivity of nuclei centroids and corresponding cell cluster graphs were extracted for TILs, non-TILs, and between-group interactions. These TIL-centric histological features were fed into a Cox Hazard regression model with least absolute shrinkage and selection operator feature selection, to stratify patients as low or high-risk. Survival models were evaluated using Kaplan-Meier estimates, across male, female, and combined cohorts.

RESULTS

Selected features (i.e., measures of area and proximity across TIL clusters) were significantly associated with OS in the validation cohort (hazard ratio (HR)=1.95, confidence interval (CI)=1.19–3.2, p=0.00278), for the female cohort. For the male cohort, the selected spatial TIL features’ association with OS for the validation cohort yielded HR=1.43, CI=0.986–2.07, p=0.0667. The spatial TIL survival validation model on the combined cohort did not yield significant survival risk stratification.

CONCLUSION

Our findings suggest that sex-specific TIL organization histological features may be prognostic of OS in GBM tumors, specifically for the female cohort.
PATH-06. SURVIVAL ANALYSIS FOR ADULT MIDLINE GLIOMA: DO ADULT MIDLINE GLIOMAS WITH THE H3 K27M MUTATION REALLY HAVE POOR PROGNOSIS?
Authors: Choi Seonah , Jung In-Ho , Lim Jaejoon , Moon Ju Hyung , Kim Eui Hyun , Kim Se Hoon , Kang Seok-Gu , Chang Jong Hee
Published: November 2022

PURPOSE

Since it is known that midline located glioma with H3K27 mutation in children has a disastrous prognosis, in 2016 WHO classification, these tumors were defined as diffuse midline glioma (DMG) and classified as grade IV. A lot of papers about pediatric DMG have been published, but there are not many papers about adult DMG. In this study, we aimed to identify factors affecting the prognosis of adult midline glioma. This is the first paper to study the prognosis of adult DMG according to histological grade and is the largest study to investigate the survival of adult DMG.

METHODS

We reviewed the chart of adult patients diagnosed with midline glioma with H3K27M mutation after undergoing resection or biopsy among patients who visited our institution between January 2010 and December 2020. Survival analysis was performed according to tumor location, histological grading, Karnofsky Performance Scale (KPS), and age.

RESULTS

Among the 125 adult midline gliomas we identified, 45 (36.0%) had the H3K27M mutation. As a result of survival analysis performed on 125 adult midline gliomas, low histological grade, KPS ≥ 80, and age ≤ 60 showed significantly better survival. After adjusting for age, the difference in survival between H3K27M mutation and wildtype group was not significant. As a result of survival analysis performed on 45 DMG, low histological grade, KPS ≥ 80, total resection, and concurrent chemoradiation therapy group showed significantly better survival.

CONCLUSION

In adult midline glioma, disastrous prognosis due to H3K27M mutation was not observed as in children. The prognosis of adult midline gliomas is determined by histological grade, age, KPS, and extent of tumor resection. Therefore, the current WHO classification, which classifies all H3K27M mutant midline gliomas as grade IV regardless of histological diagnoses, is not suitable for adults.
PATH-13. IMAGE-BASED PHENOTYPING OF GLIOMAS FOR CLINICAL USE
Authors: Becker Aline , Casukhela Ishya , Chan Jany , McElroy Joseph , Eicher Tara , Fleming Jessica , Haque S Jaharul , Machiraju Raghu , Chakravarti Arnab
Published: November 2022

Adult-type diffuse gliomas have been classified according to histopathological characteristics only. Based on molecular profiles, the World Health Organization (WHO) classification defines three distinct biologic and prognostic types of diffuse gliomas: (i) IDH wild type (IDHwt), (ii) IDH mutant, 1p19q intact (IDHmut-non-codel), and (iii) IDH mutant, 1p19q codeleted (IDHmut-codel). Gliomas with missing molecular information are classified as “Not otherwise specified” (NOS). A histopathological signature that distinguishes IDH status in gliomas using hematoxylin & eosin (H&E)-stained whole slide images (WSIs) has yet to be developed to be used as proxy for molecular alterations. We employed WSIs with corresponding molecular data from The Cancer Genome Atlas (TCGA) and reclassified the gliomas according to the 2021 WHO guidelines. Weakly supervised deep learning approaches, i.e. the Uncertainty-Aware CNN (UA-CNN), and accompanying workflows developed by our group were successful in the segmentation and classification of other cancers. We used the weak labels of IDHwt or IDHmut for given WSIs and utilized an informative sampling algorithm to identify the most relevant tiles that are predictive of their WSI-level label. Next, a second UA-CNN was trained on the relevant subset of tiles determined from the screening stage. For inferencing, given a WSI, the trained UA-CNN model yielded both a predicted label and uncertainty measure for each tile. When reassembled into a WSI, an aggregated uncertainty classification map is formed, which will allow neuropathologists to more rapidly identify regions of interest. While molecular testing is indispensable for current glioma classification, our tool may help reduce the number of NOS diagnosis, mainly in smaller services, by identifying image features that can differentiate between IDHwt and IDHmut. We expect to develop and deploy a method to increase the amount of information extracted from the H&E stain, and help prioritize downstream molecular analyses mandatory for the layered diagnosis of gliomas.
PATH-15. THE PROGNOSTIC IMPLICATION OF MGMT PROMOTER METHYLATION IN IDH-MUTANT GLIOMAS
Authors: Youssef Gilbert , Aquilanti Elisa , Muzikansky Alona , Miller Julie , Vogelzang Jayne , Lapinskas Emily , Lim-Fat Mary Jane , Rahman Rifaquat , Beroukhim Rameen , Bi Wenya Linda , Chukwueke Ugonma , Castro Luis Nicolas Gonzalez , Lee Eudocia , McFaline-Figueroa J Ricardo , Nayak Lakshmi , Reardon David A , Ligon Keith , Wen Patrick Y
Published: November 2022

BACKGROUND

MGMT promoter methylation in IDH-mutant gliomas was associated with improved survival in a recent study (PMID 35386566) but did not account for the updated WHO classification of CNS tumors. We evaluated the prognostic value of MGMT methylation in IDH-mutant gliomas incorporating the 2021 WHO classification.

METHODS

We retrospectively identified 431 patients with IDH-mutant gliomas treated at a single institution from 2010-2020. Kaplan-Meier method was used to estimate OS and PFS rates. Log-Rank test was used to evaluate differences between groups.

RESULTS

Median age was 36.2 years. MGMT promoter was methylated in 49.6%, unmethylated in 17.2%, partially methylated in 6.7%, and untested in 26.5%. Histological diagnosis was consistent with astrocytoma in 45.7%, oligodendroglioma in 33.9%, glioblastoma in 16.4%, and oligoastrocytoma in 4%. After accounting for 1p/19q and CDKN2A statuses, 190 patients had an integrated diagnosis of astrocytoma, grade 2 or 3; 94 had astrocytoma, grade 4; and 147 had oligodendroglioma, grade 2 or 3. There were 101 death events. Median OS was 33.36 years and median PFS was 5.67 years in MGMT methylated gliomas, compared to median OS of 12.54 years (p=0.0064) and median PFS of 3.91 years (p=0.0034) in unmethylated tumors. Upon univariate subgroup analysis, MGMT methylation was associated with significantly longer OS in histological astrocytomas, grade 2 or 4. However, when stratifying patients according to 2021 WHO classification of CNS tumors, there was no significant difference in OS between MGMT methylated and unmethylated astrocytomas or oligodendrogliomas, irrespective of WHO grade.

CONCLUSION

MGMT promoter methylation was associated with prolonged OS in histological astrocytomas, IDH-mutant. However, MGMT status did not impact survival after incorporating 2021 WHO classification of CNS tumors, suggesting that 1p/19q co-deletion and CDKN2A homozygous deletion are stronger prognostic factors in our cohort. The number of survival events was limited; larger datasets are required for more definitive conclusions.
PATH-16. THRESHOLDS OF MITOTIC ACTIVITY AND POST-SURGERY RESIDUAL VOLUME ARE INDEPENDENT PROGNOSTIC FACTORS IN ASTROCYTOMA IDH-MUTANT
Authors: Tran Suzanne , Thomas Alice , Touat Mehdi , Karachi Carine , Dehais Caroline , Feuvret Loïc , Mokhtari Karima , Sanson Marc , Idbaih Ahmed , Carpentier Alexandre , Hoang-Xuan Khê , Capelle Laurent , Bielle Franck
Published: November 2022

BACKGROUND

The distinction between grade 2 and 3 is instrumental to choose between observational follow-up and adjuvant treatment in resected astrocytoma IDH-mutant. However, criteria for discriminating grade 2 and 3 tumors have not been updated since the WHO 2007 classification. There is no consensus on the method of evaluation of the mitotic activity or a mitosis cut-off for grading. The objectives were to evaluate the maximal mitotic activity on a series of resected astrocytoma IDH-mutant and assess its prognostic impact on survival.

METHODS

Maximal mitotic activity on consecutive high-power fields corresponding to 3 mm2 was examined in 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity as well as other prognostic factors (including age, performance status, presurgical tumor volume, plurilobar involvement, postsurgical residual tumor volume, midline involvement) was assessed in tumors with (i) ATRX loss, and (ii) without CDKN2A homozygous deletion, lesional enhancement, histological necrosis nor microvascular proliferation.

RESULTS

Among the 75 (64%) tumors which had gone through observational follow-up after resection, maximal mitotic activity, post-surgical residual volume and plurilobar involvement were independent prognostic factors of TTT (p < 0.0001). A threshold of mitotic activity for grade 2 was fitted using TTT and OS parameters. Using this threshold, patients with “grade 2 tumors” had a median TTT of 55 months versus 19 months for “grade 3” (p= 0.0057) and a median OS of 102 months versus 73 months respectively (p= 0.001). Residual volume < 1 cm3 was associated with longer OS (113 months versus 88 months, p= 0.0021).

CONCLUSIONS

The combination of mitotic activity and postsurgical residual volume improves prognostication in resected astrocytoma IDH-mutant. This novel risk assessment method could identify the best candidates for observational follow-up.
PATH-23. HIGHLY INFILTRATING OLIGODENDROGLIOMAS SHOW DIFFERENT MORPHOLOGY FROM TYPICAL OLIGODENDROGLIOMAS WHILE MAINTAINING GOOD RESPONSE TO CHEMO-RADIATION THERAPY
Authors: Higuchi Fumi , Uzuka Takeo , Sumi Takuma , Matsuda Hazuki , Iwata Kayoko , Shin Masahiro , Ueki Keisuke , Akutsu Hiroyoshi
Published: November 2022

Oligodendrogliomas are diffuse gliomas located in the cerebral hemisphere, and the MRI typically show swollen cortex and subcortical white matter by the tumor cells. IDH mutation and 1p/19q co-deletion define oligodendrogliomas in WHO classification, and these genetic alterations are associated with good response to chemo-radiation therapy and better prognosis compared to the IDH-mutant astrocytomas. We reviewed MRI findings of 60 oligodendrogliomas with 1p/19q co-deleted tumors which were diagnosed at Dokkyo Medical University since 1999. Of those, 3 cases showed highly infiltrating pattern in which tumors were more predominant in the white matter than the cortex and the infiltration involved multiple lobes. We retrospectively investigated those 3 cases for histological features, treatment, and clinical outcome. There were 2 males and 1 female. MRI showed faint-brushed Gd enhancement around the center of the tumor-infiltrated area in 1 case, while there was no enhancing lesion in other 2 cases. All three underwent stereotactic biopsy. Histologically, all 3 cases lacked typical oligodendroglioma morphology: the tumor cells have irregular round, oval to elongated nuclei without perinuclear halo and had dense, closed chromatin similar to astrocytoma. Two cases underwent chemotherapy (TMZ and PAV accordingly), without radiation and 1 case underwent chemotherapy with radiation as the primary treatment. Interestingly, all three tumors responded well not only to the primary treatments but also to the radiation therapy administered after recurrence, although all eventually succumbed to the tumor. PFS were 16, 37, 67 months and OS were 104, 70, 115 months for each, which were at the worse end as oligodendrogliomas but are apparently better than astrocytomas. Highly infiltrating oligodendrogliomas appeared to show significantly different MRI and histological features from typical oligodendrogliomas that primarily involve cerebral cortex. The underlying mechanism of such differences might involve specific genetic alterations and/or gene expression alterations that may not affect treatment response.
PATH-26. COMPLEMENTARY CLASSIFICATION APPROACH TO RESOLVE LOW-SCORE RESULTS FROM THE DKFZ METHYLATION CLASSIFIER FOR CNS TUMOR DIAGNOSTICS
Authors: Singh Omkar , Pratt Drew , Abdullaev Zied , Quezado Martha , Aldape Kenneth , Cimino Patrick
Published: November 2022

DNA methylation-classification using the DKFZ CNS tumor classifier is highly useful, but experience indicates that approximately one-third of clinical cases do not reach the confidence threshold (0.84) for a definitive match. A low-confidence score can be observed for a variety of reasons, and addressing such instances is not always clear. We developed a complementary classification approach that differs from the DKFZ classifier in several important ways. First, it utilizes a new reference set of several thousand samples, utilizing the entire ~850k probe set on the EPIC array. Second an alternative classification approach, it establishes multiple (50) classifiers by dividing the probes into 50 independent bins, allowing dual measurements of both an overall confidence score, as well as a consistency score. To evaluate this approach, we first evaluated a set of well-classified samples (N=521, DKFZ family score > 0.84) as ground-truth, showing that our bin-based approach was equivalent (100% accuracy) in well-classified samples. Second, we then evaluated a set (n=329) of samples that did not match to the 0.84 threshold on the DKFZ classifier. Using cutoff of 0.8 consistency score and 0.7 confidence score, we identified 99/329 cases with a match. To evaluate the potential ground-truth of our findings, orthogonal data was used to validate matches in our classifier. For example, many of our matches to GBM showed the expected abnormalities (combined +7/-10 CNV and TERT promoter mutation). Two cases that received low-score IDH-glioma matches by DKFZ matched to K27-altered-DMG in our classifier and were later shown to harbor the H3-K27M mutation. One case that received a low-score suggestion of GBM-MES on DKFZ matched in our classifier to PXA; this was then shown to harbor the expected BRAFV600E mutation. Overall, our method may add to and complement the DKFZ classifier as a means to resolve a subset of otherwise difficult-to-classify CNS tumors.
PATH-28. DIFFERENCES IN METHYLATION PROFILES BETWEEN LONG-TERM SURVIVORS AND SHORT-TERM SURVIVORS OF IDH WILD-TYPE GLIOBLASTOMA
Authors: van der Meulen Matthijs , Ramos Ronald , Voisin Mathew , Patil Vikas , Wei Qingxia , Singh Olivia , Climans Seth , Kalidindi Navya , Or Rosamarylin , Diamandis Phideas , Munoz David , Zadeh Gelareh , Mason Warren
Published: November 2022

INTRODUCTION

Patients with glioblastomas (GBM) have an overall survival (OS) of approximately 15 months. However, approximately 5% of patients survive much longer, with an OS of > 5 years. This study examines the differences in methylation profiles between long-term survivors ( > 5 years, LTS) and short-term survivors (< 1 year, STS) with an isocitrate dehydrogenase (IDH) wild-type GBM.

METHODS

In a multicenter retrospective analysis, we identified 25 long-term survivors with a histologically confirmed GBM. These were age and sex-matched to a short-term survivor. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of all IDH wild-type LTS vs STS were compared.

RESULTS

After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH wild-type GBMs, all with copy number gains of chromosome 7 and loss of chromosome 10. There were no significant differences between tumour purity or GBM subtype between LTS and STS. LTS had significantly increased MGMT promoter methylation (p = 0.01), and higher FGFR3-TACC3 (p = 0.03), compared to STS. STS had significantly more often a CDKN2A/B loss (p = 0.01) and higher levels of NF1 (p = 0.02), compared to LTS. There were no significant CpGs identified between LTS vs STS at an adjusted p-value of 0.05. Unadjusted analyses identified key pathways and biological processes involved in both LTS and STS. The top pathway in LTS was the Hippo signaling pathway and the Wnt pathway. The top pathway in STS was GPCR ligand binding and cell-cell signaling.

CONCLUSION

A small group of patients with IDH wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of long-term survivors compared to short-term survivors, our study highlights potential pathways involved in aggressive and senescent GBMs.
PATH-30. BIOLOGIC AND CLINICAL SIGNIFICANCE OF NEOPLASTIC AND IMMUNE CELL STATES IN GROUP3 AND GROUP 4 MEDULLOBLASTOMA
Authors: Asanigari Saleembhasha , Mehani Bharati , Wu Di , Chung Hye-Jung , Aldape Kenneth
Published: November 2022

Medulloblastoma (MB) is a heterogeneous malignant childhood brain cancer, classified into four molecular subgroups, WNT, SHH, Group3, and Group4, based on transcriptional, genetic, and clinical features. We aimed to understand the tumor microenvironment of Group 3 and Group 4 tumors utilizing single-cell transcriptome data. We identified four neoplastic cell states, including stemness (TNF-α), proliferative, mesenchymal and quiescence, and 11 broad lymphoid and myeloid cell types from single-cell transcriptomes. We applied CIBERSORTx to enumerate cell type proportion and CODEFACS on 73 bulk MB RNAseq profiles to determine cell type-specific abundance and gene expression profiles. We noted significant associations (both positive and negative) between the abundance of neoplastic cell states and microenvironmental cell types in both group3 and group4 MB. For example, the invasive cell state negatively correlated with dendritic cells in Group3 and Group4 tumors, but the invasive cell state was oppositely correlated with a macrophage subset in group 3 versus group 4 tumors, Survival analysis showed a significant association of higher proliferative cell state with poorer survival in Group3 MB while in group4 elevated invasive cell state, as well as elevated α, NK, and CD4-T cell abundance showed trends for poorer prognosis. Using Ecotyper, we determined cellular ecotypes based on cell type-specific transcriptome states. An ecotype containing B cell, hematopoietic, dendritic, and proliferative cell states was associated with poor prognosis in group3 and group4 tumors. We further analyzed ligand-receptor interaction between cell type states of poor prognosis ecotype; and found several interactions between ligands from immune cells (SEMA4G, LAMB2) and receptors on neoplastic cells (PLXNB2). Conversely, extracellular matrix ligands on neoplastic cells (COL1A1/2 and FN1) were found on this analysis potentially associated with integrin receptors on immune cells. Overall, our study highlights the potential biologic and clinical significance of neoplastic and immune cell states in group3/4 MB.
PATH-35. HYPERMITOTIC MENINGIOMAS HARBOR DNA METHYLATION SUBGROUPS WITH DISTINCT BIOLOGICAL AND CLINICAL FEATURES
Authors: Choudhury Abrar , Chen William , Lucas Calixto-Hope , Magill Stephen , Raleigh David
Published: November 2022

Meningiomas are the most common primary intracranial tumors, and treatments for meningiomas are limited to surgery and radiotherapy. Clinically tractable biomarkers for meningiomas are under development, and multiple retrospective studies have reported genetic, epigenetic, or gene expression grouping schemes shedding light on meningioma biology, outcomes, or druggable dependencies. Here we report biologically distinct subgroups within the Hypermitotic meningioma DNA methylation group, validating an architecture that unifies contrasting theories of meningioma biology. To do so, we re-analyzed meningioma DNA methylation profiles from a discovery cohort (n=200) and an independent, consecutive validation cohort (n=365). Median follow-up was 5.6 years for 388/142/35 WHO grade 1/2/3 meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on the discovery cohort. Unsupervised hierarchical clustering of β methylation values was performed on the discovery cohort, controlling for artifacts and inaccurate β methylation values due to the presence of CNVs. As previously reported, meningioma clustering was validated with the validation cohort and revealed 3 DNA methylation groups (Merlin-intact, Immune-enriched, or Hypermitotic) that were associated with distinct biological drivers, clinical outcomes, and therapeutic vulnerabilities. Further analysis using RNA sequencing revealed differential enrichment of FOXM1 target genes across 2 subgroups of Hypermitotic meningiomas. Gene expression programs in these subgroups were concordant with Proliferative or Hypermetabolic meningiomas reported by other investigators. Analysis of meningiomas by DNA methylation subgroup conserved biological features distinguishing DNA methylation groups, including CNVs deleting NF2, immune cell enrichment, or lymphatic gene expression. Analysis of clinical outcomes suggested subgroups may refine prediction of postoperative 5-year local freedom from recurrence (54.1% for Hypermetabolic vs 5.9% for Proliferative) or overall survival (82.2% for Hypermetabolic vs 21.8% for Proliferative) within DNA methylation groups. In summary, meningioma DNA methylation groups and the subgroups they harbor provide a framework unifying contrasting theories of meningioma biology.
PATH-39. A 44-YEAR-OLD FEMALE WITH DICER1-MUTANT PRIMARY INTRACRANIAL SARCOMA WITH IMAGING NEAR END OF LIFE
Authors: Lowman Allison , Winiarz Aleksandra , Bobholz Samuel , Kyereme Fitzgerald , Duenweg Savannah , Coss Dylan , Cochran Elizabeth , Charlson John , Connelly Jennifer , LaViolette Peter
Published: November 2022

DICER1-mutant intracranial sarcomas were recently defined by WHO in the 2021 CNS tumor classifications. Currently there is a lack of literature describing the clinical nature of this disease. Here we present a case of primary intracranial sarcoma with DICER1 mutation and unknown etiology. A 44-year-old female presented with aphasia and right-sided weakness. Clinical imaging confirmed the presence of a hemorrhagic mass in the left frontal lobe and superior falx. The patient underwent two surgical resections, but a clear diagnosis was difficult to make due to heterogenous histological features and inconclusive genomic testing. The surgical samples were sent to the National Institute of Health where genetic testing indicated a DICER1 E1813D mutation with high allele frequency (97%), a TP53 mutation with high allele frequency (95%), and a high variant allele frequency NF1 splice site mutation (96%). This resulted in a diagnosis of DICER1-mutant primary intracranial sarcoma. The patient was treated with temozolomide, bevacizumab, and CPT-11. 382 days after the mass was originally identified, the patient died. A detailed analysis of the radiographic images was performed by creating T1-weighted post-contrast enhancement maps (T1C) and T2-weighted fluid attenuated inversion recovery (FLAIR) hyper-intensity maps for each timepoint. We plotted these volumes over time alongside the patient’s treatment history. Large spikes in T1C and FLAIR volume were seen 4 days prior to initiation of temozolomide and 31 days after CPT-11 treatment was ended. At the final clinical MRI, both volumes were about 4 times greater than that of the initial scan. Despite this disease’s aggressive nature, it can be difficult to accurately diagnose, due in part to very few studies investigating the clinical features of this rare tumor. With the addition of this diagnosis to WHO CNS5, future studies should examine the behavior of these tumors, aiding in earlier diagnosis and improvement of treatment guidance.
PATH-41. THE DEVELOPMENT OF PRIMITIVE NEURONAL COMPONENT AT FIRST PROGRESSION OF MALIGNANT GLIOMA, A CASE SERIES
Authors: McGranahan Tresa , Costanza Katelyn , Cimino Patrick
Published: November 2022

A subset of malignant gliomas are found to have solid-looking primitive nodules which confer a diagnosis of glioblastoma with primitive neuronal component (GBM-PNC). These tumors are associated with higher rates of isocitrate dehydrogenase (IDH) mutations and increased responsiveness to platinum-based therapies, however they are also associated with a high rate of cerebrospinal fluid (CSF) dissemination. We review four patients treated at our institution with a prior diagnosis of malignant glioma who were found to have GBM-PNC at resection of recurrent disease and evaluate the clinical significance of the development of a primitive neuronal component. Of the 4 patients, 3 had previously been diagnosed with glioblastoma with a disease-free interval after radiation and temozolomide of 17.8 years, 2.4 years, and 1.6 years. The 4th patient was diagnosed 2 years prior with a WHO grade 2 IDH mutant astrocytoma and had only been treated surgically prior to disease progression. At recurrence, all patients developed cystic masses adjacent to prior surgical site in frontal lobe and/or temporal lobe. While no patients had spinal cord symptoms, as a result of the primitive component found at re-resection 3 out of 4 patients underwent spinal cord imaging. Two patients were found to have cauda equina enhancement favored to represent CSF dissemination. This is in line with the 40% CSF dissemination reported in other case series of diagnosis of GBM-PNC and far greater than 1.1% reported for glioblastoma. In this case series, the of development of primitive neuronal component at malignant glioma recurrence was associated with radiographic appearance of a cystic mass with significant vasogenic edema as well as high rates of CSF dissemination. The clinical implication of platinum responsiveness will also be presented.
PATH-42. DIAGNOSIS AND PROGNOSTICATION OF AN ATYPICAL ADULT PRESENTATION OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) BY METHYLATION PROFILING
Authors: Karbhari Nishika , Thomas Alissa
Published: November 2022

BACKGROUND

Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare central nervous system tumors first described in the 2016 WHO classification. A paucity of data exists on this tumor. This case describes an adult presentation of DLGNT, a classically pediatric tumor, and highlights the importance of genetic and epigenetic analyses in neuro-oncologic diagnoses. CASE: A 22-year-old male presented with shoulder paresthesias and back pain, progressing to bilateral leg weakness. Spine MRI demonstrated an enhancing intramedullary T8 lesion, prompting urgent laminectomy and resection. Frozen section suggested a glial neoplasm. Four-month follow-up MRI spine showed leptomeningeal dissemination at the C-spine and caudal thecal sac. CSF analysis revealed 110 mg/dL protein, 2 cells/mcl, and negative cytology. NCI methylation profiling demonstrated 1p deletion and KIAA1549:BRAF fusion, consistent with DLGNT, subtype 1, with MAPK pathway activation; Ki-67 index was 30%. Treatment with binimetinib was initiated. After 1 month of therapy, the patient is tolerating treatment and strength is improving.

DISCUSSION

This case describes a rare presentation of a rare tumor. DLGNT, subtype 1, has a median age of diagnosis of 5 years and an indolent course. We describe an adult patient with molecular features consistent with DLGNT subtype 1, but a high proliferative index suggesting a more aggressive growth potential. In this case, methylation profiling aided in diagnosing the tumor type and guided treatment. The KIAA1549:BRAF fusion is an activating mutation in the MAPK pathway, and binimetinib was selected as a MEK inhibitor with high CNS penetration. To our knowledge, this is the first case of an adult-onset DLGNT treated with binimetinib. Based on our single patient experience, we would advocate for methylation profiling for rare CNS tumor entities.
PATH-46. COMPUTATIONAL HISTOPATHOLOGY INFORMED RAPID TARGETED NANOPORE SEQUENCING ENABLES AFFORDABLE NEXT DAY REPORTING OF COMPREHENSIVE MOLECULAR MARKERS FOR CNS TUMOUR DIAGNOSTICS
Authors: Patel Areeba , Dogan Helin , Jung Alexander , Seferbekova Zaira , Payne Alexander , Ritter Michael , Schrimpf Daniel , Stichel Damian , Hamelmann Stefan , Blume Christina , Euskirchen Philipp , Goidts Violaine , Sill Martin , Pfister Stefan , Loose Matthew , Wick Wolfgang , von Deimling Andreas , Jones David T , Schlesner Matthias , Gerstung Moritz , Sahm Felix
Published: November 2022

BACKGROUND

Integrative brain tumour diagnostics indisputably requires comprehensive reporting of molecular markers. The 2021 WHO classification of central nervous system (CNS) tumours substantially increased the set of markers for routine evaluation, with greater significance to DNA methylation analysis in diagnostics. Limited by investment and batching, smaller labs and clinics might suffer major delays in delivering clinical decisions. To make precision diagnostics accessible, we introduce an integrated computational histopathology and adaptive nanopore sequencing workflow for next day CNS tumour diagnostics.

METHODS

We used CNS-CHiP- a multitask deep transfer learning model to predict key molecular alterations and methylation classification from H&E stained CNS tumour slides. For further characterisation and subtyping, we used the predictions to formulate a custom panel for each patient. Targeted sequencing and analyses were performed using Rapid-CNS2- a custom neurooncology nanopore sequencing pipeline for parallel copy-number, mutational and methylation analysis that is flexible in target selection with no additional library preparation and can be initiated upon receipt of frozen sections. Sequencing was performed on a portable MinION or GridION.

RESULTS

We demonstrate our workflow on diagnostic samples received by the Department of Neuropathology, University Hospital Heidelberg. CNS-CHiP predicted multiple pathognomonic alterations (eg. IDH mutation, 7 gain/10 loss) with reasonable accuracy. This provided basic information regarding the tumor type instantly. Personalised panels enabled small target sizes, resulting in low sequencing time (up to 24h) and competitive costs. The GPU-accelerated bioinformatics pipeline reduced analysis time from > 24h to < 3h.

CONCLUSIONS

Our workflow harnessing histology-based molecular predictions to instruct targeted nanopore sequencing can be set up with low initial investment and has the potential to facilitate reporting of molecular results on the next day of sample collection. CNS-CHiP combined with Rapid-CNS2 thus aims to make CNS tumour diagnostics affordable and accessible to smaller hospitals and labs especially in low- and middle-income countries.