bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDRE-33. PRECLINICAL THERAPEUTIC EFFICACY OF THE NOVEL BLOOD BRAIN BARRIER PENETRANT ATR INHIBITOR LR02 IN GLIOBLASTOMA
Authors: Koul Dimpy , Balasubramaniyan Veerakumar , Li Xiaolong , Khan Sabbir , Guggi Davide , Mehrling Thomas , DeGroot John 
Published: November 2021

Abstract
Glioblastoma (GBM) remains an incurable tumor with median overall survival of 15 months despite radiation and alkylating temozolomide (TMZ) chemotherapy. DNA damage response (DDR) pathways are among the most important key players of oncogenic mutations associated with resistance to both chemotherapy and radiation in GBM. The high frequency of alterations in DDR pathways in GBM suggests that its inhibition by DDR inhibitors may render GBM cells more susceptible to DNA damaging interventions. Here, we report the preclinical in vitro and in vivo activity of a novel, orally bioavailable Ataxia-telangiectasia mutated serine/threonine protein kinase and Rad3-related (ATR) inhibitor LR02 (Laevoroc Oncology) in a panel of 15 well-characterized glioma stem-like cells (GSCs). Effects on cell proliferation, survival and tumor formation were analyzed following treatment with LR02. Growth inhibition was time- and dose-dependent with a 3-day exposure resulting in a growth inhibitory IC50 (gIC50) in the low nM range in all the glioblastoma cell lines tested. LR02 inhibited growth of GSCs at IC50 values ranging from 500nmol/L to-~2umol/L. Additional studies showed that temozolomide sensitized GSC to LR02. Importantly, we demonstrate that MGMT promotor methylation status was associated with cellular response to LR02 treatment with preferential inhibition of cell growth in MGMT promotor methylated (MGMT deficient) cell lines. LR02 showed efficacy and survival benefit in a GSC262 (MGMT methylated) orthotopic model of GBM. Further administration of LR02 further enhanced the in vivo antitumor efficacy of temozolomide (TMZ) against GBM using the GSC262 model demonstrating that ATR inhibitor LR02 may enhance alkylating agent-mediated cytotoxicity and provide a novel treatment combination for GBM patients. Our present findings establish that the ATR inhibitor LR02 can specifically be used in tumors with MGMT deficiency when combined with alkylating chemotherapy. Further studies are ongoing to evaluate the potential of LR02 to overcome radiation and chemotherapy resistance in glioblastoma.
DDRE-40. BIOINFORMATICS ANALYSIS OF GRADE I AND III MENINGIOMA GENE EXPRESSION SUGGESTS MMP28 AS A POSSIBLE POSITIVE PROGNOSTIC INDICATOR
Authors: Michelhaugh Sharon , Dyson Gregory , Ali-Fehmi Rouba , Bollig-Fischer Aliccia , Mittal Sandeep , Degen Katherine 
Published: November 2021

Abstract
Meningiomas are the most common primary brain tumor. Grade I meningiomas are slow growing with a good prognosis following surgical resection. High grade meningiomas (II and III) are more aggressive with greater rates of recurrence and poor prognosis despite surgical resection and radiotherapy. This study sought to identify key pathways and genes that contribute to the molecular mechanisms that separate these distinct meningioma phenotypes. FFPE specimens were evaluated and graded by a pathologist. Total RNA was extracted from tissue curls and RNA samples were measured with the Illumina DASL whole genome gene expression assay (n = 29,374 probes). A log2 transformation was applied to all of the data and quantile normalization using 21 samples. A t-test of the log2 expression of the 10 grade III samples and 11 grade I samples resulted in 1505 differentially expressed genes. The GeneCard Suite’s GeneAnalytics tool was used to perform pathway enrichment analysis. Similar to other comparable data sets, DNA Damage, Cell Cycle, EGF/EGFR Signaling, TGF-Beta Signaling, and PI3K-AKT Signaling pathways were among the 20 enriched pathways. Notably, matrix metalloprotease 28 (MMP28, also known as epilysin) was down regulated in grade III meningiomas compared to grade I (III/I expression ratio 0.315; P=0.015). MMP28 is expressed in numerous tissues including the nervous system during development and regeneration. In cancer, MMP28 is thought to enhance epithelial to mesenchymal transition by altering the TGF-B signaling pathways. MMP28 is an indicator of poor prognosis for pancreatic, lung, gastric and hepatic cancers as well as glioblastoma. However, MMP28 has also been reported as down regulated during malignant transformation in colon cancer. Our data suggest that MMP28 may have an alternative role in meningioma and serve as a positive prognostic indicator.
DDRE-42. TOWARDS PRECISION MEDICINE: AUTOMATED DRUG SCREENING PLATFORM UTILIZING TUMOR-ORGANOIDS TO IDENTIFY PATIENT-SPECIFIC DRUG-RESPONSES IN MENINGIOMA
Authors: Jungwirth Gerhard , Paul Adrian , Junguo Cao , Unterberg Andreas , Abdollahi Amir , Herold-Mende Christel 
Published: November 2021

Abstract
Tumor-organoids (TO) are mini-tumors generated from tumor tissue preserving its genotype and phenotype by maintaining the cellular heterogeneity and important components of the tumor microenvironment. We recently developed a protocol to reliably establish TOs from meningioma (MGM) in large quantities. The use of TOs in combination with lab automation holds great promise for drug discovery and screening of comprehensive drug libraries. This might help to tailor patient-specific therapy in the future. The aim of our study was to establish an automated drug screening platform utilizing TOs. For this purpose, we established TOs by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples in the high-throughput format of 384-well plates. The drug screening was performed fully automated by utilizing the robotic liquid handler Hamilton Microlab STAR and a drug library containing 166 FDA-approved oncology agents. Viability was assessed with CellTiterGlo3D. In total, we performed the drug screening with 166 drugs on TOs from 11 patients suffering from MGM (n=8 WHO°I, n=2 WHO°II, n=1 WHO°III). The top five most effective drugs resulted in a decrease of TO viability ranging from 84.6–63.3%. K-means clustering analysis resulted in groupings of drugs with similar modes of action. One cluster consisted of epigenetic drugs while another cluster consisted of several proteasome inhibitors. However, when looking at a patient-individual level, in 11 patients 44 of 166 drugs, were among the top 10 most effective drugs, providing strong evidence for heterogeneous drug-responses in MGM patients. Taken together, we successfully developed an automated drug screening platform pipeline utilizing TOs from MGM to identify patient-specific drug-responses. The observed intra-individual differences of drug responses mandate for a personalized testing of comprehensive drug libraries in TOs to tailor more effective therapies in MGM patients.
DDRE-48. COMPARTMENT LOCKED IL-12 - INCREASED TISSUE RETENTION AND MINIMAL PERIPHERAL EXPOSURE ALLOW HIGHER TREATMENT EFFICACY AND TOLERABILITY IN LOCAL GLIOBLASTOMA THERAPY
Authors: Beffinger Michal , Schellhammer Linda , Shekarian Tala , Deplazes Sereina , Zimmermann Ivan , Egloff Pascal , Buch Thorsten , Seeger Markus , Hutter Gregor , Vom Berg Johannes 
Published: November 2021

Abstract
Recent clinical studies in glioblastoma (GBM) highlight the potential of local IL-12 therapy, but they also bring back tolerability concerns due to leakage into the periphery. This leakage might thus hamper exploiting the full potential of local IL-12 therapy. Fusion with an IgG4 Fc portion increases the tissue retention of IL-12; but could also confer export into the blood and subsequent systemic recycling through the neonatal Fc receptor (FcRn), ultimately leading to potentially toxic IL-12 serum levels. We assessed the expression of FcRn in human and murine GBM and its role in IL-12Fc tissue retention and systemic exposure upon local delivery. Human or murine IL-12Fc was injected in GBM-bearing or naïve wt or FcRn-humanized mice continuously or as bolus via convection-enhanced delivery (CED). We screened combinations of amino-acid substitutions at the (IL-12)Fc:FcRn binding interface to abolish this interaction. Brain and blood concentrations were assessed via ELISA or cytokine bead arrays. FcRn affinity was measured by SPR/ELISA and bioactivity tested on PBMCs and human GBM explant cultures. Treatment efficacy and immunological correlates were assessed in GBM bearing mice. FcRn is upregulated in human and mouse GBM and contributes to brain export and subsequent peripheral recycling of IL-12Fc in the blood. IL-12Fc with abrogated FcRn binding due to a unique set of substitutions is fully functional and appears brain compartment locked (CL IL-12) as it exhibits enhanced tissue retention and reduced serum levels upon local injection, reaching up 100x higher brain to serum concentration ratios than regular IL-12. Compared to its non-modified counterpart, murine CL IL-12 shows significantly higher treatment efficacy at negligible systemic footprint in late stage murine GBM. In patient explant cultures, human CL IL-12 leads to successful inflammatory conditioning. Compartment locked IL-12 should thus allow a wide dosing window to fully harness its therapeutic potential for local GBM therapy.
DDRE-49. TRANSIENT OPENING OF THE BLOOD-BRAIN BARRIER BY VASOACTIVE PEPTIDES TO INCREASE CNS DRUG DELIVERY: REALITY VERSUS WISHFUL THINKING?
Authors: Smith-Cohn Matthew , Burley Nicholas , Grossman Stuart 
Published: November 2021

Abstract

BACKGROUND
Drug delivery to treat neurologic disease and cancers of the central nervous system (CNS) is severely limited by the blood-brain barrier (BBB). Vasoactive peptides (VAPs) such as regadenoson, adenosine, and labradimil have been shown in animal studies to transiently open the BBB, and regadenoson is currently under investigation in humans to determine if it might improve CNS drug delivery. There is currently limited information regarding the potential for other VAPs to open the BBB transiently.

METHODS
We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the BBB, we devised a four-tier classification system to organize data available in the literature which factors in alterations in BBB integrity and effects on normal brain vasculature and systemic blood vessels. This data was further sorted based on whether it comes from humans, animals, or in vitro systems.

RESULTS
We identified 38 VAPs with potential BBB permeability-altering properties. To date, none of these has been shown to open the BBB in humans. Thirteen VAPs increased BBB permeability in rodents. The remaining 25 had favorable physiologic effects on blood vessels but lack specific information on permeability changes to the BBB. We ranked VAPs in a four-tier ranking system related to their known physiologic actions.

CONCLUSION
Rodent studies document that analogs of bradykinin and adenosine transiently disrupt the BBB leading to higher chemotherapy concentrations in the CNS. VAPs remain an understudied class of drugs with the potential to increase drug delivery to the CNS. Dozens of VAPs have yet to be formally evaluated for this important clinical effect. This retrospective review summarizes the available data on VAPs highlighting agents that deserve further in vitro and in vivo investigations.
EPID-08. IMPORTANCE OF THE INTERSECTION OF AGE AND SEX TO UNDERSTAND VARIATION IN INCIDENCE AND SURVIVAL FOR PRIMARY MALIGNANT GLIOMAS
Authors: Wang Gi-Ming , Cioffi Gino , Patil Nirav , Waite Kristin , Lanese Robert , Ostrom Quinn , Kruchko Carol , Berens Michael , Connor James , Lathia Justin , Rubin Joshua , Barnholtz-Sloan Jill 
Published: November 2021

Abstract

BACKGROUND
Gliomas are the most common type of malignant brain and other CNS tumors, accounting for 80.8% of malignant primary brain and CNS tumors. They cause significant morbidity and mortality. This study investigates the intersection between age and sex to better understand variation of incidence and survival for glioma in the United States.

METHODS
Incidence data from 2000-2017 were obtained from the Central Crain Tumor Registry of the United States, which obtains data from the CDC’s National Program of Cancer Registries and NCI’s Surveillance Epidemiology and End Results Program (SEER), and survival data from the CDC’s NPCR Registries. Age-adjusted incidence rates and rate ratios per 100,000 were generated to compare male-to-female incidence by age group. Cox proportional hazard models were performed by age group, generating hazard ratios to assess male-to-female survival differences.

RESULTS
Overall, glioma incidence was higher in males. Male-to-female incidence was lowest in ages 0-9 years (IRR: 1.04, 95% CI:1.01 - 1.07, p=0.003), increasing with age, peaking at 50-59 years (IRR:1.56, 95% CI: 1.53 - 1.59, p&lt; 0.001). Females had worse survival for ages 0-9 (HR:0.93, 95% CI:0.87-0.99), though male survival was worse for all other age groups, with the difference highest in those 20-29 years (HR:1.36, 95% CI:1.28-1.44). Incidence and survival differences by age and sex also varied by histological subtype of glioma.

CONCLUSION
To better understand the variation in glioma incidence and survival, investigating the intersection of age and sex is key. The current work shows that the combined impact of these variables is dependent on glioma subtype. These results contribute to the growing understanding of sex and age differences that impact cancer incidence and survival.
EPID-12. MITOCHONDRIAL DNA SEQUENCE VARIATION AND MENINGIOMA
Authors: Samanic Claudine , Teer Jamie , Thompson Zachary , Creed Jordan , Fridley Brooke , Nabors L Burt , Williams Sion L , Egan Kathleen 
Published: November 2021

Abstract
Meningiomas are the most common primary central nervous system tumors. Risk factors include female sex, African American race, a higher body mass index, and exposure to ionizing radiation. Genome-wide association studies have identified two risk loci for meningioma in the nuclear genome (rs12770228 and rs2686876). Whereas mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, research on meningioma is lacking. We examined the association of 42 common (minor allele frequency ≥ 5%) germline mtDNA variants, haplogroups, and genes with meningioma risk in 1,080 controls and 478 cases from a case-control study conducted at medical centers in the southeastern US. Participant DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for meningioma overall, WHO grade 1 (n=409) and WHO grade 2/3 (n=69) meningiomas. Overall, meningioma risk was significantly higher among women (OR=2.86; 95% CI:2.21-3.71) compared to men, higher among African Americans (OR=2.37, 95% CI:1.41-3.99) compared to Caucasians, and higher among those who were overweight (OR=1.48; 95% CI:1.11-1.98) or obese (OR= 1.73; 95% CI:1.26-2.38) compared to those of normal weight. The variant m.16362T &gt;C (rs62581341) in the mitochondrial control region was positively associated with grade 2/3 meningiomas (OR=2.33; 95% CI: 1.14-4.79), but not with grade 1 tumors (OR=0.99; 95% CI:0.64-1.53). Haplogroup L, a marker for African ancestry, was identified among 3.6% of controls and 8.6% of cases and was associated with meningioma risk overall (OR=2.56; 95% CI:1.52-4.30). When stratifying by self-reported race, the association between haplogroup L and meningioma was only apparent among the small number of self-reported Caucasians with this haplogroup (OR=6.68; 95% CI=1.66-26.91) when compared to non-L haplogroups, combined. No other common mtDNA variant (minor allele &gt;5%), haplogroup, or gene was associated with meningioma risk. These findings merit further study.
EPID-13. PREDICTIVE VALUE OF SERUM PROLACTIN LEVEL TO THE TUMOR SIZE RATIO FOR PREOPERATIVE DIAGNOSIS OF PROLACTIN-PRODUCING PITUITARY ADENOMA
Authors: Kim Jeong-Hwa , Choi Jung-Won , Seol Ho-Jun , Nam Do-Hyun , Lee Jung-Il , Hong Chang-Ki , Kong Doo-Sik 
Published: November 2021

Abstract

PURPOSE
Preoperative diagnosis of prolactinomas is critical because medication of dopamine agonists instead of surgical resection has been regarded as a primary treatment. However, serum prolactin level alone is suboptimal for differentiating the prolactin producing adenoma or hyperprolactinemia-causing NFPAs. The author investigated the use of ratio of PRL levels to the tumor size as the optimal cutoff value for prolactin-producing tumor, comparing with the NFPA.

METHOD
We performed a retrospective review of patients who underwent the transsphenoidal surgery (TSS) for pituitary lesions in the single institute between January 2015 to May 2020. A total of 223 patients with hyperprolactinemia at the initial diagnosis were analyzed in the study, including NFPA patients (n=175) and prolactinoma patients (n=48). Receiver operating curve (ROC) analyses were performed for serum prolactin levels (PRL) and serum prolactin levels/tumor maximal diameter (PRL/MD).

RESULT
Prolactinoma group showed higher median values in serum PRL (258.6 μg/L) and smaller maximal tumor diameter (16.6 mm), compared to those of NFPA group (serum PRL 44.4 μg/L, p-value = 0.002 and MD 23.9 mm, p-value &lt; 0.001). A moderate correlation was found between serum prolactin level and maximal diameters in prolactinomas (r=0.43, p=0.002), whereas a weak relationship was confirmed in NFPAs (r=0.17, p=0.028). The cutoff was 8.93 μg/L*mm (area under the curve [AUC] = 0.94) for PRL/MD and 99.43 μg/L for PRL (AUC = 0.91). In prolactinomas, there was no statistical difference between the PRL/MD of macroadenomas (n=36, 21.7μg/L*mm) and microadenoma (n=12, 16.8μg/L*mm) (p=0.109).

CONCLUSION
The serum PRL levels and tumor size exhibited stronger linear correlation in prolactinomas than in NFPAs. The PRL/MD ratio showed better diagnostic value for differentiating two pathologies than the serum PRL levels alone. These findings suggest PRL/MD ratio may be an alternative method to preoperative diagnosis of prolactinomas differentiating from hyperprolactinemia-causing NFPAs.
EPID-23. THE PAKISTAN BRAIN TUMOR EPIDEMIOLOGY STUDY: PAVING THE WAY FOR A NATIONAL BRAIN TUMOR REGISTRY
Authors: Shah Mashal , Baig Erum , Bajwa Mohammad Hamza , Laghari Altaf Ali , Bin-Anis Saad , Akhunzada Naveed Zaman , Gilani Jaleed , Jawed Noyan , Khalid Usman , Qadeer Namra , Lutfi Areeb , Tahir Izza , Bajwa Rameen , Rashid Huzaifa , Sadia Haleema , Ghazi Kinzah , Gillani Mishal , Azam Iqbal , Shamsi Uzma , Consortium Pakistan Brain Tumor , Siddiqi Sameen , Enam Syed Ather 
Published: November 2021

Abstract

INTRODUCTION
In Pakistan, brain tumor epidemiology has been examined in single-centre studies or as part of general cancer registries, which are limited by catchment area, age group, or are not specific to brain tumors. The Pakistan Society of Neuro-Oncology conducted a nationwide study to assess the distribution of brain tumor distribution and associated risk factors. This unfunded study explores data from across Pakistan and serves as a potential model for LMICs to emulate.

METHODS
A cross-sectional study was designed to include patients diagnosed with brain tumors in major neurosurgical centers in Pakistan retrospectively from January-December 2019. Patients, both alive and deceased, with a radiological diagnosis of a brain tumor were included. Data were recorded on a comprehensive online form from 35 centers, encompassing an estimated 85% of all the brain tumor patients seeking initial treatment by a neurosurgeon from the public and private sectors. Data collection was split into three regions: Sindh and Balochistan; Punjab; and Khyber Pakhtunkhwa and Islamabad. Data collection occurred between August 2020 and January 2021.

RESULTS
A total of 2750 brain tumor cases were recorded of which 1897 (69%) were diagnosed in the private sector hospitals. MRIs were a more common radiological study compared to CT scans. 2666 surgeries were performed, 174 individuals underwent chemotherapy and 479 underwent radiation therapy; approximately two-thirds of the patients that require adjuvant treatment are not able to receive it. Gliomas were the most common tumor, while pineal tumors were the least common. Findings indicate a low metastasis frequency and few females seeking care.

CONCLUSION
The study shows that brain tumors are mostly diagnosed and operated on in the private sector; the public sector should be more engaged. The study also highlights that despite inconsistencies in hospital records for brain tumor patients, reliable information can be collected in LMIC settings.
EPID-24. TRANSCRIPT: A cenTRAl NERVOUS SYSTEM CANCER CLINICAL tRIals PostmorTem
Authors: Kim Yeonju , Armstrong Terri , Gilbert Mark , Celiku Orieta 
Published: November 2021

Abstract

BACKGROUND
Despite the growing number of neuro-oncology clinical trials, there have been limited advances in the treatment of malignant primary central nervous system tumors. We surveyed the landscape of past, ongoing, and planned trials to assess trends in their interventions, outcomes, and design considerations to guide future studies.

METHODS
Data on interventional trials on ClinicalTrials.gov were accessed programmatically using AACT and R. Neuro-oncology trials were isolated using primary malignant brain tumor classification terms. Instrument names from PROQOLID were used to identify clinical outcome assessment (COA) use. Linear regression was used to assess chronological trends; power analyses utilized CBTRUS survival rates among trials investigating overall survival.

RESULTS
We identified 3039 interventional brain tumor trials that started between 1966 and 2025. Trials were most frequently phase II (43%), completed (40%), non-blinded (92%), single-group assignment (65%), non-randomized (51%) studies targeting glioblastoma (45%). Planned outcomes were reported by 93% of trials; this included adverse event or toxicity (54%), overall/x-year survival (44%), progression free survival (43%), maximum tolerated dose (16%), and objective response rate (14%). Evaluating the anticipated and actual trial enrollment, we estimate that only 10% and 8% of trial arms, respectively, were sufficiently powered to assess overall survival endpoints. 21% of trials mentioned the use of a COA (first trial initiated in 1992), majority of which were patient-reported outcomes. Among these, 25% and 58% reported COA as a primary or secondary outcome, respectively. The rate of COA use increased linearly over time at 1.1%/year but remained less than 5 trials per year until 2003. Ongoing work is investigating treatment mechanisms of actions and evidence of preclinical efficacy among brain tumor studies.

CONCLUSIONS
Low randomization rates and underpowered trial design may impede interpretability of efficacy. Increasing trends in COA use suggests cumulative influence of advocacy efforts to holistically evaluate net clinical benefit of interventions.