bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDEL-03. INTRANASAL DELIVERY OF PDGFRA-TARGETED NANOTHERAPEUTICS FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMA
Authors: Mineji Kentaro , Watanabe Jun , Uchida Eita , Kaur Savneet , Zhang Peng , Hashizume Rintaro 
Published: November 2024

Abstract
Pediatric high-grade glioma (pHGG) is the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the brainstem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of nanoliposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the effect of anti-PDGFRA monoclonal antibody-conjugated immunoliposome encapsulated SN-38 (PDGFRA-iLS-SN-38) in pHGG cell lines. PDGFRA signals were assessed in pHGG cells using western blotting. Cells were treated with rhodamine (Rho)-labeled PDGFRA-iLS and cellular uptake was confirmed with a fluorescent microscope. PDGFRA-iLS-SN38 had the additive effect on the LS-SN-38 in DIPG007 cells (PDGFRA positive), but not in SF8628 cells (PDGFRA negative) in vitro. We treated mice bearing human DMG xenografts with IND of PDGFRA-iLS-SN38. Tumor growth and response to therapy are quantitatively measured by bioluminescence imaging, and efficacy is assessed by survival analysis. Results of survival analysis will be reported at the meeting. PDGFRA-targeted nanotherapeutics represented a specific effect on glioma cells expressing PDGFRA, providing a promising therapeutic approach for targeting pHGG.
DDEL-07. EFFICACY OF TEMOZOLOMIDE IN MEDULLOBLASTOMA PATIENTS: REVIEW OF SERIES OF TWO ADULT PATIENTS WITH RECENT UPDATES IN LITERATURE
Authors: Raval Ruchi , Desai Khushi , Raval Aarya , Behl Jaspreet , Raval Om , Gor4ty Aishwarya , Parikh Sakshi , Parikh Krishna , Gupta Meher , Raval Sumul 
Published: November 2024

Abstract
Medulloblastoma is a primary malignant CNS tumor commonly seen in children and rarely in adults (20% vs 1% of all primary brain tumors). Maximal safe resection and craniospinal irradiation followed by adjuvant chemotherapy have proven to be an effective treatment in children. Due to insufficient data available in adult patients, it is also the usual approach in them despite unclear long-term outcomes. Standard chemotherapeutic regimens consisting of vincristine, cisplatin, and lomustine are known to cause greater toxicity in adults making adequate dose titration a challenge. Temozolomide is a second-generation cytotoxic alkylating agent with favorable CNS penetration. It is a potential alternative that has yielded superior results in treating gliomas and preventing recurrence along with minimal toxicity. We discuss a series of two adult medulloblastoma cases which were given 24 cycles of Temozolomide monotherapy over two years following surgical resection and craniospinal irradiation. Serial MRIs did not report any signs of recurrence rendering one case cancer-free for seventeen years and the other for ten. Minimal toxicity in the form of nausea, vomiting, headache, and reversible, temporary pancytopenia was seen in contrast to other agents. Improved survival with minimal toxicity was demonstrated in both cases proving the efficacy of Temozolomide as adjuvant chemotherapy for adult Medulloblastoma. While a regimen of Temozolomide is recommended for recurrent Medulloblastoma, there is no optimal regimen available for initially diagnosed, localized tumors, especially in adults. Multi-institutional clinical trials are required to study its role as a monotherapy during an early yet critical phase of management.
DDEL-08. MEGADOSE BOSWELLIA SERRATA CAUSES SIGNIFICANT DECREASE IN CEREBRAL EDEMA WITH MINIMAL TOXICITY IN BRAIN TUMOR PATIENTS
Authors: Carrillo Jose , Wagle Naveed , Sharma Akanksha , Nguyen Minhdan , Truong Judy , Mauritson Emmaline , Kong Janet , Katz Samuel , Carrillo Cole , Carrillo-Singh Yash , Kesari Santosh 
Published: November 2024

Abstract
Boswellia serrata has been shown to reduce cerebral edema following radiation in brain tumors by Kirste et al in a prospective, randomized, placebo-controlled, double-blind pilot trial. In the study dose of Boswellia used was 4200mg/day, and was well tolerated. We report 2 patients who took doses 10x that which was recommended, after inadvertently buying much higher doses online. Both patients obtained significant reduction in cerebral edema and enhancing disease on MRI. The daily dose of 42000mg/day was tolerated well, with only mild dysphonia in one patient. The optimal dosing of Boswellia serrata to treat cerebral edema is not known, and should be studied further.
DDEL-15. PHARMACOKINETIC ANALYSIS OF CARBOPLATIN AND FLUORESCEIN BRAIN PENETRATION AND PERMANENCE FOLLOWING ULTRASOUND-BASED BLOOD-BRAIN BARRIER OPENING ON GLIOBLASTOMA CLINICAL TRIAL
Authors: Habashy Karl J , Synold Tim , Feng Ye , Kim Kwang-Soo , Gomez Cristal , Amidei Christina , Ward Rachel , VanderMolen Sarah , Zarrieneh Ashkan , Arrieta Victor A , Fares Jawad , Burdett Kirsten B , Zhang Hui , Dmello Crismita , Chen Li , Bebawy John F , Canney Michael , Stupp Roger , Portnow Jana , Sonabend Adam M 
Published: November 2024

Abstract
The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving drug delivery to the brain. The implication of this transient BBB opening on parenchymal drug permanence is unknown. We compared the parenchymal levels and permanence/retention of temozolomide, carboplatin, and fluorescein, and investigated in a clinical trial (NCT04528680) the effect of LIPU/MB on the permanence of carboplatin and fluorescein in the human brain. Four patients underwent intraoperative LIPU/MB (SonoCloud-9, Carthera) with intravenous carboplatin and fluorescein infusion. Microdialysis catheters were implanted into sonicated and non-sonicated brain for continuous drug measurement over 24 hours. Published data from a microdialysis study of temozolomide were used for comparison. Temozolomide and carboplatin exhibited similar brain-to-plasma AUC ratios (17.8 ± 13.3%; 16.3 ± 8.2%, respectively) which were higher than that of fluorescein (10.4 ± 6.9%). Parenchymal half-life was the longest for fluorescein (13.6 ± 11.0 hours), followed by carboplatin (5.1 ± 1.9 hours) and temozolomide (2.9 ± 1.6 hours). LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in AUC for both carboplatin (P = 0.02), and fluorescein (P = 0.04), and higher parenchymal than systemic drug levels starting at 21 hours and 7 hours for these drugs respectively (P &lt; 0.05), timepoints where these drugs had mostly cleared from the plasma. Fluorescein exhibits prolonged permanence in the brain parenchyma and may be “trapped” by the BBB. In the context of transient BBB opening by LIPU/MB, parenchymal carboplatin and fluorescein concentrations remain elevated over time, supporting the notion that the BBB exhibits a bi-directional restriction of drug passage. Future studies are warranted to explore the efficacy of drug trapping to achieve prolonged/sustained exposure of cytotoxic drugs for brain tumor therapy.
DDEL-16. MICROMESH FOR REVAMPING THE ‘COLD’ TUMOR MICROENVIRONMENT IN GLIOBLASTOMA IMMUNOTHERAPY
Authors: Palange AnnaLisa , Guerriero Irene , Estevez Ana Maria Lopez , Pesce Cristiano , Spano’ Raffaele , Mascolo Daniele Di , Decuzzi Paolo 
Published: November 2024

Abstract
High-grade gliomas have poor prognoses with limited treatment options, typically maximal safe resection and adjuvant radiochemotherapy. Novel therapies often face challenges due to low brain penetrance and poor bioavailability. To address these issues, a conformable, compartmentalized polymeric implant called microMESH has been developed. microMESH provides localized, sustained release of drugs, small inhibitors, antibodies, and nanomedicines, enabling novel therapeutic combinations. When applied to the tumor margins, microMESH adheres to the tissue, releasing its therapeutic cargo over weeks and reducing systemic toxicity. Its biocompatibility, cytotoxicity, and anti-tumor efficacy were tested on murine cancer cells (CT-2A) and orthotopic glioblastoma syngeneic models. Exposing primary bone marrow-derived monocytes (BMDM) to CT-2A conditioned medium increased the expression of anti-inflammatory cytokines (IL-10 and IL-4) by 2 times without significantly affecting the pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), indicating that CT-2A cells tend to establish an immunosuppressive ‘cold’ tumor microenvironment. Next, the co-incubation of CT-2A cells with BMDM followed by the administration of the immune checkpoint inhibitor aCD47 resulted in a cancer cell viability drop by 50% already at 50 μg/ml aCD47 after 1 day. Additionally, pre-treatment with docetaxel (DTXL) further decreased cell viability, suggesting a synergism between aCD47 and the chemotherapeutic drug. Flow cytometry showed that 50 nM DTXL at 3 days post-incubation was responsible for a strong translocation of the ‘immunogenic dell death’ protein calreticulin on the cell membrane, potentially explaining the synergism. Over 2 months, the intracranially deployed microMESH biodegraded without inducing any toxic effect. In orthotopic CT-2A tumors, aCD47/DTXL–microMESH (0.75 mg/kg, single intracranial application) showed a 40-day survival compared to 22 days for iv DTXL (3 mg/kg qod), 24 days for ip aCD47 (5 mg/kg qod), and 18 days for untreated mice. microMESH helped identify and enabled novel combination therapies directly at the tumor bed, demonstrating superior efficacy over systemic therapies.
DDDR-03. DEVELOPMENT OF ANTI-TUMOR AROMA THERAPY FOR GLIOBLASTOMA WITH LEMONGRASS ESSENTIAL OIL
Authors: Saito Norihiko , Hirai Nozomi , Koyahara Yuki , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Ito Keisuke , Iwabuchi Satoshi 
Published: November 2024

Abstract

INTRODUCTION
Aroma essential oils apply to cancer therapy because of their immune-enhancing and sedative effects, and their ability to reduce the side effects of chemotherapy. Recently, aroma essential oils have also been reported to have anti-tumor effects. We investigate the anti-tumor effects of aromatic compounds contained in essential oils as a novel treatment for glioblastoma. In this study, we analyzed the antitumor effect of lemongrass essential oil and investigated its antitumor aroma therapy for glioblastoma. methods and

RESULTS
Human glioblastoma cells (U87, T98G) and mouse brain tumor cells (RSV-M) were used in the study. Tumor cells were cultured in the presence of lemongrass essential oil for 72 hours, and the growth inhibitory effect was observed, suggesting that the evaporated lemongrass essential oil components acted on tumor cells in the vicinity. In addition, a similar effect was observed with citral alone, which is the main component of lemongrass. Analysis of the effects of citral revealed that citral strongly binds to MARK4 and inhibits its enzyme activity, and that citral decreases the phosphorylation of tau protein. Next, a mouse brain tumor model with RSV-M was established, and the anti-tumor effect of lemongrass essential oil was studied. The results showed that the mice that inhaled lemongrass essential oil for 12 h/day had a significantly prolonged survival period compared to the control group.

DISCUSSION
Citral is the main component of lemongrass essential oil, which contains 70-80% of lemongrass essential oil. This study suggests a mechanism of inhibition of tumor cell proliferation by citral in malignant gliomas. Citral is a volatile monoterpene, and its anti-tumor effect was demonstrated by diffusion through evaporation.

CONCLUSION
Citral in lemongrass essential oil shows anti-tumor effects and is expected to be applied to a new glioblastoma therapy using “aroma”
DDDR-16. SORTING TO ENRICH FOR CHEMOTHERAPEUTIC-RESISTANT GLIOMA CELLS BASED ON UNIQUE MEMBRANE PROPERTIES
Authors: Dang Vi , Jiang Alan , Hanamoto J Nicole , Lav Nicole , Bota Daniela , Flanagan Lisa 
Published: November 2024

Abstract
Glioblastoma, astrocytoma, and oligodendroglioma comprise a class of aggressive and deadly brain tumors called diffuse gliomas. Around 20,000 glioma cases are diagnosed yearly in the US alone. The current standard chemotherapy treatment, temozolomide (TMZ), is insufficient as the 5-year survival rate of glioblastoma patients is as low as 8%. This is due to the presence of TMZ-resistant cells within tumors that lead to chemoresistance and tumor recurrence. Thus, studying the molecular properties of TMZ-resistant cells would enable more effective means of targeting them and thus improve patient outcomes. We leveraged dielectrophoresis (DEP), a phenomenon by which non-uniform electric fields induce differential movement of cells, as a novel label-free technique to sort glioma cells based on their membrane electrophysiological properties. We were able to successfully use DEP to sort cells from glioblastoma and oligodendroglioma established cell lines, which yielded fractions that differed in membrane capacitance, the membrane’s ability to store charge. Interestingly, the DEP-sorted cell fractions also exhibited significant differences in TMZ resistance, indicating that we were able to use DEP to enrich for TMZ-resistant cells. Further, the differences in TMZ resistance were coupled with their membrane capacitance differences. Because we previously found that changes in membrane capacitance were linked to differences in glycosylation, we utilized lectin analysis to assess glycan expression of DEP-sorted oligodendroglioma cells. Our data show that TMZ-resistant oligodendroglioma cells enriched from DEP sorting had reduced levels of mannose glycans compared to less TMZ-resistant fractions. Collectively, our novel findings demonstrate (a) TMZ-resistant glioma cells can be enriched by DEP, and (b) TMZ resistance is correlated with membrane capacitance and cell surface glycosylation. These findings could enable further characterization of TMZ-resistant cells to better understand molecular mechanisms of TMZ resistance and the development of more effective treatment strategies for gliomas through targeting membrane properties such as glycosylation.
DDDR-19. PHARMACOSCOPY FOR BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER (NSCLC)
Authors: Le Rhun Emilie , Mena Julien , Lee Sohyon , Festl Yasmin , Buck Alicia , Voglis Stefanos , Zeitlberger Anna Maria , Weiss Tobias , Serra Carlo , Neidert Marian , Regli Luca , Weller Michael , Snijder Berend 
Published: November 2024

Abstract
Brain metastases remain a common and important complication in the course of disease in patients with non-small cell lung cancer (NSCLC). While targeted therapies and immunotherapies have led to prolonged disease control in subsets of patients with brain metastases from NSCLC, there is still an urgent need for novel treatments after failure of these standards and after exhaustion of local therapies including surgery and radiotherapy. Here we performed an explorative feasibility study to profile ex vivo drug sensitivities across a large panel of classical anti-cancer as well as neuroactive drugs, using an automated imaging platform called “pharmacoscopy”. The anti-cancer drug panel included chemotherapies and targeted therapies such as receptor tyrosine kinase, cyclin dependent kinase, and BCL2 inhibitors. The neuroactive drug panel included antidepressants and antipsychotics. A total of 19 samples from 17 patients were dissociated after surgery and incubated with drugs for 48 hours ex vivo to measure drug sensitivities. Patient cancer cells were identified by immunofluorescence using EpCAM, TTF-1, or CK7 as markers whereas immune cells were identified by CD45. On-target drug activity (pharmacoscopy score) was measured by quantifying the specific reduction of cancer cells upon drug treatment. Among the top ranking drugs ex vivo, several patient samples displayed on-target responses to candidate targeted therapies such as the CDK4/6 inhibitor abemaciclib, the BCL2 inhibitor venetoclax, and the MEK inhibitor cobimetinib as well as unexpected sensitivies to certain neuroactive drugs. Integration of pharmacoscopy results with molecular data from next generation sequencing in the respective brain metastases tissues is ongoing. Overall, this study demonstrates the feasibility of pharmacoscopy-based functional drug testing in NSCLC brain metastases, and highlights novel opportunities of personalized treatment for future exploratory clinical studies in patients with brain metastases from NSCLC.
DDDR-23. DECODING GLIOBLASTOMA DRUG RESISTANCE DYNAMICS USING NOVEL MICROFLUIDIC EX VIVO MODELS
Authors: Pun Sirjana , Krummel Daniel Pomeranz , Sengupta Soma , Barrile Riccardo 
Published: November 2024

Abstract
Glioblastoma (GBM) is clinically challenging due to its aggressive nature and limited treatment options. Current standard of care involves surgical resection and chemoradiation with temozolomide (TMZ). GBM, however, often returns post-treatment fueled by its complex biology and the presence of resilient GBM stem cells. Compounding the issue is the blood-brain barrier, which poses a formidable obstacle to drug delivery into the brain. Understanding the molecular dynamics post-therapy within the brain, influenced by the tissue microenvironment, is key for developing more effective therapeutic strategies. Unfortunately, existing research models have fallen short in capturing the complexity of GBM and its response to treatment. While animal models have been a mainstay in GBM research, their ability to predict human responses has been called into question, highlighted by the disappointing results seen in clinical trials. We are therefore advancing bioprinting-based approaches for modeling various components of the tumor microenvironment to gain insight into mechanisms of drug resistance. We report on the development of three novel microfluidic platforms to investigate and interrogate GBM biology. First, we have developed a novel microfluidic model of GBM, termed GlioFlow-3D, produced through a combination of 3D printing methods. GlioFlow-3D mimics specific aspects of the perivascular niche, including protection from circulating TMZ. Second, we have adapted GlioFlow-3D as part of a platform to investigate advanced ultrasound techniques for delivering novel therapeutics into the human brain. Third, we are developing a novel approach aimed at exploring the relationship between the brain extracellular matrix and tumoral cells using bioprinting of living tumor organoids obtained from patients with a history of recurrence. By integrating bioprinting technologies with patient-derived models to create novel ex vivo platforms, we aim to obtain new insights into the intricate dynamics of drug resistance in GBM, ultimately paving the way for more effective therapeutic strategies. Funding: The Brain Tumor Center Research Award (UCGNI) The ARC Project - CCHMC and UC joint Research Award
DDDR-24. REAL WORLD EXPERIENCE USING THE IDH INHIBITOR IVOSIDENIB IN IDH MUTANT GLIOMA: TOLERABILITY AND OUTCOMES
Authors: Lanman Tyler , Youssef Gilbert , Huang Raymond , Rahman Rifaquat , DeSalvo Matthew , Flood Thomas , Hassanzadeh Elmira , Lang Min , Lauer Jason , Potter Christopher , Miller Julie , Cahill Daniel P , Botero Juan Pablo Ospina , Nakhate Vihang , Stec Natalie , Shi Diana , Bi Wenya Linda , McBrayer Samuel , Arrillaga-Romany Isabel , Lee Eudocia , Chukwueke Ugonma N , Nayak Lakshmi , Forst Deborah , Gerstner Elizabeth , Jordan Justin T , Dietrich Jorg , Batchelor Tracy T , Reardon David A , Wen Patrick , Castro Luis Nicolas Gonzalez 
Published: November 2024

Abstract

BACKGROUND
Mutant isocitrate dehydrogenase (IDHm) inhibitors represent a novel therapeutic strategy for treating IDHm glioma, though their optimal use outside of clinical trials remains undefined. This study describes real world utilization of the IDH1 inhibitor, ivosidenib, in patients with IDHm glioma.

METHODS
We retrospectively reviewed clinical and radiographic data from IDHm glioma patients treated with ivosidenib monotherapy at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2020-2024. Patients with a baseline MRI at ivosidenib initiation and at least 2 subsequent scans while on ivosidenib were included in radiographic response analysis (452 scans).

RESULTS
This cohort included 77 patients (39 males) age 17-75 years (median 41). Thirty-eight patients (49%) had astrocytomas and 39 (51%) had oligodendrogliomas; 48 (62%) had grade 2, 26 (34%) grade 3, and 3 (4%) grade 4 gliomas. Twenty-four patients (31%) received ivosidenib as first-line therapy and 53 (69%) received ivosidenib after failing prior treatments. Among those in the radiographic analysis, 4 (6%) demonstrated partial response, 4 (6%) minor response, 44 (62%) stable disease, and 19 (27%) progressive disease (PD). Significantly higher PD rates were seen in those with enhancing disease (p&lt;0.001) or received ivosidenib as subsequent-line therapy (p=0.002); PD rate was similar between grades 2 and 3 in the first-line group (p=0.64). One-year progression free survival was 100% in the first-line group and 66% in the subsequent-line group. At the time of our analyses, 4 patients (5%) had died (all in the subsequent-line group). Infrequent side effects included CK elevation, QTc prolongation, transaminitis, and diarrhea. One patient (1%) was dose reduced and 3 (4%) discontinued drug due to side effects.

CONCLUSIONS
In this real world IDHm glioma cohort, ivosidenib was well-tolerated. Better response rates were seen in patients without enhancing disease at ivosidenib initiation and those who received the drug as first-line therapy.