bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-40. PSYCHOLOGICAL DOMAINS CORRELATE WITH ADHERENCE IN TTFIELDS TREATMENT OF GLIOBLASTOMA
Authors: Proescholdt Martin , Haj Amer , Schmidmeier Melissa , Muehlberger Andreas , Schmidt Nils-Ole 
Published: November 2024

Abstract

INTRODUCTION
Adherence is critical to the success of the treatment with Tumor Treating Fields (TTFields) for Glioblastoma Multiforme (GBM). Previously found factors influencing treatment adherence in general are social support, belief in the efficacy of treatment, communication with physicians, anxiety, and depression. We propose those five factors predict adherence to TTFields treatment since, to our knowledge, no systematic data exists for this treatment.

METHODS
We conducted a longitudinal study and included 25 patients with newly diagnosed GBM who received treatment with TTFields. Participants were invited to take part in six structured interviews, each four weeks apart, during their treatment with TTFields, assessing the five factors expected to influence treatment adherence over time.

RESULTS
We found a significant impact of communication, anxiety, and depression on treatment adherence with TTFields. Furthermore, also the time point during treatment (days of treatment) was significantly related to adherence. Better physician communication and a higher level of anxiety were associated with higher adherence and higher depression with less adherence. A higher belief in efficacy showed a trend toward significantly improving treatment adherence. When results were separately compared for early, middle, and later 90-day treatment phases, factors seemed to be differentially influential, with belief in efficacy being significantly relevant in the first, efficacy, communication, and anxiety in the second, and depression in the third phase of treatment with TTFields.

CONCLUSIONS
Our findings not only confirm the predictive role of psychosocial factors in treatment adherence but also provide specific targets for psychological interventions. This suggests that by addressing these factors, healthcare providers can potentially increase treatment adherence among GBM patients. Moreover, our results indicate that these interventions may be most effective when tailored to the specific phase of treatment, offering a practical approach for healthcare providers.
CTNI-69. A FIRST-IN-HUMAN FEASIBILITY STUDY TO EVALUATE THE SAFETY OF SELECTIVE YTTRIUM-90 ENDOVASCULAR RADIOTHERAPY IN PATIENTS WITH RECURRENT GBM: INTERIM RESULTS FROM THE FRONTIER TRIAL
Authors: Mouli Samdeep , Ansari Sameer , Middlebrooks Erik , Boockvar John , Weinstein Jonathan , Serulle Yafell , Butowski Nicholas , Narsinh Kazim , Kennedy Paul , Eldridge Amanda , Basarabescu Franco , Elahi-Gedwillo Kianna , Salem Riad , Stupp Roger 
Published: November 2024

Abstract

BACKGROUND
Yttrium-90 (Y90) microsphere treatment is an FDA-approved endovascular radiotherapy for Hepatocellular Carcinoma; however, extra-hepatic experience is limited. The FRONTIER trial (NCT05303467) is a first-in-human study conducted under an IDE from the FDA evaluating the safety and feasibility of intra-arterial Y90 endovascular radiotherapy in patients with recurrent glioblastoma (rGBM).

METHODS
The primary endpoint is the incidence of treatment-related limiting toxicities through 30 days, in 12 patients with rGBM. Eight subjects (50% male) with non-dominant hemisphere rGBM have been enrolled to date, with 6 patients reported herein. The treatment region, encompassing the recurrent lesion, excluding eloquent regions, and defined using cerebral angiography-MRI fusion, was selectively targeted with 40±4Gy. Immediate post-treatment imaging included MRI to evaluate acute treatment-related effects and Y90-PET to evaluate the absorbed dose distribution. Neurological assessments were performed pre- and post-treatment. Analysis of post-contrast T1w enhancing tissue volume (T1wvol) inside and outside the treated region was performed longitudinally.

RESULTS
All patients tolerated the procedure well and were discharged the following day. No decrease in neurological function and no limiting toxicities were reported through 30 days. Post-treatment MRI revealed no device-related acute ischemia or hemorrhage. Mean absorbed dose to the treatment region was 42.1±2.4Gy, within 3% of the targeted value, suggesting technical feasibility. Mean tumor absorbed dose within the treatment region was 65.1±22.6Gy most likely due to increased tumor perfusion in the treatment region. A reduction in T1wvol at 2m was observed in 4/6 patients, with the remaining 2 patients showing increased T1wvol. Disease progression by T1wvol occurred more rapidly outside the treatment region than within. All patients received subsequent therapy, with 2 patients receiving surgery 82 and 120 days post Y90 treatment.

CONCLUSION
Interim results in this first-in-human feasibility study demonstrated technical feasibility and no limiting toxicities through 30 days. Enrollment is ongoing. These data warrant additional investigation.
DNAR-11. INHIBITION OF RAD52 ACTIVITY INDUCES DNA DAMAGE BY ACCUMULATING R-LOOPS IN DIFFUSE MIDLINE GLIOMA
Authors: Uchida Eita , Ishi Yukitomo , Watanabe Jun , Kaur Savneet , Mineji Kentaro , Abdala-Valencia Hiam , Singer Benjamin , Gadd Samantha , Hashizume Rintaro 
Published: November 2024

Abstract
Diffuse midline glioma (DMG) is one of the most devastating childhood cancers with a median survival of &lt; 1year from diagnosis. There is a critical need for new therapeutics for improving treatment outcomes for DMG patients. We performed genome-wide CRISPR/Cas9 screening and identified RAD52 as a potential therapeutic target in DMG cells. RAD52 inhibition, using shRNA-mediated RAD52 depletion and treatment with RAD52 inhibitor, D-I03, suppressed DMG cell proliferation. Western blotting revealed that RAD52 inhibition increased DNA double-starand breaks (DSBs) marker γH2AX while it decreased repair markers BRCA1 and RAD51. Also, RAD52 inhibition causes a sustained level of phosphorylated RAD50 and γH2AX in irradiated DMG cells over 24 hours. Immunocytochemistry (ICC) of γH2AX and repair marker 53BP1 showed that RAD52 inhibition sustained DNA damage with high levels of γH2AX at 24 hours following radiation while the level of 53BPI was decreased, thereby inhibiting DNA DSB repair. DNA repair assay showed that RAD52 inhibition suppressed DNA DSB repair through a homologous recombination pathway. RNA sequencing showed that RAD52 inhibition downregulated genes associated with the DNA repair pathway. Importantly, RAD52 inhibition increased the radiosensitivity of DMG cells. To understand the mechanism of RAD52 inhibition on DNA damage, we performed dot plot assay and ICC of S9.6 which recognizes DNA-RNA hybrids (also known as R-loops) and found accumulation of R-loop formation in DMG cells treated with RAD52 inhibitor. In addition, RAD52 inhibition decreased the expression of RNA polymerase II. Finally, the combination therapy of RAD52 inhibitor and radiation inhibited tumor growth and increased survival of mice bearing DMG patient-derived xenografts, outperforming either monotherapy. Together, our results highlight that RAD52 inhibition induces DNA damage by accumulating R-loops, results in reducing DMG cell proliferation, while also increase DMG radiosensitivty, and providing a rationale for developing combination therapy with radiation for the treatment of DMG.
DNAR-14. MODULATING POPULATIONAL VARIANCE OF METHYL-GUANINE METHYL TRANSFERASE (MGMT) EXPRESSION THROUGH MICRORNA DEGRADATION: A NOVEL MECHANISM OF TEMOZOLOMIDE RESISTANCE
Authors: Singh Gatikrushna , Ramakrishnan Valya , Singh Shilpi , Xu Beibei , Akers Johnny , Jiang Tao , Wei Hua , Ying Mao , Chen Clark 
Published: November 2024

Abstract
O6 methyl-guanine methyltransferase (MGMT) restores alkylated DNA to its undamaged form in a stochiometric manner to prevent the cytotoxic effects of temozolomide (TMZ), a DNA alkylating agent used as a standard-of-care treatment for glioblastomas. We previously demonstrated that he microRNA, miR-181d, post-transcriptionally repressed MGMT expression. Here, we show that treatment of glioblastoma cells with TMZ induced a feed-forward cascade resulting in an ataxia telangiectasia and Rad3 (ATR) and polyribonucleotide nucleotidyl transferase 1 (PNPT1)-dependent degradation of miR-181d. Single-cell analyses revealed such miR-181d degradation induced an: 1) increased mean level of MGMT expression and 2) widened the variance in MGMT expression in the cell population. While the former is known to confer increased population fitness to temozolomide, the importance of the latter is unknown. By mixing cultures derived from isogenic glioblastoma subclones with distinct MGMT expression levels, we generated glioblastoma cell populations with comparable mean MGMT expression levels while differing in the populational variance in MGMT expression (classified as “wide” or “narrow”). Despite comparable mean levels of MGMT expression, the glioblastoma population with wide variance exhibited increased temozolomide resistance relative to the population with the narrow variance, in vitro and in vivo. Transfection of miR-181d into the wide-variance population narrows the variance of MGMT expression and restores TMZ sensitivity to levels comparable to that observed in miR-181d transfected narrow-variance populations. These findings suggest that TMZ-induced miR-181d degradation enhanced TMZ resistance through modulation of both the mean and variance of MGMT expression, mechanisms which may be extrapolated to microRNA biology in general.
DDEL-09. AS1411 APTAMER-CONJUGATED NANOSPHERES FOR TARGETING GLIOBLASTOMA THERAPY
Authors: Kim Chae-Yong , Song Yoon-Kyu , Seo Kyeongjin , Hwang Kihwan , Nam Kyung Mi 
Published: November 2024

Abstract
Postoperative chemotherapy remains essential for treating glioblastoma (GBM), with nanocarrier-based drug delivery emerging as the most efficient method. However, non-specific delivery across the blood-brain barrier (BBB) can limit drug accumulation in tumors and cause damage to nearby tissues. As cancer progresses, angiogenic processes lead to the formation of an irregular blood-tumor barrier (BTB), necessitating nanodrug platforms for precise targeting and efficient drug delivery to cancer cells. In this study, we aimed to demonstrate targeted cancer therapy by selectively identifying tumor cells overexpressing nucleolin (NCL) protein using Dox-loaded AS1411 aptamer-conjugated nanospheres. Drug nanocarriers were synthesized from small molecules with sizes ranging from 100 to 300 nm to facilitate drug delivery. Selective drug delivery and cellular uptake were demonstrated for NCL-positive GBM cells (U87 and U251) compared to NCL-negative normal human astrocyte (NHA) cells. Flow cytometric analysis using FAM dye-labeled AS1411 aptamer-conjugated nanospheres confirmed that drug delivery to GBM U87 and U251 cells was actively targeted by specific AS1411-NCL interactions. Confocal laser scanning microscopy and cytotoxicity analysis confirmed that inoculation of Dox-loaded AS1411 aptamer-conjugated nanospheres induced selective internalization in GBM U87 and U251 cells. Moreover, to evaluate cytotoxicity and anti-tumor effects after treatment with PBS, Apt-Nanospheres, Free Dox, and Dox-Apt-Nanospheres, the results were analyzed through cell counting kit (CCK-8) analysis, evaluation of differences in 3D tumor sphere radii, and an in vivo GBM xenograft tumor model. The AS1411 aptamer-conjugated nanosphere drug delivery system was developed for dual-target treatment of GBM. AS1411-mediated specific recognition and drug accumulation significantly enhanced binding to NCL-positive U87 and U251 cells and improved cytotoxicity efficiency compared to Free Dox. Additionally, this study demonstrated that the active targeting model using aptamer-mediated drug delivery was more effective in improving drug penetration and retention in tumor cells than non-specific enhanced permeability and retention (EPR)-mediated delivery and passive drug delivery.
DDEL-12. LOCAL DELIVERY OF CHEMOTHERAPIES VIA BIORESORBABLE IMPLANT IN MENINGIOMAS
Authors: Youngblood Mark , Hu Ziying , Nandoliya Khizar , Thirunavu Vineeth , Wang Wenxia , An Shejuan , McCord Matthew , Sears Thomas , Gomez Mateo , Tran Anh , Steffens Alicia , Walshon Jordain , McCortney Kathleen , Flowers Mariah , Magill Stephen , Rogers John , Horbinski Craig 
Published: November 2024

Abstract
Many meningiomas recur despite repeated surgical resections and radiation, and patients must undergo progressively morbid surgical procedures due to recurrent or progressive disease. However, unlike most gliomas, meningiomas do not diffusely infiltrate throughout the brain on a single-cell basis, but instead recur and invade locally. Thus, they may be particularly vulnerable to localized chemotherapy. To investigate this, we screened 13 patient-derived primary meningioma cell cultures and two commercially available meningioma cell lines using a library of 147 FDA-approved compounds. We identified drugs with elevated potency across all meningiomas, including bortezomib (mean IC50 = 7nM) and romidepsin (mean IC50 = 18nM), as well as drugs with selective potency against specific samples, such as docetaxel (IC50 range 6nM to &gt;10uM). We reasoned that delivery of a multi-drug cocktail with independent anti-neoplastic mechanisms would provide the strongest therapeutic effect in meningiomas. As systemic treatment with combination agents resulted in severe toxicity in mice, we performed local injection of bortezomib / romidepsin / docetaxel (BRD) triple therapy over 24 days in flank xenografts of IOMM-LEE and CH157 meningiomas. Tumor growth was reduced by 71-88% relative to vehicle (p&lt;0.01), and mice showed no systemic toxicity with local therapy. Notably, the addition of radiotherapy did not further enhance the effect of BRD. To optimize local delivery, we developed a polyanhydride bioresorbable wafer designed to fit in a meningioma resection cavity, analogous to carmustine wafers used in gliomas. Intracranial implantation of wafers caused no local toxicity or inflammation in mice. Docetaxel-loaded wafers prevented the growth of flank-injected IOMM-LEE cells relative to wafers without drug (0 mm3 vs. 230 mm3 at 3 weeks post-injection, N=5/group, p&lt;0.01). Our results demonstrate that bioresorbable wafers containing a cocktail of potent chemotherapies may be an effective new strategy against locally aggressive meningiomas.
DDEL-19. DRUG-TUMOR RESIDENCE TIME DRIVES EFFICACY OF CONVECTION-ENHANCED DELIVERY IN H3 K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Rechberger Julian S , Anderson Jacob B , Ge Jizhi , Zhang Liang , Daniels David J 
Published: November 2024

Abstract
Advancements in understanding H3 K27-altered diffuse midline glioma (DMG) biology have not yet translated into effective therapies for these tumors likely due to delivery challenges across the blood-brain barrier (BBB) and variable tumor genetics. This study systematically probes convective-enhanced delivery (CED) as a means to administer small molecule drugs directly to DMG tumors, circumventing constraints imposed by the BBB. Our findings emphasize the necessity of strategic drug selection and pharmacokinetic analysis in refining CED approaches, advocating for precision medicine techniques specialized for DMG. We demonstrate that while most small molecule drugs are rapidly cleared from the brain following CED, their retention and effectiveness are substantially improved by co-administration of systemic efflux transporter (ET) inhibitors such as everolimus. The synergistic potential of combining everolimus with topotecan or ponatinib offers a novel therapeutic pathway, advocating for further investigation into this DMG management strategy.
DDDR-01. TUMOR ASSOCIATED MACROPHAGES VIS-À-VIS TMZ RESISTANCE IN PTEN-DEFICIENT GLIOMA
Authors: Ni Xiang-rong , Zhang Ji , Yu Yan-jiao , Wang Jing , Chen Fu-rong , hen Zhong-ping C 
Published: November 2024

Abstract
Drug resistance is one of the most important obstacles during chemotherapy. Currently temozolomide (TMZ) is still first line chemotherapy agent for gliomas, while drug resistance is one of the main reasons for chemotherapy failure. It has been reported that tumor-associated macrophages (TAMs) could be related to drug resistance, and thus we have investigated the association between TAMs and TMZ response in gliomas. Firstly, our study have found that PTEN-deficient glioma can specifically induce a large number of M2 phenotype TAMs, which can attenuate the TMZ-mediated the killing effect on glioma cells. Further search for the possible mechanism, we have found TAMs may secrete cytokine IL-6 in PTEN-deficient gliomas, which in turn mediate TMZ resistance. We also revealed that IL-6 highly secreted by TAMs can enhance the stemness of glioma cells through activation of the JAK-STAT3 signaling pathway in PTEN-deficient glioma cells. Secondly, have found valproic acid (VPA) can promote the transformation of TAMs from M2 to M1, reduce its IL-6 secretion, and in turn enhancing sensitivity of TMZ in PTEN-deficient gliomas. Our study revealed that TMZ resistance may modulated through soluble factors released by TAMs. Conventional anti-epilepsy drug- VPA may enhance TMZ sensitivity in PTEN-deficient gliomas, and worth to further clinical investigation. Keywords: PTEN-deficient gliomas; tumor-associated macrophages; valproic acid; temozolomide resistance
DDDR-02. NOVEL MDM4 INHIBITOR CEP-1347-BASED THERAPY FOR P53 WILD-TYPE MALIGNANT MENINGIOMA
Authors: Mitobe Yuta , Suzuki Shuhei , Nakagawa-Saito Yurika , Togashi Keita , Sugai Asuka , Sonoda Yukihiko , Kitanaka Chifumi , Okada Masashi 
Published: November 2024

Abstract

BACKGROUND
Although a significant proportion of meningiomas are clinically aggressive, there is currently no effective chemotherapy for them. An increasing number of studies have been conducted to develop targeted therapies, but none have focused on the p53 pathway as a potential target. In this study, we determined the in vitro and in vivo effects of CEP-1347, a novel small-molecule inhibitor of MDM4 with known safety in humans, on malignant meningioma cells, and also investigated the effects of CEP-1347 when combined with MDM2 inhibition.

METHODS
The effects of CEP-1347 and MDM4 knockdown on the p53 pathway in human meningioma cell lines with and without a p53 mutation were investigated using RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 were investigated in vitro and in a mouse xenograft model of meningioma. We also investigated the effects of CEP-1347 in combination with genetic or pharmacological inhibition of MDM2 in vitro. [Results] CEP-1347 at clinically relevant concentrations inhibited MDM4 expression, activated the p53 pathway in malignant meningioma cells with wild-type p53, and inhibited growth preferentially in cells expressing wild-type p53, which was mostly mimicked by MDM4 knockdown. CEP-1347 effectively inhibited the growth of malignant meningioma xenografts at a dose substantially lower than the maximum dose that could be safely administered to humans. The small-molecule MDM2 inhibitor RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. [Conclusion] Our findings suggest that targeting the p53 pathway with CEP-1347 is a novel and viable approach to treating aggressive meningiomas, with even greater efficacy when combined with MDM2 inhibitors.
DDDR-06. ENHANCING GLIOBLASTOMA TREATMENT WITH MOLYBDENUM DISULFIDE(MOS2) NANOMATERIALS AND ULTRASOUND-TRIGGERED TUMOR GROWTH INHIBITION
Authors: Chen Tse-Yu , Yang Meng-Yin 
Published: November 2024

Abstract

INTRODUCTION
Glioblastoma, known for its high mortality rate and limited treatment options, poses a persistent challenge in oncology. Despite advances in surgery, radiation, and chemotherapy, patient outcomes have seen only marginal improvements, with ongoing issues of high recurrence and low survival rates. The advent of nanotechnology, particularly the emergence of Molybdenum disulfide (MoS2) nanoparticles, offers new perspective in semiconductors, energy storage as well as cancer therapies. With its unique physical and chemical properties, MoS2 nanoparticles might be promising in its potential roles in the battle against cancer. We aimed to see whether ultrasound-treated MoS2 nanoparticles can interfere with growth of glioblastoma cells.

METHODS
MoS2 nanoparticles were added to the medium of glioblastoma cells and ultrasound treatments were given. We monitor the cell count as well as cell migration after the treatments.

RESULTS
MoS2 nanoparticles was found to significantly interfere with tumor cell proliferation and boost the production of reactive oxygen species (ROS). These reactive oxygen species were crucial for the apoptosis of brain tumor cells when in the right concentration. Our analysis also demonstrated that MoS2 impedes cell migration and infiltration, effectively halting tumor expansion. Additionally, Comet assay techniques confirmed extensive DNA damage in the treated cells, highlighting MoS2’s potent DNA-altering capabilities which promote programmed cell death.

CONCLUSION
The implications of these findings are significant, establishing a solid scientific basis for employing MoS2 nanoparticles as a targeted anti-cancer agent for brain tumors. While this study underscores the transformative potential of MoS2 nanoparticles in clinical oncology, it also acknowledges limitations such as the need for further clinical trials to evaluate efficacy and safety in humans. Key Words: MoS2 nanoparticles, Ultrasound treatment, Reactive oxygen species, Comet assay, Programmed cell death
DDDR-13. OPTIMIZING BRAIN CANCER THERAPY: BALANCING TUMOR ERADICATION AND NORMAL TISSUE PRESERVATION WITH BPM31510
Authors: Khojasteh Abbas , Kendirli Mustafa Tansel , Narain Niven , Nagpal Seema , Nastke Maria-Dorothea , Gesta Stephane , Recht Lawrence 
Published: November 2024

Abstract
The challenges translating glioblastoma therapies lie in safeguarding normal neuronal and glial tissue. Considering that the central nervous system has the lowest regenerative capacity, the exclusive focus on tumor eradication while neglecting normal tissue response, impedes proper healing. This oversight leads to toxicities ultimately culminating in patient demise with marginal gain in survival. BPM31510 is a nanodispersion encapsulating highly hydrophobic oxidized Coenzyme Q10 (CoQ10), allowing for delivery of supraphysiological CoQ10 concentrations into cancer cells. Initial investigations demonstrated differential responsiveness between cancer and non-cancer cells in vitro, an effect associated with high superoxide levels exclusively in cancer cells. To evaluate this divergence between cancer and non-cancer cells, a competitive co-culture cell-based assay was developed with labeled pairs of glioblastoma and non-cancer cells incubated up to three weeks with various concentrations of BPM31510 to ascertain optimal concentration leading to preferential growth of non-cancer cells. Human astrocyte (HA), mouse fibroblast (NIH 3T3), and rat astrocyte (TNC1) cells were paired with U251 human glioma, mouse GL261 and rat C6 glioma, respectively. Cell growth and spatial extent of the plate containing non-cancer or tumor cells were monitored every other day. Using doxorubicin as control, no dosage was discerned in which non-cancer cells exhibited advantage over tumor cells (i.e., either cultures became all tumor cells or both cell lines were eradicated). Using various concentrations of BPM31510, we identified an optimal dose in which cancer cells diminished while non-cancer cells predominated, reflected by markedly elevated mitochondrial superoxide levels in cancer cells prior to cell death. A co-culture cell-based assay was developed to identify an optimal dose of BPM31510 with selective preservation of non-cancer cells alongside tumor cell death. This approach elucidates developing a “fine tuning” strategy, wherein BPM31510 is titrated over time, thereby promoting normal tissue and healing, and ultimately leading to superior and prolonged functional outcomes.