bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-83. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY CNS DIFFUSE B-CELL LYMPHOMA
Authors: Green Richard , Guzman-Marin Ruben , Miranda Candy 
Published: November 2023

Abstract
We report our experience treating 25 patients with newly diagnosed primary CNS diffuse B-cell lymphoma with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 66 y (range 30-85); 12 patients were men and 13 were women. Twenty-three had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 18 patients completed initial chemotherapy. Sixteen of these 18 went on to transplantation; one patient had had early disease progression, and in one no stem cells could be collected. Five patients (median 73 y; range 64-85 y) died early after 1-2 cycles. The causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One of the 16 patients who completed the entire regimen including transplantation died of fungal pneumonia and the other 15 experienced no serious acute toxicity. One patient had late disease progression and 2 developed symptomatic leukoencephalopathy. Seventeen of the 25 patients remain alive. Median TTP for the cohort is 605 days, and OS 738 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 65 y shows that the regimen is too toxic for older individuals.
CTNI-84. PNOC022: A COMBINATION THERAPY TRIAL USING AN ADAPTIVE PLATFORM DESIGN FOR PATIENTS WITH DIFFUSE MIDLINE GLIOMAS (DMGS) AT INITIAL DIAGNOSIS, POST-RADIATION THERAPY AND AT TIME OF PROGRESSION
Authors: Kline Cassie , Franson Andrea , Banerjee Anu , Reddy Alyssa T , Raber Shannon , Hoffman Carly , Minturn Jane , van der Lugt Jasper , de Vos-Kerkhof E , van Vuurden Dannis , Gerber Nicolas , Stuecklin Ana Guerreiro , Kilburn Lindsay , Elster Jennifer , Whipple Nicholas , Cohen Kenneth , Oren Michal Yalon , Gardner Sharon , Cluster Andrew , Chi Susan , Landi Daniel , McCowage Geoffrey , Resnick Adam , Phillips Joanna , Bhatia Aashim , Vossough Arastoo , George Elizabeth , Nabavizadeh Ali , Braunstein Steve , Gupta Nalin , Prados Michael , Waszak Sebastian , Boyle-Lang Janel , Molinaro Annette , Dun Matthew , Koschmann Carl , Nazarian Javad , Mueller Sabine 
Published: November 2023

Abstract

BACKGROUND
Subjects diagnosed with diffuse midline glioma (DMG) face extremely poor prognoses. PNOC DMG-ACT (DMG-Adaptive Combination Trial, PNOC022) is an open-label, multi-institutional, international trial that aims to investigate combination therapies for patients with DMG. Herein, we report on the combination study arm with ONC201, an orally available DRD2 and ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor for patients who completed standard-of-care radiation (Cohort 2).

METHODS
Children and young adults aged 2-39 years were enrolled 4-14 weeks post-radiation and received maintenance therapy with weekly ONC201 (weight-based adult equivalent of 625 mg) and daily paxalisib (27mg/m2). Plasma and CSF samples for pharmacokinetics (PK) and circulating tumor DNA (ctDNA) were collected at multiple timepoints.

RESULTS
Sixty-eight patients with biopsy-proven DMG enrolled between November 2021 and June 2023 (median age 9 years [range 3-37], n=41 female [60%]). Site-determined tumor location includes 47 pontine (69%), 16 thalamic (24%), 3 spinal cord (4%) and 2 cerebellar (2%) DMGs. Median overall survival (OS) from time of diagnosis is 16.5 months (lower 95% CI 11.6 months) with a median follow-up time of 9.9 months (95% CI: 8.5, 11.4). The H3K27M mutation was found in 91% (n=50) and 9% were classified as H3K27-altered (n=5). TP53 was mutant in 50% (22/44 available). Most common grade 3 and above treatment-related adverse events were neutrophil count decreased (n=4); mucositis (n=3); and, colitis, DRESS, lymphocyte count decreased, hyperglycemia, hypokalemia (n=2). PK and ctDNA analyses are being finalized.

CONCLUSIONS
The current median OS is encouraging compared to historical controls. At the meeting, we will present updated molecular characterization and early biological correlates in association with clinical outcomes including toxicity, OS, PK, and central imaging confirmed progression-free survival.
DNAR-02. MICROGLIA IN THE GLIOBLASTOMA MICROENVIRONMENT ASSIST REPAIR OF RADIATION INDUCED DNA DAMAGE IN A CONTACT INDEPENDENT MANNER
Authors: Palavalasa Sravya , Singer Ava , Scott Andrew , Wilder-Romans Kari , Shankar Sunita , Ravikumar Visweswaran , Bhadury Sagnik , Andren Anthony , Sajjakulnukit Peter , Zhou Weihua , Lyssiotis Costas A , Rao Arvind , Al-holou Wajd , Wahl Daniel R 
Published: November 2023

Abstract
Rapid repair of DNA damage mediates genotoxic therapy resistance and poor prognosis in glioblastoma (GBM). The GBM tumor microenvironment (TME) is heterogenous, and we hypothesized that non-malignant cells in the GBM TME support the repair of DNA damage in glioblastoma cells. Consistent with this hypothesis, we found that GBM tumors grown intracranially in mice had rapid DNA repair and were resistant to radiation when compared to tumors of identical genotype grown extracranially in mouse flanks. Further interrogation of irradiated intracranial tumors using gamma-H2AX immunofluorescence revealed spatial heterogeneity in DNA damage repair, with spatially separate regions of rapid and slow gamma-H2AX resolution. Paired spatial transcriptomic analysis and gamma-H2AX immunofluorescence revealed that tumor regions with rapid DNA repair were rich in microglia and enriched for inflammatory response and epithelial to mesenchymal transition (EMT) pathway transcripts. Spatial transcriptomic analysis of patient tissue revealed that regions enriched in DNA damage repair pathways are also enriched for microglia and not other non-malignant cell types. Having nominated microglia, we then cocultured GBM cells and microglia and found that GBM cells cocultured with microglia repair DNA damage faster in a contact-independent manner. Hence, we show that microglia in the GBM microenvironment assist GBM cells to repair radiation induced DNA damage through inflammatory response and EMT and hence, mediate treatment resistance.
DNAR-06. RHO GTPASES AS A POTENTIAL CHEMOSENSITIZER OF TMZ AND CISPLATIN-RESISTANT GBM TUMOR CELLS THROUGH A P53-DEPENDENT MECHANISM
Authors: Forti Fabio , Magalhaes Yuli 
Published: November 2023

Abstract
Rho GTPases regulate cellular processes related to tumor progression and their expression/activity determines the invasiveness and aggressiveness of GBM and, despite current aggressive therapies, effective treatments remain desired. Here we proposed that Rho GTPase acts on the genomic stability of GBM and its resistance to TMZ and cisplatin drugs in a p53-dependent mechanism. We selected GBM cell lines with different p53 status – U87-MG and A172 (wt-p53), T98G and U138-MG (mut-p53) – and subjected them to Rho inhibition by C3 toxin and subsequent DNA damage by TMZ treatments or cisplatin. Bioinformatic analysis showed that prolonged exposure to cisplatin induces the transcription of regulatory genes of Rho GTPases. Pulldown assays corroborated this analysis showing an increase in Rho activity after exposure to cisplatin or TMZ. IC50 for TMZ and cisplatin, as well as survival and proliferation assays, were all decreased by Rho inhibition in wt-p53 cells, while HCR assays showed that DNA repair capacity for both genotoxic drugs is decreased by Rho inhibition only in wt-p53 cells. To verify the role of p53 in this mechanism, we knocked down p53 in U87-MG cells, thus avoiding Rho inhibition-induced chemosensitivity and impaired DNA repair. Then, U87-MG cells were subjected to various treatment regimens with low doses of TMZ or cisplatin to obtain a subpopulation of cells resistant to these drugs. Further exposure to DNA damage led to increased p53(Ser15) phosphorylation, p53 nuclear translocation, and F-actin-induced polymerization. Two TMZ-resistant cell clones were selected, both showing a significant increase in TMZ IC50 for survival, while Rho inhibition reduced IC50 in both clones, significantly reversing the acquired resistance of these cells. These results suggest that Rho GTPase plays a role in DNA repair and in the acquired GBM wt-p53 resistance to TMZ and show that this pathway may be a fragile-point against current therapies.
DNAR-12. ATR INHIBITION AS A NOVEL RADIOSENSITIZATION STRATEGY FOR GLIOBLASTOMA
Authors: Kanji Suman , Tomimatsu Nozomi , Di Cristofaro Luis Fernando Macedo , Ghamasaee Pegah , Floyd John , Mukherjee Bipasha , Burma Sandeep 
Published: November 2023

Abstract
Glioblastomas (GBM) are lethal brain tumors for which surgical resection followed by ionizing radiation (IR) with concurrent and adjuvant Temozolomide (TMZ) remains the mainstay of therapy. GBMs are extremely radioresistant, and radiosensitization approaches are desperately needed for these tumors. IR induces DNA double-strand breaks (DSBs), and these lesions can be repaired either by error-prone non-homologous end joining (NHEJ) or the error-free homologous recombination (HR) pathway. Research in our and other laboratories has shown that the ATR kinase promotes the HR pathway. We therefore hypothesized that ATR inhibition would block DSB repair in rapidly-dividing GBM cells that are HR dependent but not in non-dividing normal brain cells that are dependent upon NHEJ for repair. We treated a panel of GBM cell lines and normal human astrocytes with the ATR inhibitor VX-803 and/or IR and assessed for multiple endpoints including HR, DSB repair, and cell survival. We found that VX-803 blocks HR and DSB repair in GBM cells but does not significantly affect repair in non-dividing normal human astrocytes. Hence, treatment with VX-803 sensitizes GBM lines to IR in vitro as measured by the colony formation assay. Next, PDX mouse models of GBM were treated with VX-803 followed by XRT, and monitored for tumor growth and survival. We found that the drug can cross the blood-brain barrier and, in conjunction with IR, block DNA repair in intracranial tumors, attenuate tumor growth, and consequently extend survival of tumor-bearing mice. Importantly, the drug does not significantly affect DSB repair in normal brain cells indicating that ATR inhibition might selectively block repair in GBM cells, thereby minimizing normal tissue toxicity. Our results indicate that regulation of HR by ATR is critical for optimal DSB repair, especially in rapidly-dividing GBM cells, and that ATR inhibition could be used to improve GBM radiotherapy in the clinic.
DNAR-13. TARGETING THE DNA DAMAGE RESPONSE IN GLIOBLASTOMA PROPAGATING CELLS: FROM MOLECULAR MECHANISMS TO PRECISION MEDICINE
Authors: Pailas Alexandros , Neumann Katrin , Jeanty Céline , Herold-Mende Christel , Toth Reka , Nazarov Petr , Scalisi Joshua , Neirinckx Virginie , Rogister Bernard , Van Dyck Eric 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most aggressive and lethal primary tumor of the central nervous system (CNS). Despite surgical resection and a combination of radiotherapy and alkylation chemotherapy, the median survival for patients with newly diagnosed GBM is only ~ 14 months. Among the many challenges confronting clinicians are subpopulations of tumor-propagating cells named GBM Stem-like Cells (GSCs), which have been proposed to drive treatment resistance and foster tumor relapse. At the mechanistic level, GSCs have been shown to display constitutive activation of the DNA damage response (DDR) due to chronic replication stress (RS), which enhances their ability to repair the DNA lesions induced by chemoradiation. Thus, developing new therapeutic strategies against glioblastoma is of paramount importance. Cell cycle regulation and DNA damage response are two crucial molecular networks altered in most cancer types. In this context, we have previously identified a DNA repair and cell cycle gene expression signature that results in the classification of GBM tumors in two major groups, G1 and G3, which differ in the expression of survival and proliferation pathways. Using bioinformatics analysis of the GLASS consortium database, we have created an exhaustive oncopanel of the molecular alterations defining the G1 and G3 groups. Furthermore, using G1- and G3-patient-derived GSC cell lines as experimental models, we have identified crucial differences in the mechanisms orchestrating the cell cycle, DDR, and treatment resistance between G1 and G3 cells. Finally, we have also identified group-specific therapeutic strategies combining repositioned FDA-approved drugs with the inhibition of crucial DDR factors. Our long-term goals are i) to understand the molecular basis behind the differential response to DNA damage and replication stress developed by G1 and G3 cells and ii) to propose group-specific, DDR-based combination therapies that prevent treatment resistance and promote long-lasting treatment.
DDEL-03. PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING OF HETEROGENEOUS DRUG PENETRATION INTO THE HUMAN BRAIN AND GLIOBLASTOMA
Authors: Li Jing , Sanai Nader , Tovmasyan Artak , Kim Seongho 
Published: November 2023

Abstract

BACKGROUD
Insufficient penetration of potentially effective therapeutic agents across the human blood-brain barrier (BBB) is a hurdle to the effective treatment of brain cancer. The BBB in glioblastoma is disrupted to varying extents. This study was to develop a PBPK model platform for prediction of heterogenous drug penetration into the human brain and glioblastoma.

METHODS
A 7-compartment CNS (7-CNS) PBPK model platform was developed to predict drug concentrations in the brain blood, brain parenchyma, cranial CSF, spinal CSF, and 3 tumor compartments representing infiltrating tumor (T1) with a slightly disrupted BBB, bulk tumor (T2) with a leaky BBB, and necrotic core (T3) with no blood vessels. The model accounted for brain/tumor general anatomy and regional pathophysiological differences. Drug transfer and fluid balance between compartments were described by differential equations. Simulations were performed using R programming. The model was verified by comparisons of predicted and observed tumor PK data of ribociclib and abemaciclib in glioblastoma patients.

RESULTS
For ribociclib, the model-predicted mean unbound drug brain-to-plasma ratio (Kp,uu) was 0.17, 2.2, 8.2, 24.9 in normal brain, T1, T2, and T3, respectively; the predicted Kp,uu in T1 and T2 was consistent with observed Kp,uu in non-enhancing (median, 2.0) and enhancing tumors (median, 10.1) from 12 patients. For abemaciclib, the predicted mean Kp,uu was 0.88, 1.4, 6.2, and 3.1 in normal brain, T1, T2, and T3, respectively; the predicted Kp,uu in T1 and T2 agreed with observed Kp,uu in non-enhancing (median, 2.1) and enhancing tumors (median, 7.2) from 38 patients.

CONCLUSION
The developed PBPK model platform well predicts heterogeneous drug penetration and distribution in normal human brain and different regions of glioblastoma, as verified by ribociclib and abemaciclib. It provides a mechanism-based computational modeling tool to assist the development and design of improved drugs and dosing regimens for more effective treatment of glioblastoma.
DDEL-05. PHARMACOKINETIC ASSESSMENT OF CONVECTION-ENHANCED DELIVERY OF SMALL MOLECULE DRUGS FOR H3 K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Rechberger Julian , Anderson Jacob , Ge Jizhi , Zhang Liang , Daniels David 
Published: November 2023

Abstract
H3 K27-altered diffuse midline gliomas (DMG) are uniformly lethal tumors for which no therapy has been found to be effective. The blood-brain barrier (BBB) restricts uptake and accumulation of systemically administered drugs in the brain. Convection-enhanced delivery (CED) circumvents the BBB by directly infusing therapeutics into the tumor, facilitating homogenous distribution of drugs at high local concentrations with minimal systemic toxicity. However, most drugs given by CED are rapidly cleared from the brain, severely limiting its therapeutic potential. Here, we determine the impact of drug characteristics rather than mechanism of action on compatibility with CED. Various medicinal chemistry prediction models were interrogated to define drug categories predicated on inherent physicochemical properties of the drugs. A panel of FDA-approved drugs with biologically validated activity in DMG were selected for each group: panobinostat/ponatinib, everolimus/topotecan, tolnaftate/tretinoin, and carmofur/eltrombopag. In vivo pharmacokinetic studies of these drugs delivered by CED into the pons of tumor-naïve mice showed that drugs expected to be less likely to undergo active efflux persisted at the site of infusion over prolonged periods of time. Conversely, efflux transporter (ET) substrate drugs were quickly excreted from the brain and readily detectable in the plasma following CED. Based on the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were much higher for ET substrate drugs compared with ET non-substrates, resulting in a significant increase in the residence time (the time spent by drugs in the brain) in the absence of ET-mediated clearance. These properties were further validated in efficacy studies in DMG animal models. The proclivity of many drugs to be rapidly effluxed from the brain after CED generates a vulnerability that can be exploited for the development of novel therapeutic regimens, such as with pharmacokinetics-informed drug selection or concomitant dosing of ET-inhibiting drugs.
DDEL-06. MICROGLIA REPAIR THE DISRUPTED BLOOD-BRAIN BARRIER FOLLOWING LOW-INTENSITY PULSED ULTRASOUND THROUGH P2RY12 SIGNALING
Authors: Habashy Karl , Arrieta Victor , Luan Yu , Kim Kwang-Soo , Dhiantravan Silpol , Najem Hinda , Gomez Mateo , Dmello Crismita , Chen Li , Saganty Ruth , Gould Andrew , Hou Ye , Heimberger Amy , Canney Michael , Stupp Roger , Yue Feng , Sonabend Adam 
Published: November 2023

Abstract
In a phase I clinical trial for patients with recurrent glioblastoma, we used an implantable ultrasound device for low-intensity pulsed ultrasound and microbubbles (LIPU/MB) to open the blood-brain barrier (BBB). This strategy increased parenchymal drug concentrations by 3.7- to 5.9-fold. Magnetic resonance imaging analysis with gadolinium injections at different timepoints post-sonication revealed that the BBB integrity began to restore within an hour post-sonication. To investigate the effect of LIPU/MB, we biopsied sonicated and non-sonicated peritumoral brain regions 45 minutes post-sonication before tumor resection in 7 patients. Single-cell RNA sequencing analysis revealed that sonicated microglia clustered separately and had enrichment of gene ontology terms related to the positive regulation of cell adhesion (p &lt; 2x10-6), wound healing (p &lt; 3x10-5), and regulation of vascular development and angiogenesis (p &lt; 4x10-5). Upregulated genes included IL1B (log2fold-change 2.9, p &lt; 1x10-140), PLAUR (log2fold-change 1.9, p &lt; 2x10-177), and VEGFA (log2fold-change 1.8, p &lt; 1x10-125). We also evaluated the spatial distribution of microglia in sonicated and non-sonicated samples by multiplex immunofluorescence. Analysis of 20 vessels per sample demonstrated that sonicated microglia accumulated around blood vessels, averaging at 14 μm from CD31+ cells, compared to 45 μm in non-sonicated biopsies (p &lt; 0.01). Based on previous reports of P2RY12-dependent microglial migration and repair of the BBB, we evaluated the effect of P2RY12 inhibition with clopidogrel on BBB repair post-sonication in mice. Permeability assay with fluorescein revealed that the BBB was 80% (p &lt; 0.001) and 50% (p &lt; 0.05) more permeable at 10 and 45 minutes post-sonication in clopidogrel-treated mice, respectively. This work provides human data supporting the role of microglia in the repair of the BBB, previously described in animals, and provides preclinical and clinical evidence for the role of these cells in the rapid restoration of vascular integrity post-LIPU/MB in humans.
DDEL-08. THE OMMAYA IN LEPTOMENINGEAL DISEASE AND CENTRAL NERVOUS SYSTEM MALIGNANCIES: A RESERVOIR OF THE PAST OR SOURCE OF THE FUTURE?
Authors: Spirollari Eris , Vazquez Sima , Durkin Daniel , Fliegelman Jacob , Carpenter Austin , Dominguez Jose , Hanft Simon 
Published: November 2023

Abstract
Advances in systemic therapies have increased survival in patients with metastatic cancer. However, such prolonged survival has been associated with increased incidence of leptomeningeal disease (LMD), a late-stage manifestation of cancer to the leptomeninges that carries a dismal prognosis. Circumvention of the blood-brain-barrier to treat LMD can be accomplished with intraventricular therapy using an Ommaya reservoir. Our objective is to determine the indications, efficacy, and future directions of the Ommaya reservoir in LMD and CNS malignancies. A systematic review of the literature was conducted. Data extracted from articles included year of publication, study design, cancer types, and findings. The search query returned 5,338 articles, of which 94 were included. Most articles (45, 47.9%) were prospective cohort studies. Forty-one (43.6%) described retrospective chart reviews, and five (5.3%) described RCTs. Ommaya was studied as a vehicle for intrathecal chemotherapy administration (76, 80.9%), an access site for CSF sampling (12, 12.8%), or a device through which to study dosimetry and pharmacokinetics of various drugs (5, 5.3%). Most studies (50, 53.2%) explored the use of Ommaya in LMD, secondary to any cancer (62%), breast cancer (20%), lung cancer (6%), glioma (6%), lymphoma (4%), and melanoma (2%). Sixteen articles (17%) focused on the use of Ommaya in malignant glioma, 11 studies (11.7%) in CNS lymphoma, and three (3, 3.2%) evaluated the efficacy of intraventricular morphine for intractable cancer pain. Since 2011, 24 studies (64.9%) reported positive outcomes with Ommaya, and two (5.4%) did not. The literature indicates that the Ommaya is a safe and reliable option for treatment of certain malignancies and LMD. The benefit appears to be most marked in the era of multi-modality treatment for cancer, particularly breast. Most recently, and perhaps most promising, is utilization of Ommaya for CSF analysis, both in tracking therapeutic response and defining pharmacokinetics in patients with LMD.