bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-28. DECONVOLUTION OF SPATIALLY RESOLVED T CELL RECEPTOR PROFILING (SPTCR-seq) UNCOVERED REGIONAL ANTI-TUMOR IMMUNITY IN GLIOBLASTOMA
Authors: Benotmane Jasim Kada , Kückelhaus Jan , Joseph Kevin , Beck Jürgen , Schnell Oliver , Ravi Vidyha , Heiland Dieter Henrik 
Published: November 2021

Abstract
The diversity to T cell responses and clonality in spatially heterogeneous glioblastoma is of paramount importance to explore underlying mechanisms of anti-tumor immunity. Spatial transcriptomics, a novel technology to map the transcriptional architecture, is technically limited to discover T cell receptor (TCR) sequences as the 3' approach lacks sufficient coverage. Here, we established SPTCR-seq, a method to capture TCR sequences followed by long-read sequencing to enable full-length TCR reconstruction. We performed 10X Visium spatial transcriptomics on 9 primary and recurrent glioblastoma with both 3’-sequencing and SPTCR-seq. For SPTCR-seq, we target enriched T cell receptor sequences by capturing by hybridization followed by Oxford-Nanopore long-read sequencing. The on-target rate was above 80% for captured TCR genes and spatial barcode was successfully aligned in more than 60%. IgBlast and MixCR were used to reconstruct the TCR and map T cell clonality. Within our recent developed spatial transcriptomic analysis framework (SPATA2), we build a novel toolbox, SPATA-Immunology, which enables integration of stRNA-sequencing data and spatially resolved TCR sequencing. Our data showed that clonal evolution of T cells is limited to regional areas underpinned by significant spatial autocorrelation coefficient (0.6-0.95, padj&lt; 0.001). In the surrounding tumor cell spots, the recently described transcriptional program “reactive immune” (RI), was significantly enriched. Using spotlight, a computational approach to project scRNA-sequencing into the spatial space, we found a local enrichment of CD163 positive macrophages exclusively in areas of large T cell clonality. Imaging mass cytometry of a consecutive section confirmed the spatial confluence of T-cell infiltration and CD163-positive macrophages. Through DeepTCR we uncovered potential epitopes which correlate with T cell clonality and might help to discover novel targets for CART therapy. Spatial profiling of TCR sequences through SPTCR-seq is a powerful tool to investigate anti-tumor immunity in glioblastoma and allows to discover general and personalized targets for immunotherapy.
IMMU-37. DISRUPTION OF PD-L1 BY ENHANCED TWO-SGRNAS CRISPR/CAS9 IN TREATMENT OF GLIOBLASTOMA
Authors: Fierro Javier , Perez joshua , Aguilar Rocio , Dipasquale Jake , Tran An , Factoriza Chris , Dou Huanyu 
Published: November 2021

Abstract
Anti-glioblastoma multiform (GBM) immunotherapy poses a great challenge due to immunosuppressive brain tumor environments and the blood brain barrier (BBB). Programmed death ligand 1 (PD-L1) plays a key role in GBM immunosuppression, vitality, proliferation, and migration. Targeting PD-L1 for immunotherapy is a promising new avenue for treating GBM. CRISPR/Cas9 gene editing can be used to knockout both membrane and cytoplasmic PD-L1, leading to an enhanced immunotherapeutic strategy. We identified two sgRNA sequences located on PD-L1 exon 3. The first sgRNA recognized the forward strand of human PD-L1 near the beginning of exon 3 and cuts at approximately base pair 82 (g82). The second sgRNA recognized the reverse strand of exon 3 and cuts at base pair 165 (g165). Two sgRNAs, g82 and g165, created an 83bp deletion in PD-L1 genomic sequence. Two sgRNAs combination with a homology-directed repair template (HDR) was designed to enhance PD-L1 knockout specificity and efficiency. Both g82 and g165 were cloned into one CRISPR/Cas9 plasmid, and was co-transfected with HDR. GFP tagged CRISPR/Cas9 plasmid containing of g82 and g165 (Cas9-g82/165) was loaded into Rhodamine labeled nanoparticles (Cas9-g82/165-NPs) and then treated to GBM U87 cells. The enhanced intracellular uptake and transfection of Cas9-g82/165-NPs were detected by a fluorescence microscopy. T7E1, qRT-PCR and western blot analysis determined that the dual sgRNA CRISPR/Ca9 system knocked out both endogenous (80%) and exogenous (64%) PD-L1 in U87 cells and PD-L1 overexpression U87 cells, respectively. Deletion of PD-L1 reduced U87 migration and proliferation, while PD-L1 overexpression promoted tumor growth and tumor-associated macrophage polarization. Together, deletion of both membrane and cytoplasmic PD-L1 altered the PD-L1-associated immunosuppressive environment and prevented tumor progression and migration. Thus, two-sgRNAs CRISPR/Cas9 gene-editing system is a promising avenue for anti-GBM immunotherapy.
IMMU-48. IMMUNOMODULATION WITH RESIQUIMOD REPOLARIZES THE IMMUNE MICROENVIRONMENT TO INHIBIT MEDULLOBLASTOMA PROGRESSION
Authors: Park Christopher , Del Mar Coral , Thang Morrent , Dismuke Taylor , Hwang Duhyeong , Lim Chaemin , Mirlekar Bhalchandra , Donson Andrew , Vibhakar Rajeev , Sokolsky Marina , Pylayeva-Gupta Yuliya , Gershon Timothy 
Published: November 2021

Abstract

BACKGROUND
New, non-cytotoxic treatments may improve outcomes for medulloblastoma, the most common malignant pediatric brain tumor. Sonic hedgehog (SHH) subgroup medulloblastoma, which includes subtypes with poor prognosis, can be modeled in immunocompetent, transgenic mice. These models are ideal for preclinical testing of immunotherapies. Here, we show that immune stimulation using resiquimod, a small molecule agonist of Toll-like receptor 7 and 8 (TLR 7/8), alters myeloid populations in medulloblastoma and significantly reduces tumor growth.

METHOD
We generated mice with medulloblastoma by interbreeding the hGFAP-Cre and SmoM2 mouse lines. The resultant hGFAP-Cre/SmoM2 (G-Smo) mice develop SHH medulloblastoma with 100% frequency. We analyzed myeloid populations and demonstrated TLR7/8 expression patterns in G-Smo tumors. We then compared survival of untreated G-Smo mice versus G-Smo mice treated with three doses of resiquimod at postnatal days 10, 12, and 14. We also assessed pharmacodynamic effects at progressive intervals after a single dose.

RESULTS
Approximately 10% of cells in G-Smo medulloblastomas were myeloid cells, and these cells were the only cells that expressed TLR7/8. Resiquimod slowed tumor growth and increased the survival of mice with medulloblastoma. Untreated median survival was 14.5 days (n=12), compared to resiquimod-treated median survival of 37 days (n=10; p=0.0003). All treated mice eventually demonstrated tumor progression. Immunohistochemistry for IBA1, a pan-macrophage marker, demonstrated significant increase in myeloid cells within the tumor by 24 hours after treatment (p=0.0178), however the IGF1+ fraction of myeloid cells decreased (p=0.0275).

CONCLUSION
Resiquimod prolongs survival in mice with SHH-driven medulloblastoma, demonstrating the potential for therapies that target myeloid cells to produce significant anti-tumor effects. Myeloid-derived IGF-1 has been shown to support tumor progression and resiquimod may act by disrupting this paracrine signaling.
INNV-07. TTFIELDS TREATMENT OF GLIOSARCOMA AND RECURRENT ANAPLASTIC OLIGODENDROGLIOMA
Authors: Blondin Nicholas , Fulbright Robert , Huttner Anita , Moliterno-Gunel Jennifer 
Published: November 2021

Abstract

INTRODUCTION
The Optune device delivers tumor treating fields (TTFields) and is considered as a standard of care for newly diagnosed and recurrent glioblastoma patients. The efficacy of Optune in other glioma subtypes, such as gliosarcoma and anaplastic oligodendroglioma, is still unclear. In this small case series, we present the clinical, pathologic and radiographic findings of two patients who utilized Optune and had improved outcomes compared to historical controls.

CASE 1
A 49 year old woman underwent resection of a right temporal lobe gliosarcoma in November 2017. She received conventional radiation therapy with concurrent temozolomide, which was complicated by significant thrombocytopenia and leukopenia. She initiated Optune as monotherapy six weeks after completing radiation, and used the device for 24 months. She still has not had a recurrence, now 3.5 years since her initial diagnosis.

CASE 2
A 46 year old woman underwent resection of a right frontal lobe oligodendroglioma, WHO Grade 2, in September 2011. She received one cycle of temozolomide in April 2014, complicated by thrombocytopenia, and no further chemotherapy was administered. In November 2017, she underwent resection of a new focus of enhancement at the margin of the resection cavity, which was confirmed to have transformed to WHO Grade 3. In August 2019, a radiographic progression of an enhancing nodule was observed. She initiated Optune as monotherapy in September 2019, and since that time, has had stable disease for 18 months. Optune treatment is still ongoing.

CONCLUSIONS
In a case of newly diagnosed gliosarcoma, Optune monotherapy has contributed to progression-free and overall survival of 3.5 years to date. In a case of recurrent anaplastic oligodendroglioma, Optune monotherapy has achieved stable disease for at least 18 months. These cases demonstrate that Optune can be safely utilized in these glioma subtypes and contributed to improved survival outcomes in these two patients.
INNV-09. SURGICAL STRATEGIES FOR OLDER PATIENTS WITH GLIOBLASTOMA
Authors: Barak Tanyeri , Hwang Lee , Chen Justin , Jin Lan , Miyagishima Danielle , Yalcin Kanat , Ogilvie Shahiba , Antonios Joseph , Theriault Brianna , Huttner Anita , McGuone Declan , Lifton Nathan , Blondin Nicholas , Corbin Zachary , Zhang Yawei , Gunel Murat , Erson-Omay Zeynep , Fulbright Robert , Tabar Tanyeri , Moliterno-Gunel Jennifer 
Published: November 2021

Abstract

OBJECTIVE
Though image-guided surgery with intraoperative magnetic resonance imaging (IoMRI) is associated with higher extent of resection, we aimed to determine the clinical outcome of its use, compared to other less time-consuming intraoperative ultrasound (IoUS), in this patient population.

METHODS
Clinical data of 221 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination of IoMRI + IoUS at Yale New Haven Hospital and Memorial Sloan Kettering Cancer Center were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed, including predictors of overall survival.

RESULTS
The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (HR=0.85, 95% CI 0.49-1.47; P= 0.56) or Karnofsky Performance Score (KPS) at 6 weeks postoperatively (OR=0.51, 95% CI 0.22-1.15; P= 0.102). On the contrary, the length of surgery (LOSx) was significantly longer (P&lt; 0.0001) in the IoMRI group. Postoperative complications were significantly less in the IoUS-only group (OR=0.17, 95% CI 0.3-0.46; P=0.002) and in patients who had a preoperative KPS score of 70 or higher (OR=0.092, 95% CI 0.018-0.47; P=0.004). Patients with relatively lower preoperative KPS scores (&lt; 70) showed significant clinical improvement at 6 weeks postoperatively (P=0.0002). Patients with postoperative complications were more likely to have lower KPS scores at 6 weeks postoperatively (OR=0.30, 95% CI 0.10-0.89; P= 0.031), while increased extent of resection was associated with improved KPS scores at 6 weeks postoperatively (OR=2.171, 95% CI 1.22-3.87; P= 0.009).

CONCLUSION
Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS scores. The use of IoMRI in this patient population does not appear to yield any survival benefit over IoUS but instead significantly prolongs the length of surgery, increasing the risk for potential postoperative complications.
INNV-18. EFFECT OF DURATION OF TUMOR TREATING FIELDS THERAPY ON CELLULARITY DISTRIBUTIONS BEYOND T1W MRI CONTRAST ENHANCING MARGIN AT AUTOPSY IN GLIOMA PATIENTS: PRELIMINARY RESULTS
Authors: Bobholz Samuel , Lowman Allison , Brehler Michael , Sherman John , Duenweg Savannah , Kyereme Fitzgerald , Connelly Jennifer , Cochran Elizabeth , Mueller Wade , Banerjee Anjishnu , LaViolette Peter 
Published: November 2021

Abstract
Tumor treating fields (TTFields) are thought to disrupt the cell division process in glioma. This study uses autopsy tissue samples from patients recruited for brain donation to determine whether TTFields treatment duration and usage affects cellularity distributions beyond the gadolinium contrast enhancing region on T1-weighted (T1w) magnetic resonance imaging (MRI). At autopsy, 43 tissue samples from 18 patients who had undergone TTFields treatment (inclusion criteria: &gt;50% compliance and 25-day duration) were collected from brain slices sectioned in-line with slices from the patients’ final MRI prior to death. Nuclei were segmented on the digitized hematoxylin and eosin (HE) stained tissue samples, which were then used to compute cell count across the slides. Tissue was then aligned to the patient’s final MRI scan prior to death using a custom in-house software, where manually defined control points were used to compute a nonlinear transform to warp the tissue to match the MRI. Histogram features including mean, median, 90th percentile, variance, and skewness, were computed from the cellularity distributions within regions outside the traditional tumor margin defined by T1w contrast enhancement for each subject. General linear models were fit to assess the effects of TTFields usage (percent of day) and duration (in days) on each histogram feature, controlling for age, overall survival, and time between TTFields treatment and death, as well as time between MRI acquisition and death. Longer TTFields treatment duration and overall survival was associated with significantly decreased skewness in the non-enhancing cellularity distributions (p&lt; 0.05) while associations with other metrics remained statistically insignificant. These preliminary results in a small patient cohort suggest that TTFields duration may reduce the presence of high cellularity tails in the non-contrast enhancing distributions. Additional research in larger patient populations is warranted to better understand these findings given the number of confounding factors.
INNV-27. AN INNOVATIVE VIRTUAL MULTI-INSTITUTIONAL, MULTIDISCIPLINARY NEURO-ONCOLOGY TUMOR BOARD: THE NIH-NOB EXPERIENCE DURING THE COVID-19 PANDEMIC
Authors: Rogers James , Acquaye Alvina , Ikiddeh-Barnes Ukeme , Benson Kaitlyn , Boris Lisa , Akindona Funto , Frederico Stephen , Jammula Varna , Kim Yeonju , Timmer Michael , Aboud Orwa , Avgeropoulos Nicholas , Burton Eric , Cachia David , Camphausen Kevin , Colman Howard , Dixit Karan , Drappatz Jan , Dunbar Erin , Forsyth Peter , Komlodi-Pasztor Edina , Mandel Jacob , Lee Eudocia Quant , Ranjan Surabhi , Lukas Rimas , Salacz Michael , Smith-Cohn Matthew , Snyder James , Wooley Joseph , Chaudhry Huma , Theeler Brett , Tsien Christina , Smirniotopoulos James , Butman John , Chittiboina Prashant , Heiss John , Zaghloul Kareem , O’Donnell Kayla , Quezado Martha , Aldape Kenneth , Raygada Margarita , Armstrong Terri , Gilbert Mark , Penas-Prado Marta 
Published: November 2021

Abstract

BACKGROUND
The American Academy of Neurology Institute and Society for Neuro-Oncology recommend multidisciplinary tumor board (MTB) meetings as a quality metric in neuro-oncology. With the COVID-19 pandemic resulting in travel restrictions, we expanded our existing MTB by transitioning to a virtual format that maintained our commitment to providing consultation for primary CNS tumor cases. This transition permitted participation by neuro-oncology teams from over 30 Brain Tumor Trials Collaborative (BTTC)/National Cancer Institute-Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) centers across the United States. Here, we describe results from opening our MTB remotely to these teams.

METHODS
We retrospectively reviewed records from remote MTB meetings held between April 2020 and March 2021. To gauge the impact of our MTB on clinical management, we administered a brief survey querying BTTC members.

RESULTS
Twenty-eight providers presented 41 cases during 24 virtual MTB meetings (range: 1-4 cases per meeting). Two cases (5%) were presented only for educational value. Approximately half (54%) of the cases discussed dealt with diagnosis/management of an NCI-CONNECT rare CNS tumor. During MTB discussions of the 39 cases seeking diagnosis/management recommendations, 32% received clinical trial recommendations, 10% were suggested to enroll in the NCI Neuro-Oncology Branch (NOB) Natural History Study (NCT02851706), 17% received a recommendation to obtain central neuropathology review, and 100% received recommendations for further disease management. Most BTTC survey respondents (83%) found these recommendations impactful in the management/treatment of their presented case or generally useful/informative for their clinical practice.

CONCLUSION
We describe the feasibility and utility of an innovative virtual multi-institutional MTB. These novel remote meetings allowed for discussion of complex neuro-oncology cases and recommendations from experts, particularly important for those with rare CNS tumors. Our study’s findings during the COVID-19 pandemic of the value of providing remote access to MTBs should apply post-pandemic.
INNV-34. NEURO NARRATIVES: AN AUTOETHNOGRAPHIC ACCOUNT OF EXPERIENCING RESILIENCE WITH A BRAIN TUMOR
Authors: Costa Christina Naegeli 
Published: November 2021

Abstract
The current research uses autoethnography as a method to share my experience as a brain tumor patient. In this piece, I reference poems from the day of my diagnosis through my surgery, recovery, and following treatment to demonstrate the thematic factors that allowed me to cope and experience positive emotions as an oncology patient. Results included the factors of trust in medical care, utilizing social support, finding meaning and purpose, and self-love and gratitude. The implications of these factors in relation to resilience structures and discourses to better serve other oncology and chronic illness patients are discussed.
INNV-42. ACTIVE VS RECEPTIVE MUSIC LISTENING THERAPY IN BREAST CANCER PATIENTS USING ARMCAN
Authors: Sengupta Soma , Rebola Claudia , Shatz Rhonna , Koehler Abigail , Rothman Yehudit , Mahammedi Abdelkader , Kirschner Michelle 
Published: November 2021

Abstract
Secondary brain tumors and neurocognitive damage from radiation or chemotherapy are often the commonest neuro-oncological problems in cancer. Breast cancer is the most commonly diagnosed cancer in women, with approximately 2 million women diagnosed in 2018.1 The 10-year survival rate for women diagnosed with breast cancer is 78% (World Cancer Research Fund, 2018). Although the 10-year survival rate is high, women who undergo chemotherapy can experience neurocognitive impairment resulting in significant effects of their cognitive functioning.2 Chemo related dysfunction is known as “chemobrain” or “chemofog.” Chemobrain can result in difficulty with attention, daily activities of living, and memory. This impacts people’s livelihoods and affects their general well-being. Current research on the topic of chemobrain in breast cancer survivors is minimal. However, this study aims to reduce the post-chemotherapy outcomes of chemobrain through the use of interactive versus receptive music. “Brain Fog” or chemobrain is the basis of significant neurological morbidities in the breast cancer population. It causes difficulty in people being able to even carry out activities of daily living. We have developed a prototype “ARMCan—a music software application to help breast cancer patients with “brain fog.” We are conducting a pilot feasibility study to beta test this interactive application which will promote executive function recovery in breast cancer patients with chemobrain.
PATH-02. TWO CASES WITH MULTIPLE HYBRID NERVE SHEATH TUMORS WITH ERBB2 MUTATIONS
Authors: Choi Yoon Jae , Perez-Rosendahl Mari 
Published: November 2021

Abstract
Hybrid nerve sheath tumors are new disease entity incorporated in WHO classification of tumors of the central nervous system 2016 version that includes benign peripheral nerve sheath tumors with combined features of more than one conventional type. Ronellenfitsch et al recently reported one case with ERBB2 D769Y mutation with good clinical response to lapatinib in 2020. We report two cases with imaging findings of multiple peripheral nerve sheath tumors with pathology proven hybrid nerve sheath tumors with ERBB2 mutations. Patient 1 has neurofibroma/schwannoma hybrid nerve sheath tumor with ERBB2 D769Y mutation and patient 2 has plexiform neurofibroma/schwannoma hybrid nerve sheath tumor with ERBB2 V777L mutation. Both of our patients have similar clinical features with adult-onset multiple peripheral nerve sheath tumors without other systemic features of neurofibromatosis type1 or vestibular schwannomas or family history. Hybrid nerve sheath tumors are newly recognized disease and more than half of the cases have multiple peripheral nerve sheath tumors, suggestive of tumor syndrome. Patients with multiple peripheral nerve sheath tumors without systemic features of neurofibromatosis type1 or vestibular schwannomas should be screened for genetic/molecular tests including ERBB2 mutation that might provide treatment options for these patients.
PATH-06. DNA METHYLATION PATTERNS AND IMMUNE MICROENVIRONMENT IN CYSTICGBM
Authors: Chen Zhihua , O’Meally Denis , Frankhouser David , Shahmanyan Mari , Tang Biao , Yao Shu , Rockne Russell C 
Published: November 2021

Abstract
As a rare subtype of glioblastomas (GBM), genetic features in cystic GBM (cGBM) are still largely unknown. We have previously identified a series of active T cell subsets and positive cytokines/chemocytokines in the cystic fluid of cGBMs, including IFN-gamma, IL-2, IL-6, IL-8, TNF-alpha, and MIP-1alpha/beta. This study aimed to evaluate the prognosis of cGBM through DNA methylation patterns and immune microenvironment transcriptional signatures. IvyGAP, EGA and fresh samples from a prospective Chinese cohort were collected to investigate genomic signatures, immune microenvironment and survival outcomes in patients with cGBMs. Gd T1-weighted, T2-weighted, T2-Flair, DWI or ADC images were used to classify cGBM. 143 cases with MGMT/IDH record were used to compare survival time and genomic analysis. Among the three cohorts, Kaplan-Meier analysis showed cystic features have benefit to overall survival (OS). Moreover, cyst feature is the forth factor (HR=0.65, [95% CI 0.42, 1.01]) of survival after IDH, MGMT and Stupp therapeutic regimen. Interestingly, in IDH-wild/MGMT-unmethyled subtype, cGBM patients have longer OS vs noncystic GBM (noncGBM) patients (HR = 0.57, [95% CI 0.33, 0.99]). Compared to noncGBM, cGBM patients have hypomethylation state both in whole gene region and cpG islands. Ivygap database showed between cystic and noncystic group, in sub-structures such as CT (cellular tumor region), CTpan (pseudopalisading cells around necrosis) and CTpnz (perinecrotic zone) there are differential gene expressions and different enrichment pathways. GSEA analysis showed within cGBM group, many gene sets associated with immune function activation such as TRL1/2/3/7 and IFN pathways. These results suggest that cysts of GBM may be associated with hypomethylation status an activated immune microenvironment which is associated with longer survival and may define a unique subgroup of GBM with intrinsically different biology and prognosis.