bluuebunny/crossref_metadata_2025 huggingface dataset:
INNV-21. COMPLETE RESPONSE TO ADJUVANT TEPOTINIB IN A PATIENT WITH NEWLY DIAGNOSED DISSEMINATED GLIOBLASTOMA (GBM) HARBORING MET AMPLIFICATION
Authors: Pham Lily , Gann Claudia , Schumacher Karl Maria , Vlassak Soetkin , Swanson Todd , Highsmith Kaitlyn , Ou Alexander , Clarke Nathan , Aaroe Ashley , Robell Lindsay , O'Brien Barbara , Nash Sebnem , DeGroot John , Majd Nazanin
Published: November 2021

MET oncogene encodes a receptor-tyrosine-kinase which drives cell proliferation, invasion and angiogenesis in a number of solid cancers including GBM where the incidence of MET amplification is 2-5%. Tepotinib is a highly selective blood-brain-barrier penetrant oral c-MET inhibitor recently FDA approved for MET-exon-14 altered non-small cell lung cancer (NSCLC). Here, we report complete radiographic response to tepotinib in a patient with newly-diagnosed disseminated GBM harboring MET amplification. A 29-years-old male presented with progressive headache. MRI brain showed a large heterogeneously enhancing intraventricular mass with epicenter in the right lateral ventricular trigone and enhancing nodules in bilateral cerebellum. MRI spine showed multifocal enhancement along the periphery of the cervicothoracic spinal cord and cauda equina concerning for leptomeningeal disease. He underwent right temporal lobectomy and subtotal resection of the mass. His KPS was 90 post-surgery due to dizziness. Pathology was consistent with GBM, IDH wild-type, MGMT-unmethylated and MET amplification at 7q31.2. He completed proton craniospinal irradiation at 3600cGy followed by boost to the tumor bed at 2400cGy without concurrent temozolomide (TMZ) due to the large radiation field. He completed two cycles of adjuvant TMZ which was put on hold due to myelosuppression. He subsequently started tepotinib monotherapy at 1000mg daily obtained on a compassionate IND. MRIs after one month of therapy showed resolution of areas of enhancement in the brain and spine. He had grade 1 creatinine elevation and abdominal discomfort and dose was reduced to 500mg daily after two cycles. Nineteen weeks after initiation of tepotinib, his complete response persists, and he remains clinically stable with mild chronic dizziness. Trials of targeted therapy in molecularly-unselected GBM have been largely disappointing, however, this case demonstrates the promise of targeting MET using tepotinib in GBM. A clinical trial of tepotinib in MET-amplified GBM and NSCLC brain metastasis is currently underway at MD Anderson.
INNV-26. NCI-CONNECT PROGRAM PROVIDES RESOURCES TO IMPROVE CARE FOR PEOPLE WITH RARE CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Odom Kristin , Cordeiro Brittany , Wall Kathleen , Chambers Claudia , Mentges Kelly , Penas-Prado Marta , Wu Jing , Barnholtz-Sloan Jill , Kruchko Carol , Patrick Lorna , Saucedo Linda , Gilbert Mark , Armstrong Terri
Published: November 2021

The National Cancer Institute Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) program focuses on improving approaches to care and treatment for 12 rare CNS tumors, each with < 2,000 diagnoses per year. To reach this rare population, the primary objective was to develop a website to share educational resources that provide patients direct access to clinical care and trials. METHODS: The NCI-CONNECT website uses the Drupal platform within NCI’s framework and the content is free to syndicate. A multidisciplinary team developed tumor-specific content in English and Spanish, clinical trial information, and survivorship resources using evidence-based sources. The Central Brain Tumor Registry of the United States provided statistics on incidence and prevalence of rare tumors. Population reach was calculated using Adobe Experience Cloud website analytics. NCI-CONNECT referrals and study participation data were collected prospectively. RESULTS: The English website launched in September 2018 and visits have increased 2,384%. The Spanish website launched in March 2020 and visits have increased 1,137%. From April 2020 to March 2021, top website page views by English page views / Spanish page views / people living with this disease include oligodendroglioma (43,859 / 8,241 / 11,757), ependymoma (31,579 / 12,684 / 13,294), meningioma (30,261 / 19,507 / 2,692), medulloblastoma (28,487 / 9,999 / 3,840), diffuse midline gliomas (23,064 / 3,851 / 6,033), and pineal region tumors (19,939 / 9,973 / 1,297). Referral rates and participation have accelerated – 45% of patients visiting the Neuro-Oncology Clinic at NIH have a rare CNS tumor and 409 patients enrolled in an NCI-CONNECT study. CONCLUSION: Patient-focused websites can provide guidance to those affected by rare cancers outside of in-person health care visits. The NCI-CONNECT website is an educational and clinical resource for patients and families affected by rare CNS tumors and was created to raise awareness and improve patient outcomes.
INNV-30. USE OF MULTIDISCIPLINARY TEAMS AND MULTIMEDIA APPROACHES TO DEVELOP AND DISSEMINATE SYMPTOM AND DISEASE EDUCATIONAL MATERIALS FOR RARE CENTRAL NERVOUS SYSTEM (CNS) TUMOR PATIENTS
Authors: Maher Molly , Odom Kristin , Acquaye Alvina , Celiku Orieta , Cordeiro Brittany , Gilbert Mark , Armstrong Terri
Published: November 2021

BACKGROUND

Primary CNS tumors represent less than 2% of all cancers, with the majority of patients receiving care outside of specialty centers. Patients are highly symptomatic while trying to navigate care for their rare disease and evidence-based tumor and symptom education is limited. Our primary objective was to create and disseminate patient-centered content utilizing multidisciplinary teams and health communication to improve access to content.

METHODS

The multidisciplinary team of neuro-oncology scientists and health care providers developed content from evidence-based sources. The team partnered with communication specialists to ensure health literacy and established outreach strategies for use on social media, e-newsletters, and web- and app-based programs. Web analytic tools assessed outreach and efficacy.

RESULTS

Educational content for 12 rare tumors and 6 self-care topics was created using evidence-based sources and multidisciplinary team review. Content was published on the National Cancer Institute Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) website and disseminated via multimedia platforms, including e-newsletters and social media (private Facebook group and Twitter). Since launching the website in September 2018, visits have increased 2,384%. The content was also shared directly to 6,156 newsletter subscribers, 4,897 Twitter followers with greater than 1 million impressions per year, 407 Facebook members, 9 non-profit advocacy partners, and thousands of attendees at more than 10 patient-focused neuro-oncology events. This outreach approach is now being replicated for symptom management content on the NCI-CONNECT website and a symptom tracking and self-care mobile application launching in 2021.

CONCLUSIONS

By marrying patient-centered health communication, education, and outreach, our team successfully created highly sought content that reflects the unique needs of CNS tumor patients and their families. This material can educate neuro-oncology patients on their specific tumor, promote self-care, facilitate symptom management, and empower families to advocate for their unique needs, reaching outside traditional health care systems.
PATH-22. GENETIC VARIATION BETWEEN IDH MUTANT AND IDH WILD-TYPE GLIOMA
Authors: Li shaoqun , Lai Mingyao , Zhou Jiangfen , Zhen junjie , Cai Linbo
Published: November 2021

OBJECTIVE

The prognosis of IDH mutant glioma was significantly different from that of IDH wild-type glioma. In order to explore the differences between them at the genetic level, we analyzed the genetic results of IDH mutant and IDH wild-type glioma.

METHODS

This study analyzed the clinical data and genetic results of 45 glioma patients from Jan. 2017 to Dec. 2019, exploring relevant prognostic indicators and the difference in genetic profile between IDH mutant glioma and IDH wild-type glioma.

RESULTS

45 patients were included in this study, including 15 IDH mutant glioma patients and 30 IDH wild-type glioma patients. Genetic analysis showed that there was no difference in tumor mutation burden (TMB) and microsatellite instability (MSI) between IDH mutant glioma and IDH wild-type glioma. But somatic mutation between IDH mutant and IDH wild-type glioma was different. The expressions of IDH1, CIC, SYNE1 and TP53 were different in the two groups, among which IDH1 and CIC were more significantly different. Copy number variations (CNV) was also different between IDH mutant glioma and IDH wild-type glioma. STIL occured more frequently in IDH wild-type gliomas. Genetic analysis also showed the difference in variant allel frequence (VAF). IDH mutant gliomas were more likely to be combined with ATRX and TP53 mutations, while IDH wild-type gliomas, in addition to the combination of TP53 mutations, often also combined with the mutations of NF1, BRAF and PTEN. In survival analysis, glioma with IDH mutation has a good prognosis, and IDH wild-type patients have a poor prognosis. In IDH wild-type patients, patients with PTEN mutation have a worse prognosis.

CONCLUSION

There is an obvious genetic difference between IDH mutation and IDH wild-type glioma, and PTEN mutation is a poor prognostic factor for IDH wild-type patients.
PATH-33. MOLECULAR TYPING AND MUTATION SPECTRUM OF CHINESE CHILDREN WITH MEDULLOBLASTOMA WERE IDENTIFIED BY NEXT-GENERATION SEQUENCING
Authors: Li Juan , Lai Mingyao , Hu Qingjun , Ai Ruyu , Cai Linbo
Published: November 2021

There are few reports on molecular typing and mutation spectrum of Chinese children with medulloblastoma. Here, we aimed to update the clinical manifestations and MB transcriptional mutation spectrum in Chinese Mb patients. Medical records of 59 Mb patients were reviewed. Genomic DNA was extracted from pathological tissues of children. Mutation analysis of whole coding regions, promoter regions and flanking splice sites in whole genome sequencing was performed. Nine cases (15%)with WNT subtype: CTNNB1 mutation was found in all specimens, and TP53 mutation was found in 33.3%. DDX3X mutation occurred in 33.3%. 33.3% had SMARCA4 mutations. Chr6 - associated large fragment deletion occurred in 88.9s. Comparison results between 19 cases (32%) with SHH data and previous studies: The proportion of SHH-TP53 mutants was11% ( 2/19).The proportion of SHH-TP53 wild-type was 89%.The prognosis of the mutated SHH-TP53 was worse than that of the wild-type SHH-TP53, and patient follow-up information could be integrated for comparison. Secondly, PTCH1 is more prevalent in patients with SHH (16%). The DDX3X mutation proportion was 11%. The mutation ratio of Gli2 amplification5%.The mutation ratio of MYCN amplification was 5%.Comparison results of 3 cases with G3 subtype data and previous studies: Variations mainly occur at the chromosomal level. Only one G3 patient had a genetic mutation (TP53 mutation). The proportion of Chr17q+ was 33.3%. CHR7 + proportion was 33.3%. The incidence rates of CHR10Q and CHR11Q were 66.7%.No MYC amplification was found. For 28 cases with G4 subtype: Chr17q +, Chr7 +, Chr18 +, and Chr8 - are the major chromosomal mutations. The incidence rate of CHR17Q + was 61%, and CHR7 + was 61%. CHR8- occurred in 11%. The above results are consistent with previous reports. The Chinese population and other population have similar molecular genotyping gene variation map on medulloblastoma.
PATH-38. APC MUTATION AS A DRIVER ONCOGENE IN NON-CTNNB1 MUTANT ADAMANTINOMATOUS CRANIOPHARYNGIOMAS
Authors: Hong Christopher , Erson-Omay Zeynep , Omay S Bulent
Published: November 2021

Craniopharyngiomas arise from the embryonic remnants of Rathke’s pouch in the craniopharyngeal duct. Their invasive capacity and geographic proximity to the optic apparatus, pituitary gland and stalk, third ventricle, and the hypothalamus can cause progressive visual, hormonal, and neurological deficits and transform these lesions into behaviorally malignant tumors. The classic subtypes of craniopharyngiomas, adamantinomatous and papillary, have conventionally been approached similarly in regards to therapeutic strategies. However, recent exome sequencing studies have revealed mutually exclusive pathways for their genetic origins. Recurrent mutations in BRAF (V600E), a regulator of MAP kinase/ERK signaling pathway have been observed in 95% of papillary craniopharyngiomas and may be amenable to targeted therapies with BRAF inhibitors. However, CTNNB1 mutations are observed in only 75%–96% of adamantinomatous craniopharyngiomas, revealing a gap in the classic genetic-histological correlation. We describe a 74-year-old male who underwent resection of a craniopharyngioma with suprasellar and third ventricular involvement. The pathology demonstrated adamantinomatous craniopharyngioma with aberrant nuclear beta-catenin activity on immunohistochemistry. Whole-exome sequencing, performed in accordance with an institutional review board-approved protocol on the tumor and blood, revealed wildtype CTNNB1 but notably two somatic stop-codon mutations in APC (rs786201856:c.C793T:p.R265X and rs587779780:c.1159T:p.R387X), considered pathogenic variants in other reported cancer types. Loss of APC leads to constitutive activation of the Wnt signaling pathway, similar to the observed downstream effects of activating CTNNB1 mutations in adamantinomatous craniopharyngioma. Our case suggests that craniopharyngiomas may arise from somatic loss of APC, which previously was only described in a handful of individuals with familial adenomatous polyposis, harboring germline APC mutations. This report adds new insight into the pathogenesis of adamantinomatous craniopharyngiomas, particularly those that are otherwise wildtype for CTNNB1. Based on accumulating evidence, we propose that along with BRAF and CTNNB1, APC should also be routinely checked in cranipharyngiomas, especially if the former two have been negative.
NIMG-06. CHARACTERIZATION OF LONG-TERM METABOLIC CHANGES OF IRRADIATED BRAIN METASTASES USING SERIAL DYNAMIC FET PET IMAGING
Authors: Galldiks Norbert , Stoffels Gabriele , Werner Jan , Bauer Elena , Baues Christian , Celik Eren , Ruge Maximilian , Fink Gereon , Langen Karl-Josef , Lohmann Philipp
Published: November 2021

BACKGROUND

In the present study, we characterized the long-term metabolic changes of brain metastases irradiated with stereotactic radiosurgery (SRS) by sequential dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value to diagnose delayed radiation-induced changes.

PATIENTS AND METHODS

From 2010-2021, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal or progressive MRI findings after SRS, and (iii) subsequently underwent at least two additional dynamic FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) and the dynamic FET PET parameter time-to-peak were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed histologically or clinicoradiologically.

RESULTS

We identified 36 patients with 98 FET PET scans (median number, 3; range, 2-6). Concurrent to SRS, 8 patients (22%) were treated with checkpoint inhibitors. Following SRS, suspicious MRI findings occurred after a median time of 11 months (range, 2-64 months). Subsequently, FET PET scans were acquired over a median period of 13 months (range, 5-60 months). The overall median follow-up time was 26 months (range, 8-101 months). Twenty-one patients (58%) had delayed radiation-induced changes. TBRs calculated from the last available FET PET scan showed the highest accuracy (92%) to identify delayed radiation-induced changes (threshold, 1.95; P< 0.001).

CONCLUSIONS

FET PET has a high diagnostic accuracy for characterizing the long-term changes of irradiated brain metastases.
NIMG-21. VARIABLE RESOLUTION HYPERPOLARIZED [2-13C]PYRUVATE MRI IN HEALTHY VOLUNTEERS AND PATIENTS WITH IDH-MUTANT GLIOMA
Authors: Vaziri Sana , Kim Yaewon , Autry Adam , Chen Hsin-Yu , Gordon Jeremy , LaFontaine Marisa , Hu Jasmine , Lupo Janine , Clarke Jennifer , Villanueva-Meyer Javier , Oberheim-Bush Nancy Ann , Chang Susan , Xu Duan , Larson Peder , Vigneron Daniel , Li Yan
Published: November 2021

INTRODUCTION

Mutations in isocitrate dehydrogenase (IDH) have been investigated as a prognostic biomarker in glioma. The presence of the IDH mutation (IDHm) is associated with 2-hydroxyglutarate (2HG) production and inhibition of glutamate synthesis (McBrayer, Cell 2018). Hyperpolarized carbon-13 (HP-13C) MRI enables dynamic measurements of in-vivo metabolism using a [2-13C]pyruvate labeled probe that undergoes conversion to [2-13C]lactate and [5-13C]glutamate. Here, we present HP [2-13C]pyruvate data from healthy volunteers and patients with IDHm diffuse glioma. Due to its intrinsic low signal-to-noise ratio (SNR), we demonstrate the ability of post-processing denoising to improve its utility and aid in detection of metabolic changes associated with IDHm.

METHODS

Dynamic HP 13C data were acquired following intravenous injection of [2-13C]pyruvate from five healthy volunteers and one patient with IDHm grade III astrocytoma. A novel multi-resolution frequency specific multislice EPI sequence was used to obtain [2-13C]pyruvate, [5-13C]glutamate, and downfield and upfield [2-13C]lactate signals (3s temporal resolution, pyruvate/lactate/glutamate spatial resolutions = 0.75x0.75cm2/ 2.25x2.25cm2/ 2.25x2.25cm2, 5 slices 3cm thick). Following phase correction, patch-based tensor decomposition denoising was applied to metabolite images. Metabolite differences between normal-appearing white matter (NAWM) and T2 lesion were examined for the patient data.

RESULTS

HP [2-13C]pyruvate imaging is able to simultaneously probe glycolytic ([2-13C]lactate) and oxidative ([5-13C]glutamate) metabolism. Denoised pyruvate/lactate/glutamate signals achieved a 4-9/3-6/3-7 fold increase in SNR. T2 lesion exhibited decreased glutamate-to-pyruvate and glutamate-to-lactate AUC ratios versus contralateral NAWM (p< 0.018, p < 1.5e-5), consistent with IDH mutant status.

CONCLUSION

We successfully demonstrated the feasibility of applying variable resolution HP [2-13C]pyruvate metabolic imaging to detect IDHm specific metabolism. This technique addresses a major hurdle in HP 13C MRI by improving SNR while permitting robust metabolism quantification. Future studies will optimize methods for acquiring and processing data to evaluate further data acquired from IDHm glioma patients. Supported by NIH T32 CA151022, P01 CA118816, and NICO.
NIMG-48. TLR7/8-AGONIST-LOADED NANOPARTICLES REPROGRAM TUMOR-ASSOCIATED MYELOID CELLS FOR EFFECTIVE IMMUNOTHERAPY OF EXPERIMENTAL GLIOMA AND MRI-BASED TREATMENT MONITORING
Authors: Pfleiderer Kira , Turco Verena , Horvat Natalie K , Hunger Jessica , Karimian-Jazi Kianush , Schregel Katharina , Brugnara Gianluca , Nguyen Duy , Jähne Kristine , Fischer Manuel , Alsasa Abdulrahman , Bunse Theresa , Schlesner Matthias , Muckenthaler Martina , Weissleder Ralph , Wick Wolfgang , Heiland Sabine , Vollmuth Philipp , Bendszus Martin , Rodell Christopher B , Breckwoldt Michael O , Platten Michael
Published: November 2021

Drivers of glioblastoma progression include the immunosuppressive tumor microenvironment (TME), dominated by tumor-associated myeloid cells. Therefore, we investigated a new approach targeting the myeloid compartment to reprogram myeloid cells in the TME using a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the toll-like receptor 7 and 8 (TLR7/8) agonist R848. Biodistribution confirmed specific targeting of CDNP-R848 to tumor-associated macrophages (TAMs) (labeling efficiency: 34.0% ± 22.2%), whereas tumor microglia (5.4% ± 4.4%) and splenic macrophages (13.2% ± 0.7%) revealed less uptake. Interestingly, intravenous application of CDNP-R848 induced strong tumor regression with an overall response rate of 80% (2.5% complete response, 52.5% partial response and 25% stable disease, n=40 mice) in Gl261 syngeneic experimental gliomas, while CDNP vehicle treated animals showed exponential tumor growth (100% progressive disease, n=12 mice). As advanced imaging is essential to monitor intracranial disease and possibly predict response and resistance, we performed high resolution magnetic resonance imaging using ultrasmall iron oxide nanoparticles (USPIO) for macrophage tracking. Increased levels of USPIO uptake in vehicle treated animals compared to CDNP-R848 treated animals were found as an early marker of responding mice (ΔT2*: -11.7 ± 4.2 vs -4.0 ± 2.8 ms, p=0.01). This correlated with an increased influx of myeloid cells into the TME of vehicle treated animals and showed a strong correlation of macrophage recruitment and USPIO uptake (R2: 0.78, p=0.004). Mechanistically, phenotyping of macrophages (CD45high/CD11b+) indicated a pro-inflammatory shift of TAMs with an increased infiltration of pro-inflammatory F4/80+/MHCII+ macrophages during CDNP-R848 treatment. Surprisingly, the anti-tumor effect of CDNP-R848 was independent of CD8+ T cells, CD4+ T cells or NK cells during selective depletion experiments. In summary, this work demonstrates the ability of myeloid-targeted therapies to re-shape the tumor microenvironment for an effective immunotherapy of glioma.
NIMG-71. IDENTIFYING CLINICALLY APPLICABLE MACHINE LEARNING ALGORITHMS FOR GLIOMA SEGMENTATION USING A SYSTEMATIC LITERATURE REVIEW
Authors: Tillmanns Niklas , Lum Avery , Brim W R , Subramanian Harry , Lin Ming , Bousabarah Khaled , Malhotra Ajay , cui Jin , Brackett Alexandria , Payabvash Sam , Ikuta Ichiro , Johnson Michele , Turowski Bernd , Aboian Mariam
Published: November 2021

PURPOSE

Nowadays Machine learning (ML) algorithms are often used for segmentation of gliomas, but which algorithms provide the most accurate method for implementation into clinical practice has not fully been identified. We performed a systematic review of the literature to characterize the methods used for glioma segmentation and their accuracy.

METHODS

In accordance to PRISMA, a literature review was performed on four databases, Ovid Embase, Ovid MEDLINE, Cochrane trials (CENTRAL) and Web of science core-collection first in October 2020 and in February 2021. Keywords and controlled vocabulary included artificial intelligence, machine learning, deep learning, radiomics, magnetic resonance imaging, glioma, and glioblastoma. Publications were screened in Covidence and the bias analysis was done in agreement with TRIPOD.

RESULTS

Sixty-six articles were used for data extraction. BRATS and TCIA datasets were used in 36.6% of all studies, with average number of patients being 141 (range: 1 to 622). ML methods represented 45.3% of studies, with deep learning used in 54.7%; Dice score for the tumor core ranged from 0.72 to 0.95. The most common algorithm used in the machine learning papers was support vector machines (SVM) and for deep learning papers, it was Convolutional Neural Networks (CNN). Preliminary TRIPOD analysis yielded an average score from 12 (range: 7-16) with the majority of papers demonstrating deficiencies in description of the ML algorithm, funding role, data acquisition and measures of model performance.

CONCLUSION

In the last years, many articles were published on segmentation of gliomas using machine learning, thus establishing this method for tumor segmentation with high accuracy. However, the major limitations for clinically applicable use of ML in glioma segmentation include more than one-third of publications use the same datasets, thus limiting generalizability, increase the likelihood of overfitting, show and lack of ML network description and standardization in accuracy reporting.
NIMG-73. CAPTURING GLIOBLASTOMA HETEROGENEITY USING IMAGING AND DEEP LEARNING: APPLICATION TO MGMT PROMOTER METHYLATION
Authors: Saxena Sanjay , Kazerooni Anahita Fathi , Toorens Erik , Bakas Spyridon , Akbari Hamed , Sako Chiharu , Mamourian Elizabeth , Koumenis Costas , Mohan Suyash , Bagley Stephen J , Lustig Robert A , O’Rourke Donald M , Ganguly Tapan , Nasrallah MacLean , Davatzikos Christos
Published: November 2021

PURPOSE

Intratumor heterogeneity is frequent in glioblastoma (GB), giving rise to the tumor’s resistance to standard therapies and, ultimately, poorer clinical outcomes. Yet heterogeneity is often not quantified when assessing the genomic or methylomic profile of a tumor, when a single tissue sample is analyzed. This study proposes a novel approach to non-invasively characterize heterogeneity across glioblastoma using deep learning analysis MRI scans, using MGMT promoter methylation (MGMTpm) as a test-case, and validates the imaging-derived heterogeneity maps with MGMTpm heterogeneity measured via multiple tissue samples.

METHODS

Multi-parametric MRI (mpMRI) scans (T1, T1-Gd, T2, T2-FLAIR) of 181 patients with newly diagnosed glioblastoma, who underwent surgical tumor resection and had MGMT methylation assessment results, were retrospectively collected. We trained a 5-fold cross-validated deep convolutional neural network with six convolutional layers for a discovery cohort of 137 patients by placing overlapping regional patches over the whole tumor on mpMRI scans to capture spatial heterogeneity of MGMTpm status in different regions within the tumor. Our approach effectively hypothesized that despite heterogeneity in the training examples, dominant imaging patterns would be captured by deep learning. Trained model was independently applied to an unseen replication cohort of 44 patients, with multiple tissue specimens chosen from different spatial regions within the tumor, allowing us to compare imaging- and tissue-based MGMTpm estimates.

RESULTS

Our model yielded AUC of 0.75 (95% CI: 0.65–0.79) for global MGMT status prediction, which reflected the heterogeneity in MGMTpm, but also that a dominant imaging pattern of MGMT methylation seemed to emerge. In methylated patients with multiple tissue samples, a significant Pearson's correlation coefficient of 0.64 (p< 0.05) was found between imaging-based heterogeneity maps and MGMTpm heterogeneity.

CONCLUSION

A novel method based on mpMRI and deep neural networks yielded imaging-based heterogeneity maps that strongly associated with intratumor molecular heterogeneity in MGMT promoter methylated tumors.
NCMP-14. WHOLE BRAIN RADIOTHERAPY COMBINED WITH INTRATHECAL LIPOSOMAL CYTARABINE FOR LEPTOMENINGEAL METASTASIS – A SAFETY ANALYSIS AND VALIDATION OF THE EANO-ESMO CLASSIFICATION
Authors: Iglseder Sarah , Nowosielski Martha , Bsteh Gabriel , Muigg Armin , Heugenhauser Johanna , Nevinny-Stickel Meinhard , Mayer Elke , Grams Astrid , Stockhammer Guenther
Published: November 2021

BACKGROUND

Although there is no proven standard therapy for leptomeningeal metastases (LM), treatment often includes intrathecal chemotherapy combined with whole brain radiation therapy (WBRT). Little is known on the toxicity of such combination therapies. We performed a retrospective safety analysis for the combination of intrathecal liposomal cytarabine with WBRT in patients with LM and validated the EANO-ESMO classification in this unique cohort.

METHODS

Treatment toxicities in patients diagnosed with LM between 2004 and 2014 were retrospectively analyzed according to the RTOG (Radiation Therapy Oncology Group) and NCI CTCAE V5.0 (Common Toxicity Criteria Adverse Events) toxicity criteria. Diagnostic criteria and treatment response as assessed by EANO-ESMO classification were correlated with survival by Kaplan Meier analysis and Breslow test.

RESULTS

40 patients with LM who were treated with combined WBRT and intrathecal cytarabine, were identified. Ten patients (25%) experienced adverse events ≥ grade 3 according to the RTOG-toxicity criteria, in 22 patients (55%) CTCAE criteria ≥3 grade were detected. Median overall survival (mOS) was 124.0 days [72.9;175.1]. Median time to neurological progression was 52.0 days [41.1; 62.8]. When comparing the diagnostic criteria, patients with a positive CSF cytology (n=26) showed worse prognosis compared to patients with a negative CSF cytology (n=14) (mOS 84 days [44.0;124.0] versus 198.0 days [162.6;233.4] days, p=0.006, respectively). The EANO-ESMO response assessment correlated significantly with survival - “stable” (n=7) mOS 233.0 [76.5;389.5] days, “response” (n=10) mOS 206.0 [193.9;218.9] days, “progression” (n=17) mOS 45.0 [34.4;55.6] days, “suspicion of progression” (n=6) mOS 133.0 [65.8;200.2] days (overall, p< 0.001).

CONCLUSIONS

In this retrospective analysis, the treatment combination of WBRT and intrathecal liposomal cytarabine shows an acceptable safety profile. The EANO-ESMO classification for diagnosis and treatment response predicts survival
EXTH-06. ATR INHIBITORS AS MONOTHERAPY AND COMBINATORIAL THERAPY WITH TEMOZOLOMIDE IN PRECLINICAL GLIOBLASTOMA MODELS
Authors: Koul Dimpy , Li Xiaolong , Wu Shaofang , singh Sanjay Kumar , Akdemir Kadir Caner , Yung W K Alfred
Published: November 2021

Glioblastoma (GBM) is an aggressive brain tumor and has an extremely poor prognosis despite the use of multiple treatment modalities. DNA damage response (DDR) signaling plays an important role in inducing radiation and temozolomide (TMZ) resistance and hence has emerged as a molecular target for therapeutic development. The Ataxia Telangiectasia and Rad3-related protein (ATR) kinase is a key regulator of the DDR machinery, activated by DNA damage. Here, we show that three clinical-grade ATR inhibitors (Bay1895344, AZD6738 and Berzosertib) had similar selective sensitivity pattern across 16 glioma-like stem cell (GSC) lines tested. ATR inhibitors inhibited the growth of GSCs at low nanomolar range concentrations. Interestingly, all three ATR inhibitors showed a significant synergism with TMZ in a selective group of GSCs (Combination index and Bliss model). Importantly, we demonstrate that MGMT promoter methylation status was associated with cellular response to combination treatment with preferential inhibition of cell growth in MGMT promotor methylated (MGMT deficient) cell lines. Further, we compared the RNA-seq data from GSCs in the synergism and non-synergism group and used multiple complementary approaches to identify the response marker that confer sensitivity to combination therapy. Our preliminary data analysis identified several genes that confer sensitivity to combination treatment and studies are underway to validate the data. We also investigated the efficacy of BBB penetrant ATR inhibitor BAY 1895344 in orthotropic xenografts and administration of BAY 1895344 and TMZ combination significantly reduced tumor size and extended survival in an intracranial animal model. Combining ATR inhibitor with TMZ was well tolerated and did not confer additional toxicity as the body weights of TMZ and combination groups were comparable. The findings from this study provides a rationale to use ATR inhibitors in combination with TMZ in MGMT methylated tumors to improve therapeutic efficacy of standard of care for GBM patients.
EXTH-34. ION CHANNELS AS A THERAPEUTIC TARGET IN PAEDIATRIC HIGH-GRADE GLIOMAS
Authors: Griffin Michaela , Smith Stuart , Khan Raheela , Basu Surajit , Branter Joshua
Published: November 2021

Pediatric Glioblastoma Multiforme (GBM) is a leading cause of CNS cancer-related death in children. The scarcity of treatments for GBM has opened the field to new pathways in adults, such as tumour treating fields(TTF). Studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence suggests that ion channels not only regulate electrical signalling of excitable cells, but are also crucial in the development/progression of brain tumours. Ion channels are essential in cell-cycle control, invasion and migration of cancer cells, therefore presenting as valuable therapeutic targets. Candidate ion channel genes(ICG) associated with high-grade glioma (HGG) were identified via analysis of inhouse and publicly available data sets. Expression patterns of selected ICGs were assessed along with clinician correlations.. Protein and RNA expression of target ICGs was assessed in pGBM cell lines/ TMAs. Finally, the Human ClariomTMS array was used for whole transcriptome gene expression analysis of paediatric GBM cell lines treated with tumour treating fields or low frequency electrical fields via deep brain stimulating electrodes. Paediatric brain tumour cells were exposed to genetic and pharmacological manipulation of CLIC1 and CLIC4 ion channels individually or in combination. We have shown that HGG exhibit increased expression of CLIC4 and CLIC1 at protein and RNA levels in both publically available data sets and inhouse cell lines / TMAs. Clinical correlation determined that high CLIC4 and CLIC1 expression was associated with poor overall survival. Further to this, DNA array analysis revealed a downregulation of CLIC1 and CLIC4 ion channels genes in KNS42 cells when treated with electrotherapy compared to untreated cells. Inhibition of CLIC1 and CLIC4 reduces Cl- flux across cell membranes and reduces cell proliferation. These data provide rationale that manipulation of ICGs will reduce the capacity of childhood brain tumours to proliferate and invade.
EXTH-46. MRS BASED BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO THE IDH INHIBITOR BAY-1436032
Authors: Hong Donghyun , Minami Noriaki , Taglang Céline , Batsios Georgios , Gillespie Anne Marie , Pieper Russell , Costello Joseph , Viswanath Pavithra , Ronen Sabrina
Published: November 2021

Gliomas are the most prevalent type of brain tumor in the central nervous system. Mutations in the cytosolic enzyme isocitrate dehydrogenase 1 (IDH1) are a common feature of primary low-grade gliomas, catalyzing the conversion of α-ketoglutarate (αKG) to the oncometabolite 2-hydroxyglutarate (2HG), and mutant IDH1 is a therapeutic target for these tumors. Several mutant IDH inhibitors are currently in clinical trials, nonetheless, complementary non-invasive early biomarkers to assess drug delivery and potential therapeutic response are still needed. The goal of this study was therefore to determine the potential of 1H and hyperpolarized 13C magnetic resonance spectroscopy (MRS)-based biomarkers as indicators of mutant IDH1 low-grade glioma response to treatment with the clinically-relevant IDH1 inhibitor BAY-1436032 in cells and animal models. Immortalized human astrocytes engineered to express mutant IDH1 were treated with 500nM (IC50 value) of BAY-1436032 and BT257 tumors implanted in rats were treated with 150mg/kg of BAY-1436032. To assess steady-state metabolite levels, 1H MRS spectra were acquired on a 500 MHz MRS cancer for cells and a 3 T scanner for animal studies. To assess metabolic fluxes, we used hyperpolarized 13C MRS and probed the fate of hyperpolarized [1-13C]αKG. 1H MRS showed a significant decrease in 2HG as well as a significant increase in glutamate (Glu) and phosphocholine (PCh) following BAY-1436032 treatment in both cell and animal models compared to controls. Furthermore, hyperpolarized 13C MRS showed that hyperpolarized 2HG production from hyperpolarized [1-13C]αKG was decreased and hyperpolarized glutamate production from hyperpolarized [1-13C]αKG was increased in the BAY-1436032 treated groups compared to controls. These findings are consistent with our previous study, which investigated the MRS-detectable consequences of two other mutant IDH inhibitors: AG120 and AG881. Collectively, our work identifies translatable MRS-based metabolic biomarkers of mutant IDH1 inhibition.
QOLP-01. EXPERIENCES FROM PATIENT, CAREGIVER, AND PHYSICIAN SURVEYS ON DIAGNOSIS AND TREATMENT OF BRAIN METASTASES
Authors: Kim Albert , Wang Gi-Ming , Waite Kristin , Elder Scott , Fine Avery , Ahluwalia Manmeet , Brat Daniel , Mehta Minesh , Page Robin , Dunbar Erin , Calderone Heather , Robins Debra , DeVitto Ralph , Willmarth Nicole , Barnholtz-Sloan Jill , Brastianos Priscilla
Published: November 2021

The development of brain metastases (BM) is one of the most feared complications of cancer due to the substantial neuro-cognitive morbidity and grim prognosis. In the past decade, targeted therapies and checkpoint inhibitors have demonstrated remarkable intracranial response rates for tumors of multiple histologies. As overall survival for these patients improves, there is a growing need to identify issues surrounding patient survivorship and to standardize physician practice patterns for these patients. To date, there has not been an adequate study to specifically explore these questions of survivorship and practice standardization for patients with advanced cancer and BM. Here, we present results from a cross-sectional survey in which we analyze responses from 237 patients, 209 caregivers, and 239 physicians to identify areas of improvement in the clinical care of BM. In comparing physician and patient/caregiver responses, we found a disparity in the perceived discussion of topics pertaining to important aspects of BM clinical care. We identified variability in practice patterns for this patient population between private practice and academic physicians. Many physicians continue to have patients with BM excluded from clinical trials. Finally, we obtained patient/physician recommendations on high-yield areas for federal funding to improve patient quality of life. Therefore, by identifying potential areas of unmet need, we anticipate this wealth of actionable information will translate into tangible benefits for both patients and caregivers. Future studies are needed to validate our findings.
QOLP-11. WORKING MEMORY TRAINING FOR ADULTS WITH GLIOMA
Authors: Braun Sarah , aslanzadeh Farah , Lanoye Autumn , Loughan Ashlee
Published: November 2021

BACKGROUND

CogMed Working Memory Training (CWMT) is a computer-based program shown to improve working memory (WM) among those with cognitive impairment. No study to date has investigated its feasibility, acceptability, and satisfaction in adult patients with glioma, despite the well-documented incidence of WM impairment in this population.

METHODS

Twenty patients with glioma and objective and/or perceived WM deficits enrolled in the study: 52% high-grade, 57% female, Mage=47 (range=21-72 years). Adverse events were monitored to determine safety. Feasibility and acceptability were assessed based on established metrics. Satisfaction was explored by exit-interviews. Neurocognitive tests and measures of psychological distress were administered pre-/post-CWMT to assess preliminary efficacy.

RESULTS

Of 20 enrolled patients, 16 completed the study protocol (80% retention rate). Reasons for withdrawal included time burden (n=2); tumor-related fatigue (n=1) or lost to follow-up (n=1). No adverse events were determined to be study-related. Adherence was 69%. The perceived degree of benefit was only moderate. Pre- to post-CWMT assessments showed medium to large effects on near-transfer tasks (h p 2 =.35, p=.01 and h p 2 =.25, p=.04) and far-transfer tasks (h p 2 =.20, p=.07 and h p 2 =.16, p=.12) but small to no effects on perceived WM (h p 2 =.01, p=.79) and psychological distress (h p 2 =.01-.06, p=.35-.79).

CONCLUSION

CWMT was found to be safe and acceptable in adult patients with glioma. Enrollment, retention rates, and treatment adherence were all adequate, yet only moderate perceived benefit was reported. Given that objective measures of WM improved but psychological distress did not, it may be worth considering a less burdensome CWMT protocol, perhaps investigating a less time intensive intervention with respect to both frequency and length of training sessions.
QOLP-17. YOGA THERAPY AS A SUPPORTIVE CARE STRATEGY FOR FAMILY CAREGIVERS OF HIGH GRADE GLIOMA PATIENTS: RESULTS OF 3-ARM PILOT RANDOMIZED CONTROLLED TRIAL
Authors: Milbury Kathrin , Li Jing , Weathers Shiao-Pei , Silva Rosangela , Snyder Stella , Li Yisheng , Lorenzo Cohen
Published: November 2021

BACKGROUND

This pilot RCT compared the feasibility and preliminary efficacy of a dyadic versus individual yoga intervention as a supportive care strategy for family caregivers of high grade glioma patients.

METHODS

Caregivers completed self-reported assessments of QOL (SF-36) and caregiver burden (CRA) and were then randomized to a patient-caregiver dyadic yoga (DY), caregiver yoga (CY) or usual are (UC) arm while patients were undergoing standard radiotherapy. Both yoga programs were delivered over 15 sessions either in-person or via videoconference (Zoom). All groups were re-assessed at the end of treatment and then again 3-months later.

RESULTS

We consented 76 dyads (59%) and randomized 23 to the DY, 22 to the CY, and 22 to the UC arm. Attendance in the DY was higher than in the CY group (means, DY=12.23, CY=9.00, P=.06, d=.57). Caregivers reported significantly more overall subjective benefit in the CY compared to the DY arm (means, CY=1.39, DY=1.81, P< .05, d=1.45). Caregivers slightly favored the in-person delivery (means, in person: 1.48; zoom: 1.82, P=.10; d=.77). A clinically significant, medium effect size was found for improved QOL in favor of the CY over the DY group (means, CY=49.45, DY=44.45; F=3.58, P=.07; d=.67). Caregivers in the CY group reported less caregiving-related health declines compared to the DY group (means, CY=2.18; DY=2.48; F=4.23, P< .05; d=.42). Caregivers in the CY group reported less caregiving-related financial burden than the UC group (means: CY=2.79; UC=3.21; F=3.32, P=.08; d=.35).

CONCLUSION

Despite lower attendance, caregivers in the CY arm reported greater subjective overall benefit, experienced better mental QOL and less caregiver burden compared with those in the DY and UC comparison arms. It appears that individual rather than dyadic delivery may be a superior supportive care approach for this vulnerable caregiver population. An adequately powered, larger trial of this intervention strategy is warranted.
QOLP-23. EVALUATION OF FINANCIAL TOXICITY (FT) IN PEOPLE WITH RARE CENTRAL NERVOUS SYSTEM (CNS) TUMORS USING AN INNOVATIVE WEB-BASED STUDY DESIGN
Authors: Timmer Michael , Vera Elizabeth , Acquaye Alvina , Chambers Claudia , Christ Alexa , Levine Jason , Wooley Joseph , Leeper Heather , Raygada Margarita , Scheurer Michael , Wall Kathleen , Gilbert Mark , Armstrong Terri , Penas-Prado Marta
Published: November 2021

BACKGROUND

Financial toxicity (FT) refers to the negative financial impact of cancer. Research exploring FT in patients with CNS tumors is limited to more common diagnoses or within single institutions. Total income, work interference and symptom burden are all key parameters when investigating FT in patients with rare CNS tumors.

METHODS

A web-based study of 210 participants’ responses to financial, clinical, symptom burden (MDASI-BT/MDASI-SP), depression and anxiety (PROMIS-Depression/Anxiety), work interference (SF-36) and general health status (EQ-5D-3L) is reported using descriptive statistics and tests of associations.

RESULTS

Patients were white (93%) employed (48%) females (72%), with median age of 47 (19-75). The most common diagnosis was ependymoma (80%). Original tumor location was the brain in 83 (40%) and spine in 115 (55%). Median time from tissue diagnosis was 48 months (0 – 402). Income was lower than the poverty level in 6% and lower than the median U.S. in 23%. A change in work due to their tumor was reported by 60%, with the majority stopping work (31%). One-third reported lack of access to health-care services and 10% required home care services. Difficulty walking was reported by 42% and difficulty in performing activities due to physical health by over 60%. Anxiety and depression scores aligned with the average for the U.S. population; however, 21% were taking antidepressants and 42% reported not being able to complete work or activities due to depression. Half of all patients reported moderate-severe pain, fatigue, and weakness with higher symptom burden and depression associated with change in work status (p < 0.003).

CONCLUSION

Patients with rare CNS tumors report an impact of their tumor diagnosis on activities/work patterns, with an associated higher symptom burden. Future studies exploring financial impact in patients with rare CNS tumors and targeted programs to address these outcomes are needed.
RBIO-04. LACTATE DEHYDROGENASE A (LDHA) MEDIATES NOVEL CROSSTALK BETWEEN METABOLIC GLYCOLYSIS AND CHROMATIN REMODELING
Authors: Li Jie , Ning Jianfang , Koga Tomoyuki , Li Ming , Zhu Shan , Venteicher Andrew , Taha Birra , Akers Johnny , Chen Clark
Published: November 2021

INTRODUCTION

Lactate dehydrogenase A (LDHA) encodes an enzyme that catalyzes the inter-conversion between pyruvate and lactate in glycolysis. Here, we demonstrate that LDHA mediates a novel role in DNA repair independent of this metabolic function.

METHODS

siRNA screen, The Cancer Genome Atlas (TCGA) survival analysis, ionizing radiation (IR), g-H2AX, and chromatin assays, site-directed mutagenesis.

RESULTS

In an orthogonal siRNA-informatic screen to identify genes 1) when silenced caused IR sensitivity in patient-derived glioblastoma lines and 2) lowered expression is associated with improved survival in TCGA, LDHA surfaced as the top candidate. The survival association was validated by LDHA immunohistochemical staining in an independent collection of glioblastoma samples. In vitro and in vivo, silencing of LDHA sensitized glioblastoma lines to IR and enhanced radiation-induced g-H2AX accumulation. Such sensitization was not observed after treatment with an LDHA inhibitor, suggesting the metabolic function of LDHA is distinct from its role in DNA repair. Supporting this hypothesis, truncation mutations that suppressed the LDHA glycolysis function minimally affected its role in DNA repair. Mechanistically, cytoplasmic LDHA translocates into the nucleus in response to IR. This translocation was associated with subsequent chromatin transition into an open conformation and enhanced homologous recombination.

CONCLUSION

The novel LDHA function in DNA repair suggests intricate crosstalks between glycolytic metabolism and DNA repair, offering a new platform for glioblastoma therapeutic development.
SURG-04. THE CLINICAL COURSE AND ROLE OF SURGERY IN PEDIATRIC MALIGNANT PERIPHERAL NERVE SHEATH TUMORS: A DATABASE STUDY
Authors: Lu Victor , Wang Shelly , Daniels David , Spinner Robert , Levi Allan , Niazi Toba
Published: November 2021

BACKGROUND

Malignant peripheral nerve sheath tumors (MPNST) are rare tumors found throughout the body, with their clinical course in children still to be completely understood. Correspondingly, this study aimed to determine survival outcomes and specific clinical predictors of survival in this demographic from a large national database.

METHODS

All MPNST patients aged ≤18 year in the U.S. National Cancer Database (NCDB) between 2005-2016 were retrospectively reviewed. Data were summarized and overall survival (OS) was modeled using Kaplan-Meier and Cox regression analyses.

RESULTS

A total of 251 pediatric MPNST cases were identified. Overall, mean age at diagnosis was 13.1 years (range, 1-18) with there being 132 (53%) females and 119 (47%) males. There were 84 (33%) MPNSTs located in extremities, 127 (51%) less than 1cm in size, and 22 (9%) have metastasis at diagnosis. In terms of treatment, surgery was pursued in 187 (74%) patients, chemotherapy in 116 (46%) patients, and radiation therapy in 129 (61%) patients. Five-year overall survival was estimated to be 52% (95% CI, 45-59%), and with median survival of 64 months (range, 36-136). Multivariate regression revealed older age (HR 1.10, P< 0.01), with metastases at time of diagnosis (HR 2.14, P=0.01), and biopsy only (HR 2.98, P< 0.01) all significantly and independently predicted shorter overall survival. Chemotherapy and radiation therapy were not statistically significant.

CONCLUSIONS

Pediatric MPNSTs are rare malignant entities, and only approximately half of patients will survive to five years. There remains a clear survival benefit in pursuing maximal safe resection in these patients. As such, judicious workup with meticulous surgical resection by an expert team should then be considered the standard of care for these tumors in children.