bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-03. DEVELOPMENT OF NOVEL ANTI-BRAIN METASTASIS INHIBITORS
Authors: Kieliszek Agata , Mobilio Daniel , Bassey-Archibong Blessing , Johnson Jarrod , Venugopal Chitra , Magolan Jakob , Singh Sheila 
Published: November 2022

Abstract
The current standard of care for (surgery and radiation) for brain metastases (BM) is inadequate as BM have a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need. The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from BM patient tumor samples. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective BM cascades and additionally captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but represent a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RNA sequencing of pre-metastatic BM cells revealed a unique deregulated transcriptomic profile that is specific to pre-metastatic cells despite the tumor of origin. Connectivity Map analysis was applied to the gene expression signatures of pre-metastatic BM cells to identity a compound (Drug A) which selectively inhibits BM cell proliferation but is not blood-brain barrier (BBB) penetrant and has not been previously considered in the context of brain metastasis. We synthesized a BBB-penetrant analogue of Drug A and found, using our patient-derived xenograft (PDX) models, that it increased survival benefit relative to both placebo and Drug A. Beginning with this promising scaffold, we will conduct structure-activity hypothesis-driven medicinal chemistry campaigns to optimize this scaffold for brain permeation while maintaining selective anti-BM activity. Development of novel small molecules that target premetastatic BM cells could slow or prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.
DDDR-39. IDENTIFICATION OF A NOVEL THERAPEUTIC TARGET THAT IS SYNTHETICALLY LETHAL WITH MUTANT IDH INHIBITOR IN GLIOMA USING THE CRISPR/CAS9 GENOME EDITING TECHNOLOGY
Authors: Maeda Sachi , Aoki Kosuke , Hinohara Kunihiko , Yamaguchi Junya , Ohka Fumiharu , Motomura Kazuya , Kibe Yuji , Natsume Atsushi , Saito Ryuta 
Published: November 2022

Abstract
Diffuse glioma is the most frequent and malignant neuroepithelial tumor in the central nervous system. IDH mutations are the most frequent genetic mutations in adult gliomas. The WHO Classification of Tumors, 5th edition, volume 6: Central Nervous System Tumours revised in 2021, defines the presence of IDH mutations in gliomas as astrocytoma IDH-mutant and oligodendroglioma IDH-mutant and 1p/19q-codeleted. In addition, more than 90% of IDH mutations found in gliomas are IDH1 R132H mutation. Several clinical trials of mutant IDH1 inhibitors targeting the IDH1 R132H mutation have shown their efficacy, but it has also been reported that IDH1 inhibitors alone may not provide sufficient tumor suppression. In this study, we performed genome-wide knockout screening using CRISPR/Cas9 genome editing technology to search for new drug targets that are synergistic with the mutant IDH1 inhibitor DS-1001b. The results of CRISPR screening and RNA sequence analysis revealed that several metabolism-related genes are factors that define resistance to mutant IDH inhibitor. In a tumor suppression study, treatment of two IDH1 R132H mutant glioma cell lines (MGG152 and BT142) with mutant IDH1 inhibitor suppressed production of the oncometabolite D2-HG, but did not significantly alter cell growth. However, when mutant IDH1 inhibitor were combined with inhibitor for metabolism-related genes, cell survival was significantly reduced, and the effects were synergistic. In this study, we found that administration of mutant IDH inhibitors to IDH mutant gliomas significantly altered intratumor metabolism using various molecular approaches. We then identified targets that, when combined with mutant IDH inhibitor, provide synergistic tumor suppression. These results are expected to provide a new therapeutic approach for a subset of patients who have difficulty responding to mutant IDH1 inhibitors.
EOLP-04. A CALL TO ACTION TO INCREASE ACCESS TO POST-MORTEM BRAIN TUMOR DONATIONS: GIFT FROM A CHILD
Authors: Lyons Nicole , Waanders Angela , Williams Melissa , Nazarian Javad , Eze Augustine , Bornhorst Miriam , Frenkel Elizabeth , Mason Jennifer , Minturn Jane E , Koptyra Mateusz , Monje Michelle , Hysinger Jared , Souweidane Mark , Greenfield Jeffery P , Campbell Cindy , Uceda Esteban , Smith Amy , Hegert Julia , Campion Stephani , McLean Ginny , Gustafson Patti , Gustafson Allen 
Published: November 2022

Abstract
Implementation of access to donate post mortem tissue among pediatric brain tumor patients remains a challenge[DSM1] . Previous attempts to develop a post-mortem network have been jeopardized by barriers such as a lack of education, logistical coordination of donation, and difficulties effectively communicating the benefit of post-mortem donations to families. [CC2] Utilizing feedback from patients’ families, clinicians, and researchers, standard operating procedures (SOP) were developed and utilized by six “tissue navigators” (TN) working across institutions. Tissue navigators are critical in implementation of access to donate as they serve as a liaison between patients’ families and clinical team to ensure post-mortem tissue is procured correctly and respectfully. From 2018 through 2021, there has been an increase in donations, which has led to establishment of tumor cell cultures translating rapidly to clinical development, and a growing network of centers participating in GFAC procedures. Donations have been facilitated at over 75 institutions. GFAC has coordinated 146 donations in this 3-year launch timeframe, with nearly half from families outside GFAC’s primary institutional network. Barriers to implementation were addressed with the design of GFAC’s SOPs, which lead to the successful implementation of access to donation. GFAC is developing CME training for clinicians and researchers to address communication of post-mortem donation, continuing awareness campaigns with collaborators in the field, advocating for families to receive feedback on the donation, and expanding on the SOPs as more is learned from clinicians and families.
EPID-08. AGE-STRATIFIED SURVIVAL ANALYSES OF PHARMACOLOGICAL TREATMENTS IN PATIENTS WITH GLIOBLASTOMA
Authors: Rabin Erik , Mi Xinlei , Huang Jonathan , Kim Miri , Mozny Andreas , Amidei Christina , Sieg Erica , Bell April , Zhai Lijie , Bommi Prashant , Lauing Kristen , Lukas Rimas , Wainwright Derek 
Published: November 2022

Abstract
Glioblastoma is the most common primary malignant brain tumor in adults. Age is a prognostic factor for grade IV glioma (GIV) survival, where older adults 65 and older, tend to have quicker mortality compared to adults 18-64. This may be due to intrinsic aspects of the aged host, including age-dependent changes to the brain and immune systems. We studied pharmacologic management of GIV patients treated with medications affecting the brain, immune, and other systems for associations with age and survival. Electronic records for 1,208 GIV patients were collected at a single institution from 1/1/2000 to 9/8/2021 and used to construct a multivariable time-dependent cox model that examined intra-cohort hazards associated with 14 different categories of outpatient medications. Date of diagnosis was identified as the start-time and subject death was used to define the event-time. Patients who were alive or lost to follow-up were censored to last recorded date. Survival time was calculated as the difference between diagnosis date and event time or censorship. For positive control, we confirmed that younger and older patients experienced an improved hazard with temozolomide. Strikingly, younger, but not older patients, experienced increased hazard with a steroid prescription (1.46 [1.12,1.90], **). In contrast, older, but not younger patients experienced improvements in hazard with prescription of neurological medications including benzodiazepines (0.47 [0.27, 0.80] **) and anti-convulsants (0.28 [0.08, 0.90] *), in addition to heart failure treatments including angiotensin II inhibitors (0.48 [0.27, 0.85] *) and diuretics (0.30 [0.15, 0.87] *). Patients prescribed antidepressants didn’t show improved hazard across younger and older GIV patients, which consistent with our previously published work. These data indicate novel associative benefits due to prescription of select pharmacologic agents that vary with patient age. This work may be used to better understand therapeutic approaches that selectively benefit younger vs. older adults with GIV.
EPID-17. CENTRAL NEUROCYTOMA: RESEARCH TRENDS, MOST CITED PAPERS, AND SCIENTOMETRICS ANALYSIS TO DATE
Authors: Durrani Sulaman , Qamar Mohammad Aadil , Tebha Sameer Saleem , Nathani Karim , Bydon Mohamad 
Published: November 2022

Abstract

INTRODUCTION
Central neurocytoma is the most common primary intra-ventricular tumor in adults being classified by the World Health Organization (WHO) as a benign grade II tumor with a good prognosis. Given the recent advances with regards to this tumor, a bibliometric analysis was due to study the change in research interest and patterns to identify the future direction of research for neurocytomas. MATERIALS AND

METHODS
A comprehensive Elsevier’s Scopus database search was performed to capture all published and indexed studies to date using the keywords "neurocytoma" and "central neurocytoma". A discrete set of validated bibliometric parameters were extracted and analyzed. All statistical analyses were performed on R 4.1.2.

RESULTS
A total of 1,002 documents were included in our analysis covering a period between 1910-2021 (111 years). Around 98.5% of the documents were multi-author publications with a collaboration index (CI) of 4.21. Acta Neuropathologica, The American Journal of Surgical Pathology, and Cancer were the journals to include the most number of top ten cited articles (2 out of 10 most cited articles, 20%). Switzerland (4 out of 10, 40%) accounted for the country to have the most number of top 10 most cited articles. The United States of America (5588 out of 16395 citations, 34.1%) had the most number of citations. Lastly, our analysis reported an annual growth rate of 6.9% for the number of papers produced by year.

CONCLUSION
This is the first bibliometric analysis to study the top 10 most cited articles with regard to neurocytomas. A shift from histopathologic and clinical symptoms toward treatment and management of the tumor was observed in our analysis. These findings highlight the need for investigation into treatment modalities for future research.
DISP-03. FEMALE-SPECIFIC CANCER METASTASES TO THE BRAIN: OUTCOMES IN A MEDICALLY UNDERSERVED AREA
Authors: Shaffer Annabelle , Krist David , Smith Emily , Naik Anant , Mittal Anisha , Smith Alexander , Janbahan Mika , Najafali Daniel , Hassaneen Wael 
Published: November 2022

Abstract

INTRODUCTION
Cancer care in medically underserved areas (MUA) is challenging and not widely reported. This report seeks to characterize the outcomes of female patients with brain metastases from breast, ovarian, cervical, and endometrial cancer who underwent surgical resection in an MUA.

METHODS
Our institution’s electronic medical record was queried for patients who underwent a craniotomy from 2013-2022. All female patients with brain metastasis from breast, ovarian, cervical, or endometrial cancer were included. The following variables were collected: alive or deceased, survival time, demographics, past medical history, metastasis location and number, extent of resection, time to metastasis, and time to recurrence. MUA was defined by the Health Resources & Services Administration’s database (data.hrsa.gov).

RESULTS
Nine patients had metastases from breast, four from endometrial, one from ovarian, and one from cervical cancers. Metastases were most commonly located in the posterior fossa. The median age at surgery was 65 years. The median time from primary cancer diagnosis to brain metastasis diagnosis was 2.1 years. Gross total resection (GTR) was achieved in 15/21 metastases. Recurrence occurred in 7/15 patients after a median of 10 months. At the conclusion of the study, eight patients were deceased (53%), two patients were alive with no known new metastases (13%), four were alive with new metastases (27%), and one (6.7%) was lost to follow-up. In patients who died during the study, the median survival was 9.4 months, the median age at death was 65.7 years, and 7/8 had GTR of the metastasis(es).

CONCLUSION
To our knowledge, this is the first report of female-specific cancer brain metastases in an MUA. The median survival time was approximately nine months, which is similar to survival reported in multi-center studies. Further studies are recommended to identify and manage cancer care disparities in MUAs.
IMMU-39. NANOPARTICLE TREATMENT REBALANCES IMMUNODOMINANCE OF ANTI-VIRUS IMMUNITY TO ENHANCE ANTI-TUMOR IMMUNITY DURING ONCOLYTIC ADENOVIRUS THERAPY IN SOLID TUMORS
Authors: Shin Dong Ho , Jiang Hong , Gillard Andrew , Kim Debora , Nguyen Teresa , Fan Xuejun , Yi Yanhua , Ban Kechen , Alemany Ramon , Alonso Marta M , Lang Frederick , Gomez-Manzano Candelaria , Ozpolat Bulent , Fueyo Juan 
Published: November 2022

Abstract
Oncolytic virotherapy shows great potential for treating brain tumors and other solid tumors that metastasize to the brain. A phase I clinical trial testing the oncolytic adenovirus Delta-24-RGD (DNX-2401) in patients with recurrent malignant gliomas demonstrated significant clinical benefits for a subset of patients, and another phase I trial testing Delta-24-RGD in patients with pediatric brain tumors also indicated similar clinical benefits. However, virus injection in tumors initiates both anti-virus and anti-tumor immune responses by activating respective clones of CD8+ T-cells, which compete for limited resources for clonal expansion. Expansion of T-cells against highly immunogenic viral antigens might limit the expansion of subdominant clones against tumor antigens. We hypothesized that inducing immune tolerance for the dominant viral antigens will allow the expansion of previously subdominant tumor-specific T-cells. In this work, we observed that nanoparticles encapsulating adenoviral antigens successfully induced immune tolerance for viral antigens. These nanoparticles were taken up by liver resident macrophages, which are involved in maintaining peripheral immune tolerance. RNA-sequencing revealed that T-cells recognizing the encapsulated antigens had unique transcriptome signatures with upregulation of genes specifically involved in peripheral immune tolerance, including immune coinhibitory molecules. Virus-specific immune tolerance using nanoparticles redirected the focus of the immune response towards antigens for melanoma as measured by interferon-gamma secretion (P &lt; 0.0001). Reduction of virus-specific T-cells and simultaneous expansion of tumor-specific T-cell clones were confirmed with tetramer staining (P &lt; 0.05). Importantly, virotherapy in combination with nanoparticle-induced immune tolerance towards viral antigens increased the percentage of long-term survivors compared to virus treatment alone (100% versus 50%). Our data provide the basis to develop future clinical trials that aim to maximize the potential of cancer virotherapy in solid tumors.
INNV-06. DETECTION OF MUTANT P53 POSITIVE GLIOBLASTOMA CELLS IN CEREBROSPINAL FLUID (CSF) USING A MICROFLUIDIC BASED IMMUNOASSAY
Authors: Hsiao Steven , Pircher Tony , Sweed Nathan , Armijo Kaitlyn , Marrin Mikayla , Cho Leslie , Dugan Michael , Kesari Santosh 
Published: November 2022

Abstract

BACKGROUND
Metastatic involvement of the CSF by non-CNS neoplasms surpasses that of primary brain tumors, although conventional glioblastoma (GBM) can occasionally be identified in the CSF. Here, we apply Biocept’s CNSide test to examine a patient CSF sample with GBM, verified with an antibody against mutant p53. The p53 pathway is deregulated in 84% of glioblastoma patients and point mutations lead to expression of mutant p53 protein.

METHODS
A CSF sample from 65-year-old male patient, with GBM diagnosed by MRI & CT, and prior identified p53 mutation on R273C by NGS was collected into Biocept’s CSF collection tubes at Providence Saint John’s Health Center. CSF-cells were incubated, 2 days post collection, with a proprietary antibody cocktail, including anti-CD9, followed with a biotinylated secondary, which enables enrichment of capture antibody labeled cells in a streptavidin coated microfluidic device. Cells were fixed and permeabilized immunofluorescence was performed against mutant p53, CD45, fluorescently labeled streptavidin, for capture antibody detection, and DAPI. Microfluidic chips were scanned and analyzed on a Bioview system. The specificity of the mutant p53 antibody was verified using the same test on tumor cells with either wildtype p53 vs various p53 mutations.

RESULTS
CSF analysis by the CNSide platform detected 3 tumor cells / mL. Immunofluorescence confirmed strong expression of mutant p53 protein on about 1/3 of cells identified as tumor cells. Besides the patient R273C mutation, we demonstrated detection of P223L/V274F, E285K and Q331R mutations on tumor cell lines.

DISCUSSION
Our work suggests that a microfluidic based GBM capture test paired with appropriate biomarkers can be used as sensitive means to detect GBM cells in CSF and may be useful for diagnostics and treatment monitoring. Further, we demonstrated the utility of a mutant p53 antibody to identify tumor cells. Technical and clinical studies are needed to substantiate this hypothesis.
PATH-07. MULTIPLATFORM MOLECULAR ANALYSES REFINE CLASSIFICATION AND PROGNOSTICATION OF GLIOMAS ARISING IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Lucas Calixto-Hope , Sloan Emily , Jung Jangham , Gupta Rohit , Wu Jasper , Vasudevan Harish , Shai Anny , Whipple Nicholas , Bruggers Carol , Samuel David , Maher Ossama , Lu Rufei , Mirchia Kanish , Sullivan Daniel , Pekmezci Melike , Tihan Tarik , Bollen Andrew , Perry Arie , Banerjee Anu , Gupta Nalin , Mueller Sabine , de Groot John , Clarke Jennifer , Raleigh David , Phillips Joanna J , Reddy Alyssa , Chang Susan M , Berger Mitchel S , Diaz Aaron , Solomon David A 
Published: November 2022

Abstract

BACKGROUND
Gliomas arising in patients with neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade (LG) or high-grade (HG), and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 and epigenetic classification of these tumors remain limited.

METHODS
Next-generation sequencing and DNA methylation profiling was performed on gliomas from 47 NF1 patients and correlated with clinicopathologic features, treatment, and outcomes.

RESULTS
30 tumors demonstrated biallelic inactivation of NF1 without additional oncogenic alterations (“molecular LG subgroup”, median age 14 yrs). The remaining 17 tumors harbored additional oncogenic alterations beyond NF1 (“molecular HG subgroup”, median age 28), most frequently CDKN2A homozygous deletion (n=13), ATRX mutation (n=8), PIK3CA or PIK3R1 mutation (n=4), and TP53 mutation (n=3). Survival analysis showed significant differences in time to progression (137 vs 11 mos, p&lt; 0.0001) and median survival time (undefined vs 37 mos, p &gt; 0.0001) for molecular LG versus HG subgroups. DNA methylation profiles of the molecular LG subgroup resolved into a new epigenetic cluster closest to but divergent from the three existing reference classes of sporadic pilocytic astrocytoma. DNA methylation profiles of the molecular HG subgroup demonstrated most tumors epigenetically align with either HGAP or various subclasses of IDH-wildtype GBM.

CONCLUSION
NF1-associated gliomas stratify into two molecular subgroups. The “molecular LG subgroup” occurs primarily during childhood, harbors biallelic NF1 inactivation only, follows a more indolent clinical course, and has a unique epigenetic signature for which we propose the terminology “pilocytic astrocytoma, arising in the setting of NF1”. The “molecular HG subgroup” occurs primarily during adulthood, harbors additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, follows a more aggressive clinical course, and is epigenetically diverse. These findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.
NIMG-42. DURABLE OVERALL RESPONSE RATE (ORR) TARGETS FOR RECURRENT GLIOBLASTOMA (RGBM) CLINICAL TRIALS BASED ON THE HISTORIC ASSOCIATION BETWEEN ORR AND MEDIAN OVERALL SURVIVAL (MOS)
Authors: Ellingson Benjamin , Wen Patrick Y , Chang Susan , van den Bent Martin , Vogelbaum Michael , Li Gang , Li Shanpeng , Kim Jiyoon , Youssef Gilbert , Wick Wolfgang , Lassman Andrew , Gilbert Mark , de Groot John , Weller Michael , Galanis Evanthia , Cloughesy Timothy 
Published: November 2022

Abstract
Durable overall response rate (ORR) remains a meaningful endpoint in recurrent GBM; however, the target ORR for single arm recurrent GBM trials has not been based on historic information or tied to patient outcomes. The current study reviewed past trials in recurrent GBM in order to judiciously define target ORRs for use in recurrent GBM trials. After reviewing 69 treatment arms comprising 4,971 patients, ORR was 6.1%[95% CI 4.23; 8.76%] for cytotoxic chemotherapies (ORR=7.59% for CCNU, 7.57% for TMZ, 0.64% for CPT-11, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for immunotherapies (select trials), and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2=0.4078, P&lt; 0.0001), biologics (R2=0.4003, P=0.0003), and immunotherapy trials (R2=0.8994, P&lt; 0.0001), but not anti-angiogenic agents (R2=0, P=0.8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2=0.3164, P&lt; 0.0001; mOS[weeks]=0.6xORR+28.9), suggesting an ORR &gt;20% results in an mOS of &gt; 40.9 weeks, which is double the survival estimate of a treatment with ORR=0% and ≥ 2 months longer than treatments with ORR=5%. Assuming an ineffective therapy (control) has ORR=5%, a trial of 32 patients with a target ORR=20% leads to the 95% confidence interval higher than the control group. We conclude that single arm phase II studies in recurrent GBM with ≥ 32 patients should have a target ORR ≥ 20%. This was associated with a median OS of approximately 1 year. Importantly, durability of response should also be considered and was not assessed in the current meta-analysis.