bluuebunny/crossref_metadata_2025_split huggingface dataset:
BSCI-12 BREAST TO BRAIN METASTASIS IS EXACERBATED WITH CHEMOTHERAPY THROUGH BLOOD-CEREBRAL SPINAL FLUID-BARRIER AND INDUCES ALZHEIMER’S-LIKE PATHOLOGY
Authors: Neman Josh , Saatian Behnaz , Herrera Robert , Martirosian Vahan , Eisenbarth Rachel , Iyer Mukund , Julian Alex , Lowman Allison , LaViolette Pete , Remsik Jan , Boire Adrienne , Sankey E , Fecci Peter E , Shiroishi Mark , Chow Frances , Hurth Kyle 
Published: August 2022

Abstract
Control of breast to brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have also shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through formation of neurofibrillary tangles (NFT) independently. Now, in this study we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT. Results show chemotherapies promote increased brain-barrier permeability and facilitate enhanced tumor infiltration, particularly through the blood-cerebrospinal fluid-barrier (BCSFB). This is attributed to increased expression of matrix metalloproteinase 9 (MMP9) which, in turn, mediates loss of Claudin-6 within the choroid plexus cells of the BCSFB. Importantly, increased MMP9 activity in the choroid epithelium following chemotherapy results in cleavage of Tau released from breast cancer cells. This cleaved Tau forms tumor-derived NFT that further destabilize the BCSFB. Our results underline for the first time the importance of the BCSFB as a vulnerable point of entry for brain-seeking tumor cells post-chemotherapy and indicate that tumor cells themselves contribute to Alzheimer’s-like tauopathy.
BSCI-20 STING EPIGENETIC SILENCING IN GLIOMAS CAN BE RESCUED BY METHYLTRANSFERASE INHIBITION: IMPLICATIONS FOR NOVEL THERAPEUTIC APPROACHES
Authors: Low Justin , Chandramohan Vidya , Bowie Michelle , Brown Michael , Waitkus Matthew , Briley Aaron , Stevenson Kevin , Fuller Rebecca , Hostettler Janell , Reitman Zachary , Charbonneau Casey , Keir Stephen , Khasraw Mustafa , Ashley David 
Published: August 2022

Abstract
The stimulator of interferon genes (STING) is a key component of the innate immune response to pathogenic cytosolic DNA, resulting in IRF3- and NFκB-dependent transcription of type I interferons (IFN) and pro-inflammatory cytokines. STING activation primes endogenous antitumor immunity and is disrupted in a variety of cancers. Here we investigate STING signalling in glioblastoma (GBM) patient samples. STING agonist treatment of ex vivo gliomas leads to inconsistent induction of type I IFN responses that are restricted to tumor associated myeloid cells. Indeed, single-cell transcriptome and multiplex immunofluorescence analyses demonstrate that STING expression is suppressed in neoplastic cells but not tumor-associated immune cells or stroma. Methylation analyses reveal a STING promoter region that is highly methylated in bulk tumor samples from glioma and other neuroectoderm-derived cancers, but not in most extracranial cancers. Methylation in this region strongly correlates inversely with STING RNA expression. STING epigenetic silencing is also present in normal fetal and adult brains. We demonstrate that STING expression in glioma cell lines may be rescued by decitabine, a DNA methyltransferase inhibitor (DNMTi) that is commonly used to treat hematologic malignancies. However, transduction of a STING-expressing vector into these glioma cell lines is insufficient to reconstitute STING signalling, suggesting that additional decitabine-stimulated mechanisms are necessary for STING pathway rescue. Collectively, our results suggest that epigenetic silencing of STING occurs early in brain development and may provide an immunosuppressive context for the genesis of brain tumors. Furthermore, our work raises the potential of epigenetic modulation to reconstitute STING signalling as a therapeutic strategy for glioblastoma and potentially other STING-silenced, immunologically-cold cancers.
BSCI-23 ANEUPLOIDY PROFILING IN GLIOBLASTOMA IDENTIFIES MECHANISMS OF DISEASE PROGRESSION AND TREATMENT VULNERABILITIES
Authors: Jermakowicz Anna , Stukenberg P Todd , Ayad Nagi 
Published: August 2022

Abstract
Glioblastoma (GBM) is the most common and malignant adult brain tumor. Despite years of research, few advancements have been made in its management. One challenging area of glioblastoma research is patient stratification in clinical trials based on genomic features. Although several regions of aneuploidy have been known to drive disease progression in GBM, the degree of aneuploidy across the genome varies widely and the significance of regions of aneuploidy has not been assessed. Using whole genome sequencing profiles for matched tumor and non-tumor samples, we were able to accurately determine the degree of aneuploidy and loss of heterozygosity for a set of primary GBM tumors. Next, using machine learning techniques, distinct patterns of aneuploidy and loss of heterozygosity emerged among a set of GBM tumors, allowing us to define distinct aneuploidy subgroups. Interestingly, these aneuploidy subgroups showed distinctly different rates of patient survival, suggesting that regions of aneuploidy may be driving disease progression. Differing rates of various GBM genomic subtypes including IDH mutation, EGFR mutation, MGMT methylation, and tumor subtypes was also seen among the aneuploidy subgroups. We were able to derive a gene expression signature for each of these aneuploidy subgroups and revealed distinct pathways that were driving tumor growth. Furthermore, using a perturbagen-response dataset we were able to predict compounds to distinctly target each subgroup. Collectively, this suggests that aneuploidy profiling provides important clues to varying mechanisms of disease progression and is a promising approach for targeted therapy in a patient-specific manner.
CLRM-02 SINGLE CENTER EXPERIENCE OF DOPAMINE ANTAGONIST ONC-201 FOR RECURRENT H3K27M-MUTANT GLIOBLASTOMA IN ADULTS
Authors: Ekhator Chukwuyem , Rak Ramin , Tadipatri Ramya , Fonkem Ekokobe , Grewal Jai 
Published: August 2022

Abstract

OBJECTIVE
To report the single center experience of three adult subjects receiving ONC-201 as part of the ONC018 expanded access clinical trial [NCT03134131].

BACKGROUND
ONC-201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the H3K27M mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. H3K27M tumors are generally located in the midline of the central nervous system which co-localize, for unknown reasons, with key dopaminergic pathways. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review.

DESIGN/METHODS
Our site enrolled three subjects on the ONC018 trial. We present the demographic, clinical, and molecular characteristics for our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, time-to-progression, response, Karnofsky Performance Status [KPS] and quality-of-life measured by the MD Anderson symptom inventory instrument [MDASI].

RESULTS
Three subjects were registered at our site onto ONC018 with age range 18-44yrs, 2/3 female, residing in Norway, India and United states. Tumor locations: brainstem, corpus callosum and thalamus. Pathology: glioblastoma(3/3), MGMT methylated (2/3), IDH1 mutant (0/3), EGFR amplification (0/3) and ATRX (3/3). Median change from baseline KPS: ≤20% decrease; MDASI:2/3 experienced decrease from baseline [median 6%],consistent with improved quality of life. No clinically significant laboratory abnormalities. No serious adverse events observed in any cases. All adverse events grade I-II.

CONCLUSIONS
In three subjects with H3K27M-mutant malignant glioma that received ONC201 as part of this expanded access clinical trial, we found that study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy of this agent for this patient population.
CLRM-03 INCIDENCE OF INTRACRANIAL HEMORRHAGE IN GLIOMA PATIENTS WITH VENOUS THROMBOEMBOLISM CONVERTED FROM LMWH TO APIXABAN
Authors: Aboud Orwa , Ye Xiaobu , Grossman Stuart 
Published: August 2022

Abstract
Venous Thromboembolism (VTE) occurs in approximately 15-30% of patients with glioma 1,2 who are treated with therapeutic anticoagulants. Anticoagulation treatment increases the incidence of intracranial hemorrhage (ICH) with variable incidence between studies 1.9% to 20s% 3-6. The “common practice” treatment for VTE in glioma patients includes subcutaneous administration of low molecular weight heparin (LMWH, enoxaparin) injection, which requires daily self-injection. Switching glioma patients with VTE from LMWH to oral anticoagulants would limit the difficulty and the inconvenience of daily self-injecting in primary brain tumor patients and decrease the room for error in administering the dose along and the risk for heparin induced thrombocytopenia7. The goal of this project is to evaluate the incidence of intracranial hemorrhage in glioma patients with VTE converted from LMWH to Apixaban. We hypothesize that patients with brain tumors and Venous Thromboembolism can be converted safely from LMWH to Apixaban. To examine this hypothesis, we will enroll adult patients with pathologically confirmed supra-tentorial glioma and VTE, patient must have been treated with LMWH for ≥ 5 days. We will exclude patients with bleeding diathesis, severe hypersensitivity to Apixaban or pregnant or unable to provide informed consent. To assess the validity of our hypothesis: Primary Objective: To estimate the incidence of ICH in glioma patients with history of VTE after the conversion from LMWH to oral Apixaban. Secondary Objective: To estimate the incidence of recurrent VTE in glioma patients with history of VTE after the conversion from LMWH to oral Apixaban. To our knowledge, this is the first of its kind study to estimate the risk of ICH in glioma patients with VTE treated with oral anti-coagulation. Successful completion of our trial will provide answers to an important clinical question that could allow our patients using more convenient yet effective treatment by establishing and implementation of best practices.
CLRM-06 PROSPECTIVE CLINICAL STUDY OF CONVENTIONALLY FRACTIONATED CONCURRENT CHEMORADIOTHERAPY AND HYPOFRACTIONATED CONCURRENT CHEMORADIOTHERAPY AFTER THE SURGERY OF HIGH-GRADE GLIOMAS
Authors: Weiyan Shi 
Published: August 2022

Abstract

PURPOSE
To observe and evaluate the efficacy and safety of conventional fractionated concurrent chemoradiotherapy and hypofractionated concurrent chemoradiotherapy for adjuvant treatment of newly treated high-grade glioma.

METHOD
For newly treated patients with high-grade gliomas with WHO grade III-IV, all patients started concurrent chemoradiotherapy within 1 month after surgery, and received concurrent temozolomide 75 mg/m2 during radiotherapy until the end of radiotherapy. Sequential temozolomide chemotherapy at 200 mg/m2 for at least 6 cycles. All patients were randomly divided into groups, one group was given conventional fractional irradiation, 60Gy/30f in high-risk areas, 46Gy/23f in low-risk areas, and the other group was given low-fractionated irradiation, 53Gy/15f in high-risk areas, and 53Gy/15f in low-risk areas 43Gy/15f. The overall survival (OS), progression-free survival (PFS), radiation-induced cerebral edema and radiation-induced brain necrosis were evaluated.

RESULT
As of December 31, 2022, a total of 60 patients were enrolled, including 30 in the conventional fractionation treatment group and 30 in the hypofractionated treatment group. At present, 58 patients survived and 2 died, 2 in the conventional fractionation group, one due to tumor recurrence and one due to cardiac accident; 7 patients recurred, including 4 in the conventional fractionation group and 3 in the low fractionation group. Radiation cerebral edema occurred in 9 cases, 6 cases in the hypofractionated group and 3 cases in the conventional fractionation group, all of which were completely relieved after dehydration with mannitol, which did not affect the progress of radiotherapy. No radiation necrosis occurred during follow-up.

CONCLUSION
Compared with the standard stupp regimen, using 53Gy/15f in the high-risk area and 43Gy/15f in the low-risk area as an adjuvant therapy with concurrent temozolomide and sequential temozolomide, there was no increased risk of disease recurrence, no increased risk of death, and no increased risk of death.
CLRM-07 A MULTIVARIATE RETROSPECTIVE ANALYSIS OF 159 PATIENTS WITH HIGH-GRADE GLIOMAS: OVERALL SURVIVAL, PROGRESSION-FREE SURVIVAL, AND PROGNOSTIC FACTORS
Authors: Liu Shiyu , Jiang Xin , Dong Lihua 
Published: August 2022

Abstract

BACKGROUND AND PURPOSE
High-grade gliomas are highly malignant, aggressive, high incidence rate, and mortality. The purpose of this study was to analyze retrospectively and identify prognostic factors of patients with high-grade gliomas diagnosed by biopsy or postoperative pathological examination.

METHODS
In this retrospective study, we analyzed the patient’s demographic data, tumor characteristics, treatment approaches, immunocytochemistry results, the overall survival (OS) time, and the progression-free survival (PFS) time in a series of 159 histologically proven high-grade gliomas recruited from January 2011 to December 2019. OS time and PFS time were analyzed by Kaplan-Meier survival analysis with log-rank test and found the independent factors by using Cox regression analysis.

RESULTS
Survival analysis showed that an OS of 84.90%, 55.35% and 13.20% was observed at 1, 2 and 5 years, respectively. And a PFS of 56.6%, 25.26% and 3.14% was observed at 1, 2 and 5 years, respectively. The mean OS was 52.73 months and mOS was 35 months. Univariate analysis showed that postoperative pathological classification and grade and age were statistically significant for patient outcome (P &lt; 0.01). 147 patients underwent concurrent chemoradiotherapy and 80 of them died; 12 patients did not undergo concurrent chemoradiotherapy and 10 died (P = 0.03); There were statistically significant differences in the prognostic impact of Ki-67 expression, MGMT, IDH1R132H and p53 mutations by immunohistochemistry (P = 0.001; P = 0.016; P = 0.003; and P = 0.021, respectively). Similarly, we concluded that different grades, age, pathological classification, Ki-67 and IDH1R132H expression by immunohistochemistry were statistically significantly associated with PFS (P &lt; 0.01; P = 0.004; P = 0.003; P = 0.001; P = 0.028).

CONCLUSIONS
Tumor grade and concurrent chemoradiotherapy after surgery were independent prognostic factors affecting patients’ survival, and grade was also an independent factor affecting PFS.
CLRM-10 METIS (EF-25): A PIVOTAL, RANDOMIZED CONTROLLED STUDY OF TUMOR TREATING FIELDS IN PATIENTS WITH 1–10 BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER
Authors: Mehta Minesh , Brown Paul , Gondi Vinai , Ahluwalia Manmeet 
Published: August 2022

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division. TTFields treatment showed efficacy in preclinical non-small cell lung cancer (NSCLC) models. Furthermore, TTFields therapy improved survival with a tolerable safety profile in patients with glioblastoma. The objective of the pivotal METIS trial [NCT02831959] is to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with brain metastases.

METHODS
NSCLC patients (N=270) with 1–10 brain metastases will be randomized 1:1 to stereotactic radiosurgery (SRS) followed by continuous TTFields therapy using NovoTTF-200M (150 kHz, recommended &gt;18 h/day) with best standard of care (BSC) or SRS followed by BSC alone. Follow-ups will be conducted every 2 months until second intracranial progression. Key inclusion criteria are: Karnofsky Performance Status ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS, and optimal therapy for extracranial disease. Key exclusion criteria are: prior whole brain radiotherapy, single operable, or recurrent brain metastases. Primary endpoint is time to first intracranial progression. Secondary endpoints include time to neurocognitive failure, overall survival, radiological response rate (RANO-BM and RECIST V1.1), quality of life, adverse events, time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases, bi-monthly intracranial progression rate from 2–12 months, and time to second intracranial and distant progression. The study is powered at 80% (2-sided alpha of 0.05) to detect a hazard ratio of 0.57. In July 2021, an independent Data Monitoring Committee (DMC) reviewed the study data and recommended continuation as planned. The trial is currently recruiting at 92 sites in North America, Europe, Israel, mainland China and Hong Kong.
CLRM-11 CURRENT STATE OF CLINICAL TRIALS FOR PATIENTS WITH MELANOMA BRAIN METASTASES
Authors: Elghawy Omar , Banfield Walter , Horton Bethany , Kaur Varinder 
Published: August 2022

Abstract

INTRODUCTION
Clinical trials have traditionally excluded patients with melanoma brain metastasis (MBM), despite evidence of CNS activity of systemic therapy. The true extent of variation in MBM-related enrollment criteria in ongoing melanoma clinical trials has not been evaluated.

METHODS
A systematic search of clinicaltrials.gov website was performed to characterize trends in clinical trial enrollment of MBM patients in interventional drug trials. Trial data search was limited to “open”, “interventional studies” and advanced stage melanoma in adult patients. Logistic regression was used to model inclusion of active MBMs. Covariates considered were phase of study, location, therapy type, melanoma specific, and sponsor category

RESULTS
Of a total of 475 trials identified, 365 met inclusion criteria. 230 (63.0%) were phase I, 119 (32.6%) were phase II, 14 (3.8%) were phase III and 2 (0.5%) were phase IV trials. 184 (50.4%) were pharmaceutical industry sponsored, 183 (50.1%) were specific for melanoma. Forty-seven (12.8%) trials strictly excluded brain metastasis and 173 (47.3%) strictly excluded leptomeningeal disease (LMD). 261 (71.5%) trials allowed patients with previously treated MBM, and 73 (20.0%) allowed patients with active MBMs. No explicit mention of CNS metastasis was made in 13.6% of trials and no mention of LMD was made in 43.8% trials. In univariate models, trials not employing immunotherapy (odds ratio 2.23; 95% CI: 1.2, 4.3; p = 0.0174) and non-pharma trials (odds ratio 1.98; 95% CI 1.0, 3.9; p= 0.0461) were twice as likely to include MBM patients. In a combined model, only therapy type remained significant at the α=0.05 level.

CONCLUSION
Despite the evidence of CNS activity of immunotherapy in randomized trials, only 20% ongoing trials are enrolling patients with active MBMs. Efforts should be made to tailor future clinical trial designs to include MBM patients to assess CNS activity of systemic therapeutics early on in drug development.
CLRM-13 RELEVANCE OF RECURSIVE PARTITIONING ANALYSIS (RPA) CLASSIFICATION IN THE CURRENT CARE OF PATIENTS WITH BRAIN METASTASES (BMETS)
Authors: Sarai Guneet , Amidon Ryan F , Bovi Joesph A , Thomas Alissa A , Novicoff Wendy , Schuetz Samantha , Singh Rohit , Chang Amy , Sheehan Jason P , Fadul Camilo E 
Published: August 2022

Abstract

BACKGROUND
Patients diagnosed with BMETS want to know their prognosis and the benefit of treatment to make informed decisions. Clinician and patient biases frequently provide survival estimates that are too optimistic or pessimistic. We postulated that that RPA remains a useful tool to communicate prognosis and potential benefit from brain-directed treatment (BDT). We evaluated real-world data on RPA class and survival of patients with newly diagnosed BMETS from three academic institutions.

METHODS
We retrospectively reviewed the records of patients with BMETS between 2017 and 2019 who had at least 6 months of follow up. Excluded were patients with leptomeningeal or only dural/calvarial metastases. We calculated the RPA and according to class compared Kaplan-Meier survival curves.

RESULTS
We have data on 642 cases with median age of 65 years; 80% had lung, breast, melanoma, and renal as the primary cancer. Sixty (9.3%) patients received palliative care only, while 582 (90.7%) had BDT. The median survival of all patients according to RPA in months was 18.0 (I), 9.4 (II), and 2.4 (III) and for those receiving BDT (n=582), it was 19.2 (I), 11.2 (II), and 2.9 (III). There were statistically significant differences for BDT survival curves adjusted for multiple comparisons (I-II p=0.0124; II-III p&lt;0.0001; I-III p&lt;0.0001). For patients in RPA class III who received WBRT (n=62), the median survival was 2.9 months, and, for SRS (n=37), it was 3.5 months. We will present updated data including additional 238 cases and propose predictive/prognostic models based on our cohort that optimizes the RPA application in clinical practice.

CONCLUSION
In contemporary practice, the RPA classification remains significantly relevant in making care decisions for patients diagnosed with BMETS. Treatment recommendations for patients in RPA class III should be the result of multidisciplinary discussions with consideration for early palliative care involvement to de-escalate and avoid inefficacious BDT.
LOCL-06 SUPERVISED MACHINE LEARNING IDENTIFIES RISK FACTORS ASSOCIATED WITH LEPTOMENINGEAL DISEASE AFTER SURGICAL RESECTION OF BRAIN METASTASES
Authors: Morshed Ramin , Saggi Satvir , Cummins Daniel , Young Jacob , Viner Jennifer , Villanueva-Meyer Javier , Boreta Lauren , Braunstein Steve , McDermott Michael , Theodosopoulos Philip , Berger Mitchel , Hervey-Jumper Shawn , Aghi Manish , Daras Mariza 
Published: August 2022

Abstract

BACKGROUND
Resection of brain metastases (BMs) can help with local disease control, yet predictors of leptomeningeal disease (LMD) after surgery are not well defined. This study examined rates and predictors of LMD in patients who underwent resection of a BM.

METHODS
A retrospective, single-center study was conducted examining LMD risk for adult patients with a BM that underwent resection with postoperative adjuvant radiation. Logistic regression analyses and a supervised machine learning algorithm (Random forest) were implemented to identify factors within the cohort that were associated with LMD.

RESULTS
Of the 182 patients in the cohort, 43 patients (23.6%) developed LMD in the postoperative setting with 18 cases of classical LMD (9.9%) and 25 cases of nodular LMD (13.7%). Median censored time to LMD was not reached, and 6-, 12-, and 24-month LMD-free rates from surgery were 93%, 86.3%, and 71.8%, respectively. Median time from surgery to classical and nodular LMD were 13.1 and 9.5 months, respectively (Log-rank p=0.71). Patients diagnosed with classical LMD had worse survival outcomes from LMD diagnosis compared to nodular LMD (2.6 vs 9.7 mo, Log-rank p=0.02), and LMD-subtype was significantly associated with overall survival from the date of surgery (classical vs nodular vs none: 16.1 vs 20 vs 36.7 mo, p &lt;.0001). Random forest analysis identified primary cancer type, absence of extracranial disease, and tumor volume as the top 3 factors associated with LMD. On multivariate regression analysis, absence of extracranial disease at index surgery was associated with any LMD (OR 2.65, 95% CI 1.15-6.10, p=0.02). Treatment with postoperative checkpoint inhibitors, type of radiation, and performing additional craniotomies were not associated with risk of LMD.

CONCLUSIONS
Classical-type LMD is associated with worse prognosis compared to nodular-type LMD. Absence of extracranial disease at the time of surgery was the most consistent factor associated with LMD on follow-up.