bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDEL-03. ASSESSING THE DEPTH OF DRUG PENETRATION INTO BRAIN PARENCHYMA FROM LOCAL DRUG DELIVERY SYSTEMS IN AN ORTHOTOPIC HIGH GRADE GLIOMA ALLOGRAFT USING ORBITRAP-SECONDARY ION MASS SPECTROMETRY
Authors: Moloney Cara , McCrorie Phoebe , Bastianchich Chiara , Ucakar Bernard , Alexander Cameron , Marlow Maria , Préat Véronique , Rahman Ruman 
Published: November 2022

Abstract
Local intracranial drug delivery for high-grade glioma has been developed over the last two decades with chemotherapeutic agents administered immediately adjuvant to neurosurgery to overcome poor blood brain barrier permeability. In addition to this, the incorporation of nanoparticles (NPs) into local drug delivery systems (DDS) can result in increased penetration of chemotherapeutics through brain parenchyma, transporting the drug further from the administration site than by drug molecule diffusion alone.Here we adopted two model local DDS containing NPs to compare the depth of penetration through brain parenchyma. Approach one consisted of a thermosensitive in situ assembling polymer matrix loaded with polymer-doxorubicin conjugated NPs which can line the resection cavity walls, while approach two consisted of drug-loaded (etoposide and olaparib) poly(lactic acid)-poly(ethylene glycol) polymeric NPs held within a bioadhesive pectin hydrogel and delivered via a spray device.We assessed the efficacy of both DDS at preventing recurrence of high-grade glioma in an orthotopic rat 9L gliosarcoma model following surgical resection. In addition to monitoring long-term survival, the effect of each DDS was measured histologically by H&E and by caspase-1 (inflammatory response) and ki67 (cell proliferation) immunostaining staining. Depth of drug penetration was evaluated on post-sacrificial sections using Orbitrap-Secondary Ion Mass Spectroscopy (OrbiSIMS) and fluorescent microscopy. In vivo data suggests that the delivery mechanism of the NPs affects the efficacy of the DDS, whereby long-term survival was observed in rats treated with the sprayed olaparib/etoposide NP formulation, relative to rats where olaparib/etoposide was simply pipetted into the resection cavity. OrbiSIMS confirmed the presence of doxorubicin, olaparib and etoposide in brain tissue. Our work encourages consideration of mass spectrometry modalities to complement in vivo efficacy studies, as an analytical tool to assess brain distribution of systemically administered drugs, or localised brain penetration of drugs released biomaterial-based DDS.
DDEL-07. DETERMINATION OF TOTAL AND UNBOUND LEVELS OF A POTENT INHIBITOR OF POLY ADP-RIBOSE POLYMERASE, NIRAPARIB, IN HUMAN PLASMA, CEREBROSPINAL FLUID AND BRAIN TUMOR BY A VALIDATED LC-MS/MS ASSAY
Authors: Knight William , Margaryan Tigran , Sanai Nader , Tovmasyan Artak 
Published: November 2022

Abstract

BACKGROUND
Niraparib is an orally available inhibitor of poly ADP-ribose polymerase with high selectivity for PARP1 and PARP2. It is currently approved in the United States for the treatment of ovarian, fallopian tube, and primary peritoneal cancer. Herein we present the development and validation of an LC-MS/MS method for determination of total and unbound levels of niraparib in human plasma, cerebrospinal fluid (CSF) and glioblastoma tissue.

METHODS
Niraparib was extracted from human plasma, CSF and glioblastoma homogenate samples by protein precipitation with methanol. Unbound fractions of niraparib in plasma and brain tissues were determined by equilibrium dialysis. Validation was performed using Sciex ExionLC UHPLC system coupled with Sciex QTRAP 6500+ MS/MS detector using positive electrospray ionization mode. The method was validated according to FDA guidelines and CAP/CLIA regulations.

RESULTS
The method was validated for 1-10,000 nmol/L concentration range using plasma as matrix for all biospecimens. The chromatographic separation was performed on Phenomenex Kinetex™ PS C18 column with total run time of 3.5 min with gradient elution. Maximum coefficient of variation for intra- and inter-day precision was 10.6% and the accuracy was within 92.8-118.5% in all matrices. The analyte is stable in plasma and brain homogenate for at least 6 hours at room temperature (RT) and at least 32 days at -20°C. Stability of stock and working solutions was demonstrated for at least 21 hours (RT) and 41 days (4°C). The fraction unbound of niraparib in human plasma and brain were determined to be 0.15 and 0.05, respectively.

CONCLUSIONS
A sensitive and rapid bioanalytical method is developed and validated to quantify total and unbound niraparib levels in human plasma, CSF and glioblastoma tissue. This method is currently employed to assess plasma pharmacokinetics and CNS penetration of niraparib in newly-diagnosed glioblastoma and recurrent IDH1/2(+) ATRX mutant glioma patients (NCT05076513).
DDEL-15. METHOTREXATE AREA UNDER THE CURVE IN PRIMARY CNS LYMPHOMA
Authors: Moussalli Dana , Vo Anh Huan , Turchan Maria , Fu Rochelle , Ambady Prakash 
Published: November 2022

Abstract

INTRODUCTION
There is consensus that high-dose methotrexate-based (HD-MTX) chemotherapy is the first line treatment for primary central nervous system lymphoma (PCNSL) but there is no consensus on drug dosing and duration. Area under the curve of Methotrexate (MTX-AUC) is a measure of exposure, and we hypothesize that a high MTX-AUC is associated with improved overall survival (OS) and progression free survival (PFS).Method: This retrospective study was approved by the institutional review board. HIV negative PCNSL patients who received Rituximab and HD-MTX at our institution from 2002-2020 were included. HD-MTX dose ranged from 1.2 gm/m2-8 gm/m2 based on creatinine clearance. MTX-AUC was calculated using mtxpk.org. OS and PFS were analyzed using Kaplan-Meier method and Cox proportional hazard regression. Result: 34 PCNSL patient’s charts (mean age: 67 yrs ± 15, 22F/12M) were reviewed. The mean MTX dose (5313 mg/m2) strongly correlated with the mean MTX-AUC (3648 μmol*l−1h, range: 698 – 6634). Patients with MTX-AUC &lt; 3648 μmol*l−1h median PFS is 44.6 months (95% CI: 3.8– non-estimable), not significantly different from patient with MTX-AUC &gt; 3648μmol*l−1h (PFS: 53.2 months, 95% CI: 4.3– non-estimable; P = 0.96). Results were similar after adjusting for patient characteristics in the Cox regression with hazard ratio (HR): 0.84; 95% CI: 0.29–2.43; P = 0.75). The median OS was 44.6 months (95% CI, 12.5– non-estimable) for patients with MTX AUC &lt; 3648 μmol*l−1h and not estimable for patients with MTX-AUC &gt; 3648 μmol*l−1h , HR of 0.43 (95% CI: 0.08–2.33; P = 0.33). Higher KPS prior to chemotherapy was associated with improved PFS/OS with HR: 0.95 (95% CI: 0.93–0.98; P = 0.0006) and HR: 0.91 (95% CI: 0.87–0.96; P = 0.0005) respectively.

CONCLUSION
Our patients PFS and OS is improved compared to historical control but our data suggests that there is no statistically significant association with MTX-AUC in PCNSL.
DDDR-02. CDK4/6 INHIBITION WITH ABEMACICLIB SENSITIZES INTRACRANIAL TUMORS TO CHECKPOINT BLOCKADE IN PRE-CLINICAL MODELS OF BRAIN METASTASIS
Authors: Nayyar Naema , de Sauvage Magali , Sullivan Emily , Chuprin Jane , Yamazawa Erika , Michael Brehm , Brastianos Priscilla 
Published: November 2022

Abstract
Although immune checkpoint inhibitors (ICI) have become a useful tool in the management of central nervous system (CNS) metastases, only a subset of patients experience durable clinical responses and prognosis continues to remain poor. In particular, the role of ICI for CNS metastases from breast cancer has also not been adequately explored. CDK4/6 inhibition has been shown to sensitize extracranial tumors to ICI, and we previously reported intracranial efficacy of combination CDK4/6 inhibition with abemaciclib and anti-PD-1 in preclinical models of melanoma brain metastasis. We have now investigated this combination strategy further in a mouse model of triple negative breast cancer brain metastasis. 4T1 mammary carcinoma cells were first injected into the mammary fat pad and then intracranially 3 days later. While single agent anti-PD-1 antibody or abemaciclib were both ineffective at reducing tumor growth, we found a significant reduction in intracranial and extracranial tumor burden when abemaciclib was combined with anti-PD-1. Immunofluorescence for CD8 and CD3 revealed a significant increase in tumor-infiltrating CD8+ T cells with abemaciclib monotherapy as well as combination therapy in intracranial 4T1 tumors. We observed a similar increase in intracranial tumor-infiltrating CD8+ T cells in two melanoma brain metastasis models, YUMM1.7 and B16-F10, following combination therapy. We conclude that combination with abemaciclib can improve intracranial efficacy of ICI by driving CD8+ T cell infiltration into intracranial tumors. Future work will focus on investigating additional treatment-induced changes in the tumor immune microenvironment and dissecting the effect of CDK4/6 inhibition on T cell activation and function.
DDDR-04. CA-4948 IN COMBINATION WITH BRAF/MEK INHIBITION IN MELANOMA BRAIN METASTASES
Authors: Doonan Bently , Von Roemeling Christina , Archibald Vincent , Klippel Kelena , Elliott Tyler , Matich Erica , Hoang-Minh Lan , Mitchell Duane 
Published: November 2022

Abstract
Melanoma brain metastases (MBM) remain a primary driver of melanoma morbidity and mortality. It is estimated that as many as 60% of all metastatic melanoma patients will develop MBM during the course of their disease. Once found, dual checkpoint inhibitor therapy or BRAF/MEK inhibition in BRAF mutated cancers, are the best options currently available. Even with these treatments, the response to therapy is less than what is seen with disease outside the. In BRAF mutated cancers, which constitute 50% of all patients, initial response to targeted therapy is rapid but resistance to therapy develops 3 months sooner than resistance outside of the brain. Novel strategies to prevent onset of resistance or to work in concert with BRAF/MEK inhibition are needed for this treatment population. The exact mechanism of resistance to targeted therapy in MBM is not known, but mutations in EphA2, PI3K, pAKT, and re-activation of MAPK signaling through secondary mechanisms have all been identified as drivers of resistance. One pathway of MAPK reactivation is through activation of phospho-ERK (eIF2alpha kinase) which also activates the JNK pathway. Our group has previously shown that MBM express high levels of the inflammatory transcription factor IRAK-4, the terminal chaperone of the inflammatory myddosome downstream of TLR and IL1R signally. This increase in IRAK-4 results in constitutive activation of NF-KB, JNK, and MAPK. We have additionally shown the novel oral IRAK-4 inhibitor CA-4948 can reach therapeutically relevant concentrations past the blood brain barrier in both tumor-bearing and naïve mice. We additionally show CA-4948 inhibits MAPK expression in melanoma and suppresses the escape pathways pERK and JNK signaling which can contribute to the prevention of resistance to targeted therapy. This study supports further investigation into the combination potential of CA-4948 with BRAF/MEK inhibitors as triplet therapy to delay intracranial resistance.
DDDR-21. REGULATORY REDUCTASE SUBUNIT RRM2 AND DEHYDROGENASE IMPDH2 INTERACT IN GLIOBLASTOMA IN A TMZ-DEPENDENT MANNER
Authors: McManus Graysen , Perrault Ella , Shireman Jack , Ventarapragada Divya , Lahmadi Linna , Lin Peiyu , Ali Eunis , Park Cheol , Baisiwala Shivani , James David , Ben-Sahra Issam , Pott Sebastian , Basu Anindita , Miska Jason , Ahmed Atique 
Published: November 2022

Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor characterized by poor prognostic outcomes. Nearly all GBM tumors recur, due to cellular resistance against chemotherapies, including temozolomide (TMZ), which develops during active treatment. To investigate these adaptive mechanisms, our lab conducted a single-cell RNA sequencing analysis utilizing an in vivo patient-derived xenograft (PDX) model of GBM, prior to, during, and post TMZ-based therapy. Our data revealed 149 genes to be uniquely expressed in the during-TMZ condition (p &lt; 0.0001), including two regulatory enzymes involved in purine metabolism: the Ribonucleotide Reductase (RNR) Regulatory Subunit 2, RRM2, and inosine monophosphate dehydrogenase 2, IMPDH2. Previous work in this lab has independently established both RRM2 and IMPDH2 as significant drivers of TMZ-resistance in GBM, through their respective abilities to alter tumor metabolism during therapy. Network analysis of genetic pathways enriched during TMZ therapy revealed a previously unidentified interaction between IMPDH2 and the RRM1 subunit of the RNR enzyme. Given these data, we aimed to determine if there was also an interaction between IMPDH2 and RRM2 in GBM. Immunocyto- and histochemistry of GBM-PDX primarily demonstrated significant co-localization between RRM2 and IMPDH2 during TMZ therapy. Immunoprecipitation (IP) and reverse-IP analyses were subsequently conducted, and revealed a previously unreported molecular interaction between the two proteins in GBM lines, which increased in a TMZ-dependent manner. These results were not corroborated in neural stem cell lines. Additionally, immunoblot analyses revealed that in RRM2-knockdown GBM-PDX, IMPDH2 protein expression is decreased compared to controls. We hypothesize the dynamic interaction of RRM2 and IMPDH2 to enhance the metabolic adaptations underlying GBM chemoresistance. The efforts of this study are now focused on investigating the potentially synergistic mechanisms of FDA-approved RRM2 and IMPDH2 inhibitors, previously shown to enhance the efficiency of TMZ. This novel and targetable interaction may present a promising clinical opportunity for GBM therapy.
DDDR-28. EGFR AND SRC-MEDIATED ACTIVATION OF STAT3 DRIVES RESISTANCE TO MITOTIC INHIBITORS IN GLIOBLASTOMA, AND CAN BE REVERSED WITH FDA-APPROVED DRUGS
Authors: Kenchappa Rajappa , Dovas Athanassios , Argenziano Michael , Meyer Christian , Stopfer Lauren , Banu Matei , Pereira Brianna , Griffith Jessica , Mohammad Afroz , Talele Surabhi , Zarco Natanael , Elmquist William F , White Forest , Quaranta Vito , Sims Peter , Canoll Peter , Rosenfeld Steven 
Published: November 2022

Abstract
While the allure of targeted therapies in oncology has been their high degree of specificity and potency for key tumor drivers, they have been disappointing in glioblastoma (GBM), even for drugs that are blood brain barrier permeable and CNS retained. This point is highlighted by the experience with mitotic spindle inhibitors, drugs which block the G2M transition and induce mitotic catastrophe—a phenotype characterized by cell enlargement and polyploidy that leads to apoptotic cell death. We have shown that one of these, a potent inhibitor of the mitotic kinesin Kif11 (ispinesib), is highly active against GBM tumor initiating cells and prolongs survival in murine models of this disease. However, tumors eventually progress, reflecting the development of drug resistance. Although ispinesib resistant GBM cells develop mitotic catastrophe, they become highly resistant to the apoptosis that typically follows and continue to proliferate. We find that this apoptosis resistance requires phosphorylation of the transcription factor STAT3 at two residues—Y705 and S727. Phosphorylation of Y705, mediated by SRC kinase, translocates STAT3 to the nucleus where it induces transcription of anti-apoptotic proteins. Phosphorylation at S727, mediated by EGFR, translocates STAT3 to the mitochondria where it blocks release of cytochrome c—the penultimate effector in apoptosis. Simultaneously inhibiting both SRC and EGFR with FDA-approved, CNS permeant inhibitors reverses this resistance and significantly prolongs survival in ispinesib-treated GBM-bearing mice. Furthermore, we find that resistance to several other mitotic inhibitors also utilizes this STAT3-driven mechanism and can likewise be reversed with combined EGFR and SRC inhibition. Thus, our work demonstrates how a promising therapeutic approach, which has been disappointing in GBM, can in fact be rendered effective by anticipating and prospectively treating ab initio the mechanism that drives treatment resistance.
DDDR-34. RECURRENT RELA FUSION-POSITIVE EPENDYMOMA TREATED WITH VAL-083 UNDER EXPANDED ACCESS: A CASE REPORT
Authors: Kamiya-Matsuoka Carlos , Knight Stephanie , Langlands John , Brown Dennis , Puduvalli Vinay 
Published: November 2022

Abstract
Ependymoma is a relatively rare central nervous system tumor accounting for 2-9 % of all neuroepithelial tumors. RELA fusion-positive ependymoma is a subgroup associated with supratentorial location, higher WHO grade and worse prognosis. In addition, there is no standard systemic chemotherapy treatment for adults with recurrent disease. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA-repair in high-grade gliomas. We report a 40-year-old male who was initially diagnosed with a right parieto-occipital high-grade glioma, with no somatic mutations including IDH1/2 genes, and with unmethylated MGMT promoter status. He initially underwent gross total resection, followed by chemoradiation with concurrent and adjuvant temozolomide for 12 cycles. Sixteen months later, he developed recurrent disease and had a second resection. Inter- and intragenic fusion analysis of tumor tissue revealed C11orf95-RELA fusion and the diagnosis of RELA fusion-positive ependymoma was established. The patient was not eligible to participate in any clinical trial and received VAL-083 under an expanded access program. He was then treated with VAL-083 (30 mg/m2 for 3 consecutive days every 21 days) and completed 12 cycles during a period of 9 months. No grade 3/4 adverse events such as thrombocytopenia, anemia, neutropenia, or lymphopenia were observed. His liver and renal functions were normal. No dose reduction was required. He also received levetiracetam, alprazolam and prochlorperazine, with no drug interactions. Steroid were not required. He has been under surveillance since completion of systemic treatment with VAL-083 and has remained radiologically stable, with no CSF dissemination, after 12 months. This case highlights that VAL-083 may be a treatment option for recurrent RELA fusion-positive ependymoma refractory to temozolomide-based regimens. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for this EAP patient were approved by MD Anderson Cancer Center IRB.
EOLP-01. PALLIATIVE CARE REFERRAL ACROSS THE DISEASE TRAJECTORY IN HIGH-GRADE GLIOMA
Authors: Crooms Rita , Taylor Jennie , Jette Nathalie , Morgenstern Rachelle , Agarwal Parul , Goldstein Nathan , Vickrey Barbara 
Published: November 2022

Abstract

BACKGROUND
Patients with high-grade glioma (HGG), WHO grade 3 or 4, have substantial palliative care needs. As evidence suggests early palliative care consultation (PCC) yields improved quality of life in advanced cancer, our aim was to determine the occurrence, timing, and factors associated with PCC in HGG.

METHODS
Adults with HGG diagnosed between 8/3/2011 and 1/23/2020 were identified retrospectively from a large, academic, multi-center health system cancer registry. Patients were stratified by any prior PCC (yes/no), and timing of PCC by disease phase: (1) diagnosis (before radiation), (2) initial treatment (first-line chemotherapy/radiation), (3) second-line treatment (second-line to last chemotherapy), and (4) end-of-life (after last chemotherapy). Univariate analyses (e.g., Chi-square test) were conducted to compare PCC to non-PCC groups, based on data distribution.

RESULTS
Of 621 HGG patients, 134 (21.58%) received PCC, with 14 (10.45%) referred during phase 1; 35 (26.12%) in phase 2; 20 (14.93%) in phase 3; and 65 (48.51%) in phase 4 with a median of 74 days (IQR 15, 277) from initial PCC to death. The majority of referrals were inpatient (111 (82.84%)). The PCC group did not differ significantly from non-PCC in age, sex, language, race, or ethnicity, but did differ by marital status: single (263 (42.35%) vs 187 (38.4%)), divorced/separated (37 (27.61%) vs 107 (21.97%)), married/civil union (17 (12.69%) vs 154 (31.62%)); (Chi-square p &lt; .01). Compared to non-PCC, more patients in the PCC group had glioblastoma histopathology (89.55% vs. 82.14%, p = .04).

CONCLUSION
A minority of HGG patients ever received PCC, which primarily occurred in the inpatient setting, and half of those referred for PCC received it during the end-of-life phase. Thus, only about one in 10 patients in the entire cohort potentially received the benefits of early PCC. Further studies should elucidate barriers and facilitators to early palliative care in HGG.
EOLP-05. POSTMORTEM TISSUE DONATION: GIVING FAMILIES THE ABILITY TO CHOOSE
Authors: Ramaswamy Vijay , Lyons Nicole , Frenkel Elizabeth , Gerismov Elena , Gustafson Allen , Gustafson Patti , McLean Ginny , Ochasi Aloysius , Waanders Angela 
Published: November 2022

Abstract
To our knowledge, Gift From a Child (GFAC) is the only dedicated consortium providing autopsy resources for children with brain tumors. Using the parental data and the experience of being a multi-institutional post mortem CNS tumor collection program, GFAC seeks to inform medical professionals of the need to approach families about post-mortem donation and demonstrate how barriers to donation can be overcome. Much like the one that occurred for organ donation, a cultural shift is needed with the goal to offer every family the option to donate. Collected survey data shows, 98% of families who donated were satisfied with their decision, compared to 20% of families who did not donate being satisfied with their decision. Most families want to be provided the opportunity to chooseto donate, citing the desire to advance research and help future families. For families who donated, over 71% initiated the donation conversation with their clinician. Among those who did not donate, 58% reported they had not been asked. The healthcare team initiated the donation conversation only 20% of the time for both groups. Without the conversation being initiated, many families remain unaware of the necessity and impact of donation on advancing research. The timing and structure of how donation is brought up impacts if families proceed with donating, however, data shows that withholding this option is frequently more distressing for families. Parent interviews and survey data indicate the majority of families are most open to this conversation once it’s evident a child will not survive and during transition to hospice care. Presentation donation as a driver for research, helping the next child, and as a key step in the family’s grieving process positively correlate with a family’s decision to donate.