bluuebunny/crossref_metadata_2025 huggingface dataset:
SURG-27. DIRECTIONALLY NON-ROTATING ELECTRIC FIELD THERAPY (DNEFT) DELIVERED THROUGH IMPLANTED ELECTRODES: A NOVEL SURGICAL PLATFORM FOR GLIOBLASTOMA IMMUNOTHERAPY
Authors: Ma Jun , Singh Shilpi , Li Ming , Seelig David , Molnar Gregory , Wong Eric , Dhawan Sanjay , Kim Stefan , Helland Logan , Chen David , Tapinos Nikos , Lawler Sean , Singh Gatikrushna , Chen Clark
Published: November 2024

BACKGROUND

While directionally rotating Tumor Treating Fields (TTF) therapy has garnered considerable clinical interest in recent years, there has been comparatively less focus on directionally non-rotating electric field therapy (dnEFT).

OBJECTIVE

Here, we explore dnEFT generated through implanted electrodes as a glioblastoma therapeutic platform, with the goal of facilitating clinical translation.

METHODS

Using custom-designed electrode arrays to study the effect of dnEFT using in vitro and in vivo glioblastoma models.

RESULTS

In vitro, dnEFT generated using a clinical grade spinal cord stimulator showed anti-neoplastic activity against independent glioblastoma cell lines. In support of the results obtained using the clinical grade electrode, dnEFT delivered through a customized, two-electrode array induced glioblastoma apoptosis. To characterize this effect in vivo, a custom-designed four-electrode array was fabricated such that tumor cells can be implanted into murine cerebrum through a center channel equidistant from the electrodes. After implantation with this array and luciferase expressing murine GL261 glioblastoma cells, mice were randomized to dnEFT or placebo. Relative to placebo treated mice, dnEFT reduced tumor growth (measured by bioluminescence) and prolonged survival (median survival gain of 6.5 days). Analysis of brain sections following dnEFT showed a notable increase in the accumulation of peri-tumoral macrophage/microglia with increased expression of M1 genes (IFNγ, TNFα, IL-6) and decreased expression of M2 genes (CD206, Arg, IL-10) relative to placebo tumors.

CONCLUSIONS

Our results suggest therapeutic potential in glioblastoma for dnEFT delivered through implanted electrodes as a novel immunotherapy platform, supporting the concept of a proof-of-principle clinical trial using commercially available deep brain stimulator electrodes.
SURG-29. EXTENDED RESECTION IMPROVES PATIENT SURVIVAL OUTCOMES AFTER GROSS-TOTAL RESECTION OF GLIOBLASTOMA
Authors: Tanaka Kazuhiro , Nagashima Hiroaki , Yamanishi Shunsuke , Muragaki Yoshihiro , Sasayama Takashi
Published: November 2024

In recent years, the effectiveness of extended resection (ER) beyond the contrast-enhanced (CE) lesion has been reported as a surgical strategy for glioblastoma. This study was to determine whether ER of FLAIR-hyperintense area beyond the CE tumor affected the overall survival (OS) and progression-free survival (PFS) of patients with glioblastoma after gross-total resection (GTR). From October 2019 to March 2022, a total of 62 patients who underwent resection of glioblastoma (GBM) at Kobe University Hospital were retrospectively examined. Volumetric measurements of the CE area and surrounding FLAIR-hyperintense area were performed, and clinical variables related with OS and PFS were analyzed. In total, 33 patients with GBM who underwent GTR of the CE tumor met the inclusion criteria. The mean volume of CE tumor and FLAIR hyperintensity area before resection was 36.5 cm3 and 77.2 cm3 respectively. The mean excision rate of FLAIR-hyperintense area was 18.2%. Removal rates of 20% or more in the FLAIR-hyperintense region significantly increased OS and PFS (p=0.040 and 0.026, respectively). In multivariate analysis, age ≥ 65 years (HR 2.73; 95% CI 1.09–7.22; p=0.032) were associated with shorter OS, but ER ≥ 20% (HR 0.41; 95% CI 0.17–0.99; p=0.049) and MGMT promotor methylation (HR 0.36; 95% CI 0.15–0.85; p=0.020) were associated with longer OS. ER of FLAIR-hyperintense lesions of 20% or more in glioblastoma contributed to prolonging patient survival. It is necessary to validate the effect of ER in prospective clinical trials.
SURG-30. SURVIVAL AND OUTCOMES ANALYSIS OF PATIENTS TREATED WITH LASER INTERSTITIAL THERMAL THERAPY FOR LARGE-VOLUME GLIOBLASTOMA
Authors: Berke Chandler , Knott Maxon , Shah Khushi , Khalafallah Adham , Rivera Cameron , gurses muhammet , Shah Ashish , Komotar Ricardo , Iva Michael
Published: November 2024

INTRODUCTION

Laser interstitial thermal therapy (LITT) has shown increased patient survival and outcomes in glioblastoma multiforme (GBM). However, its safety and survival in large-volume GBM tumors has been poorly elucidated.

OBJECTIVE

To evaluate the use of LITT in large-volume GBMs.

METHODS

A retrospective cohort of adult patients with grade IV IDH-wt GBM measuring ≥ 10 cm3 who were treated with LITT was compared to a control group with volumes <10 cm3. A Kaplan-Meier analysis, followed by a Cox-proportional hazards model with overall survival (OS) as the timeline and death as the event, were performed with volume group, mFI-11 score, 30-day readmission, age at surgery (AOS), recurrent vs. primary lesions, and EOA as covariates.

RESULTS

The cohort consisted of 46 large-volume patients (mean: 22.0 cm3, STD: 10.8) with a mean age of 63 years and 57% male predominance, compared to 41 controls (mean: 4.4 cm3, STD: 2.8). Lesions were primary in 78% and 60%, and recurrent in 22% and 40%, of the large and small-volume groups, respectively. Kaplan-Meier analysis showed no significant survival difference between the large (OS=245 days) and small-volume (OS=358 days) groups (p=0.261). No covariate showed significant risk of hazard in the large compared to small-volume cohorts (p>0.05). Across the entire cohort, mFI-11 score, recurrent lesions, and EOA showed no significance as individual predictors of death (p>0.25). AOS (p<0.005) and 30-day readmission (p<0.005) showed significantly increased hazard for the entire cohort. Importantly, volume group did not significantly increase hazard (1.16 [0.68, 1.98], p=0.60).

CONCLUSION

This is the first study evaluating the safety and efficacy of LITT in large-volume GBMs, specifically, with a larger cohort than any existing analysis sub-grouped by volume. We show LITT can be safe and efficacious, without significantly increased mortality compared to in small-volume GBMs.
SURG-33. INTRAOPERATIVE ULTRASSOUND X SODIUM FLUORESCEIN FOR GLIOMA SURGERY: WHICH IS BETTER?
Authors: Campos Paiva Aline Lariessy , Araujo João Luiz Vitorino , Lovato Renan Maximillian , Santos Gabriel José dos , de de Mendonça André Luca Barongeno , de Andrade Hallison Rodrigues , de Oliveira Jean Gonçalves , Veiga José Carlos Esteves
Published: November 2024

BACKGROUND

Improve quality of life with a maximum surgical resection is the main goal of neurosurgeons. A better delimitation of intrinsic brain tumors are required for achieving a maximum tumor removal. There are several technologies that may help. Considering two of them that have an easier access and are cheaper, we compared a high definition ultrasound (BK 3000) and sodium fluorescein (SF) during glioma surgeries.

METHODS

Adult patients with main radiological hypothesis of low or high grade glioma were included in a PhD study previously approved by ethics committee. 3-5mg/kg of SF was administered by intravenous infusion during anesthetic induction. An specific craniotomy transducer was used in all cases. All procedures were guided by the same neurosurgeon.

RESULTS

High definition ultrasound allows an excellent tumor delimitation in high and low grade tumors. However the gray scale and distinction of brain structures and residual lesion was difficult for surgeons who are not habituated to ultrasound use. SF did not help low grade glioma removal, and in these cases ultrasound were superior. Increased fluorescence is easily detected when compared to ultrasound information’s. For small residual tumor, SF helps more than US. For both technologies, when the surgical site had blood, the evaluation about grade of resection is not accurate because in ultrasound appears a posterior shadow and considering SF it seems that there are not further tumor because blood does not have increased fluorescence.

CONCLUSIONS

US showed superiority for low grade gliomas resection. Considering high grade, both technologies helps in different moments during the surgery and are complimentary. We used an specific probe for neurosurgery that has high quality and allowed detailed evaluations. These technologies helps surgeons take quick decision and optimized brain tumor removal. The neurosurgeon should be more familiar to US images because provide a real time evaluation with low cost. KEY WORDS: ultrasound; fluorescein; gliomas; brain tumors
SURG-40. PEDIATRIC LOWER GRADE GLIOMA SURGERY IN THE ERA OF GENOMIC MEDICINE
Authors: Gomi Akira
Published: November 2024

INTRODUCTION

In the 2021 WHO Brain Tumor Classification, pediatric-type gliomas are distinctly categorized from their adult counterparts. The continual evolution of cancer genomics has significantly broadened the spectrum of available treatment options. Here we would like to consider surgery for pediatric low-grade gliomas.

METHODS

We retrospectively analyzed 41 cases of low-grade gliomas or glioneuronal tumors in pediatric patients who underwent surgery at our institute from 2002 to 2023. We discussed surgical strategies based on molecular classification.

RESULTS

Among the cases, there were 34 gliomas and 7 glioneuronal tumors. According to the new WHO classification, they corresponded to 1) Adult-type diffuse gliomas, 2) Pediatric-type diffuse low-grade gliomas, 3) Circumscribed astrocytic tumors, or 4) Glioneuronal and neuronal tumors. Cases without molecular diagnosis were also considered in light of the new WHO classification. Among molecularly diagnosed astrocytomas involving the cerebral hemisphere, brain stem, spinal cord, there were no cases of 1), and 2) 3) were the main cases. It is important in surgical selection to note that these cases generally have a more favorable prognosis compared to the adult type and have usefulness in diagnosing MAPK pathway abnormalities leading to the selection of molecularly targeted drugs. 3) includes pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma. Among these, in the treatment of pilocytic astrocytoma of the visual tract and hypothalamus, biopsy is essential for molecular diagnosis and therapeutic agent selection. 4) is mainly an epilepsy-related tumor. While their removal contributes to genetic diagnosis and epileptic seizure control, total removal may not always be deemed necessary.

CONCLUSION

Based on the new WHO classification, a reevaluation of treatment strategies for pediatric brain tumors is necessary.
SURG-42. THE T1/T2 RATIO IS ASSOCIATED WITH RESECTABILITY IN PATIENTS WITH IDH-MUTANT ASTROCYTOMAS CNS WHO GRADES 2 AND 3
Authors: Weller Jonathan , de Dios Eddie , Katzendobler Sophie , Corell Alba , Dénes Anna , Schmutzer-Sondergeld Michael , Javanmardi Niloufar , Thon Niklas , Tonn Joerg-Christian , Jakola Asgeir Store
Published: November 2024

PURPOSE

IDH-mutant astrocytomas CNS WHO grade 2 and 3 show heterogenous appearance on magnetic resonance imaging (MRI). In the pre-molecular era, the discrepancy between T1 hypointense and T2 hyperintense tumor volume in absolute values has been proposed as a marker for diffuse tumor growth. We set out to investigate if a ratio of T1 to T2 tumor volume (T1/T2 ratio) is associated with resectability and overall survival in patients with IDH-mutant astrocytomas.

METHODS

Patient data from two centers (Center A: Sahlgrenska University Hospital, Gothenburg, Sweden; Center B: LMU University Hospital, Munich, Germany) were collected retrospectively. Inclusion criteria were as follows: pre- and postoperative MRI scans available for volumetric analysis (I), diagnosis of an IDH-mutant astrocytoma between 2003-2021 (II), and tumor resection at initial diagnosis (III). Tumor volumes were manually segmented. The T1/T2 ratio was calculated and correlated with extent of resection, residual T2 tumor volume, and overall survival.

RESULTS

The study comprised 134 patients with 65 patients included from Center A and 69 patients from Center B. The median overall survival was 134 months and did not differ between the cohorts (p=0.29). Overall, the median T1/T2 ratio was 0.79 (range 0.15-1.0). Tumors displaying a T1/T2 ratio of 0.33 or lower showed significantly larger residual tumor volumes postoperatively (median 17.9 cm3 versus 4.6 cm3, p=0.03). The median extent of resection in these patients was 65% versus 90% (p=0.03). The ratio itself did not correlate with overall survival. In multivariable analyses, larger postoperative tumor volumes were associated with shorter survival times (HR 1.02, 95% CI 1.01-1.03, p<0.01).

CONCLUSION

The T1/T2 ratio might be a good indicator for diffuse tumor growth on MRI and is associated with resectability in patients with IDH-mutant astrocytoma. This ratio might aid to identify patients in which an oncologically relevant tumor volume reduction cannot be safely achieved.
SURG-47. SUPRAMAXIMAL RESECTION IMPROVES OVERALL SURVIVAL IN PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Mendoza Mireles Eduardo Erasmo , Blakstad Hanne , Mughal Awais Ahmad , Server Andres , Brandal Petter , Leske Henning , Aarhus Mads , Helseth Eirik , Rønning Pål Andre , Vik-Mo Einar O
Published: November 2024

INTRODUCTION

Glioblastoma is highly resistant to radio- and chemotherapy and its heterogeneity is a therapeutic challenge. O6-methylguanine–DNA methyltransferase (MGMT) promotor methylation is an established biomarker for favorable effect of chemotherapy. Supramaximal resection has proven predict the best overall survival (OS), but whether this benefit applies equally to patients with different MGMT-promotor methylation status is still to be debated.

MATERIAL AND METHODS

Population based retrospective study that examined all adult patients in South-Eastern Norway that underwent resection for IDH wildtype glioblastoma between January 2019 and December 2021. Extent of resection (EOR) was classified according to RANO resect classification and MGMT-promotor methylation status by pyrosequencing-qPCR.

RESULTS

The study included 281 patients. MGMT-promotor methylated patients (MGMT+) had a median OS of 18.4 months compared to 13.1 months in MGMT-unmethylated (MGMT-) patients (p<0.0001). Patients with supramaximal resection had a median OS of 20.4 months compared to 14.9 months (p<0.01) with maximal resection. For patients with supramaximal resection we found no significant difference in median OS (25.5 vs. 18.3 months (p=0.24)) dependent on MGMT-status. Separated analysis between MGMT-status and EOR showed a median survival of 18.3, 13.4 (p<0.001), and 8.5 (p<0.001) months for MGMT-, and 25.5, 18.4 (p=.99), and 9.0 (p<0.001) months for MGMT+ in patients where supramaximal-, maximal-, and submaximal resection was achieved, respectively.

CONCLUSIONS

Patients with supramaximal resection and MGMT+ have a 50% 2-years survival probability. In patients where supramaximal resection was achieved, survival benefit was not dependent on MGMT-status. There was a significant improved survival in MGMT- patients between supramaximal and maximal resection, that was not present for MGMT+ patients. Intraoperative molecular diagnosis has the potential to guide the surgical strategy dependent on MGMT-promotor methylation status, especially in tumors where supramaximal resection has a higher risk of new neurological deficits.
SURG-48. LASER INTERSTITIAL THERMAL THERAPY REMODELS THE TUMOR IMMUNE LANDSCAPE IN A MOUSE GLIOMA MODEL
Authors: Giles David , Woodiwiss Timothy , Han Rowland , McCornack Colin , Beck Loren , Fu Yiwei , Leidig Will , Anzaldua-Campos Markus , Mok David , Cleary Ryan , Kim Albert
Published: November 2024

BACKGROUND

Laser interstitial thermal therapy (LITT), a minimally invasive surgical technique for tumor ablation, is increasingly being used to treat primary and recurrent glioma. While the primary goal of using LITT has been to destroy tumor tissue, little is known about the impact of LITT on the overall immune response. To investigate changes in the tumor immune landscape, we utilized a mouse model of LITT and applied it to a poorly immunogenic mouse model of glioma.

METHODS

SB28 glioma cells were implanted in the right frontal lobe of C57BL/6 mice, and on day 7, an optical fiber is inserted into the tumor, paired with a thermocouple for real-time temperature monitoring. A 30W laser was activated in pulses to maintain a peri-lesional temperature of 44C for 150-180 seconds. The tumor and LITT-associated immune response was analyzed by multiparameter flow cytometry, single cell RNA-seq, and multiplex immunofluorescence.

RESULTS

LITT (versus sham control) triggered an increase in neutrophils in the tumor during the acute phase at day 3 following treatment. Total immune cell numbers increased over time in both sham- and LITT-treated mice, but there was a significant increase at post-LITT day 7 in select adaptive immune cell populations including type 1 conventional dendritic cells, NK cells, and gamma delta T cells. Monocytes/macrophages comprised the majority of the immune infiltrate, and multiplex immunofluorescence revealed these populations localized to the perimeter of the LITT lesion. scRNA-seq also revealed enrichment of a Fabp5- and Gpnmb-expressing macrophage subset following LITT.

CONCLUSIONS

LITT modifies the tumor immune infiltrate with increases in neutrophils as well as select adaptive cell and macrophage subsets. Future studies will explore adjunct therapies to further augment the immune response in the setting of LITT.
SURG-52. LEPTOMENINGEAL DISSEMINATION AFTER GAMMATILE AND LITT IN HIGH GRADE ASTROCYTOMA PATIENTS
Authors: Magalhaes Pereira Rosalina , Mian Tabarak , Patel Toral , Dan Tu , Youssef Michael
Published: November 2024

PURPOSE

To present a case series of leptomeningeal dissemination after localized treatment with GammaTile or laser interstitial thermal therapy (LITT) in patients with high grade astrocytoma.

BACKGROUND

Leptomeningeal dissemination occurs primarily in glioblastoma patients with prolonged survival and those who undergo aggressive treatment courses. Targeted therapies such as GammaTile (which contains cesium-131 radiation-emitting seeds) or LITT may provide localized disease control following recurrence and serve as an immediate treatment modality for patients with recurrent disease in the weeks leading up to radiotherapy or systemic treatment.

METHODS

We retrospectively reviewed all consecutive patients with high grade astrocytoma treated with GammaTile or LITT who were found to have leptomeningeal dissemination of disease. Histological diagnosis, NGS and immunohistochemistry of tumor tissue were performed at both original diagnosis and at time of GammaTile placement or LITT procedure. Leptomeningeal dissemination was diagnosed through MRI findings on brain and spine. Cases were analyzed for time to development of leptomeningeal dissemination, median overall survival, survival from time of leptomeningeal dissemination diagnosis, time of dissemination to second radiation therapy. Tumor location, MGMT status and other molecular markers were also reviewed.

RESULTS

Out of 90 high grade astrocytoma patients treated with gamma tile radiation, 4 progressed to exhibit disseminated disease. There were 2 female patients, mean age was 50 years. Location of tumor was in the left temporal lobe in 3 patients and right temporal in 1. They were all IDH wild type. Two were MGMT methylated, two were non methylated. The median time from initial glioma diagnosis to LMD was 221 months (range 11-152) and overall survival after disseminated disease diagnosis was 7.5 weeks (range 3–13).

CONCLUSION

Leptomeningeal dissemination is a devastating complication of aggressive gliomas. Currently, there is no standard treatment for disseminated disease in high grade astrocytoma patients. Systemic therapy is needed following localized therapies to control disease. Further research into new therapies is needed to allow for better outcomes.
TMET-02. CELL-INTRINSIC METABOLIC PHENOTYPES IDENTIFIED IN GLIOBLASTOMA PATIENTS USING MASS SPECTROMETRY IMAGING OF 13C-LABELED GLUCOSE METABOLISM
Authors: Tsyben Anastasia , Dannhorn Andreas , Hamm Gregory , Couturier Dominique-Laurent , Briggs Mayen , Mair Richard , Brindle Kevin
Published: November 2024

Glioblastoma (GB) is an inherently heterogeneous and invasive primary brain cancer. Genomic and transcriptomic studies have attempted to classify GB into subtypes that predict survival and that have different therapeutic vulnerabilities. An outstanding question and technical challenge is to visualize the metabolism of a tumour within its native microenvironment and understand to what extent its metabolism is driven by the microenvironment. Patients with GB tumours were infused with [U-13C]glucose and intra-operative multi-regional tumour samples were rapidly snap frozen for analysis using mass spectrometry imaging (MSI). Tissue microenvironment was assessed using multiplexed antibodies in immunocytochemistry (IMC) of contiguous sections. Isotope tracking in human-derived neurospheres and patient-derived xenografts were used to confirm the presence of metabolic phenotypes detected in the human samples and to test the susceptibility of each phenotype to a panel of drugs targeting cellular metabolism. Three metabolic signatures were identified in patient tumours: glycolytic, oxidative and a mixed glycolytic/oxidative phenotype. The phenotypes did not correlate with microenvironmental features, including proliferation rate, immune cell infiltration, and vascularisation. The phenotypes were retained when patient-derived cells were grown in vitro, or as orthotopically implanted xenografts, and were robust to changes in oxygen concentration, demonstrating their cell intrinsic nature. The spatial extent of the regions occupied by cells displaying these distinct metabolic phenotypes are large enough to be detected using clinically applicable metabolic imaging techniques. The phenotypes also demonstrate differential drug sensitivities, suggesting imaging of these phenotypes may be used to stratify patients for personalised therapy trials. This is the first report to demonstrate high resolution imaging of metabolic fluxes in a human tumour in vivo and the presence of different metabolic phenotypes within GB that are tumour cell intrinsic and largely independent of the tumour microenvironment.
TMET-06. CLIP3 DOWNREGULATION LEADS TO RADIORESISTANCE IN GLIOBLASTOMA BY PROMOTING GLYCOLYTIC FLUX
Authors: Kim Dahye , Lee Haksoo , Kim Byeongsoo , Yum Soomin , Kang Wooseok , Kim HaYeon , Kang Hyunkoo , Youn HyeSook , Youn BuHyun
Published: November 2024

Glioblastoma Multiforme (GBM), a highly aggressive primary brain tumor, often develops resistance to standard treatments such as ionizing radiation (IR), which leads to a median survival of about 15 months. GBM contains glioblastoma stem cells (GSCs), which are crucial in driving therapeutic resistance and recurrence. In our study, we conducted comprehensive analyses to evaluate the molecular changes associated with radioresistance and explored the role of the Spy1-CLIP3 axis as a key regulator of GSC maintenance. Our methods included quantitative PCR and immunoblotting to measure CLIP3 mRNA and protein levels, revealing a significant reduction in expression among radioresistant GBM cells. We found that exposure to IR leads to the upregulation of Spy1 and downregulation of CLIP3, contributing to the development of radioresistance in surviving GBM cells. We used metabolic flux analysis techniques to observe changes in glycolytic activity, which increased in correlation with CLIP3 downregulation. IR induces CLIP3 downregulation, increasing glycolytic activity by facilitating the trafficking of GLUT3, the primary glucose transporter in GSCs. Additionally, colony-forming ability was evaluated using colony-forming assay after treatment of glimepiride with or without IR. Glimepiride didn’t reduce colony-forming ability in non-irradiated cells, but when combined with IR, it significantly reduced colony-forming ability, possibly by disrupting maintenance of GSCs. Importantly, our data reveal that glimepiride, a CLIP3 activator targets GSCs metabolism and enhances radiosensitization while maintaining low toxicity. The radioresistant GBM cells that survive radiotherapy exhibit increased stemness and glycolytic activity mediated by the Spy1-CLIP3 axis. Overall, our findings suggest that clinical trials using glimepiride for GBM patients may potentially improve survival rates, particularly for those experiencing recurrence after radiotherapy. This research highlights the importance of targeting cellular metabolism and stem cell properties in the context of GBM radioresistance and suggests potential avenues for improving the effectiveness of existing treatments.
TMET-09. SEX-BIASED ROLE OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA IRON METABOLISM
Authors: Pappus Sahu Aurosman , Palsa Kondaiah , Shenoy Ganesh , Slagle-Webb Becky , Connor James R
Published: November 2024

Glioblastoma (GBM) is an aggressive brain cancer that is extremely difficult to treat. GBM is sexually dimorphic in nature, where females are less susceptible to developing GBM, respond to therapy better, and get a survival advantage. Sex-biased differences in tumor iron metabolism play a significant part in making this disease sexually dimorphic. Macrophages constitute a significant population in the GBM tumor microenvironment and are key players in tumor iron homeostasis. Here, we examine macrophage iron homeostasis as a potential driver of sex biases in glioblastoma using bone marrow-derived macrophages (BMDM) isolated from C57BL/6 mice. Immunoblot analysis revealed higher ferritin L-chain (FTL) expression in male BMDM than in females (Fold change: 3.18, P = 0.02). Flow cytometric analysis revealed that male BMDMs had a significantly higher labile iron pool (LIP) (Fold change: 1.62, P = 0.0081). We used a stable isotope of iron (Fe57) to determine macrophage iron uptake by ICP-MS, and observed that male BMDMs have a higher iron uptake (fold change: 1.623, P = 0.0018) than females. These results indicate that macrophage iron metabolism is sexually dimorphic in nature. Next, we used a transwell co-culture system to study how macrophages regulate the iron status of GL261 cells. We found that GL261 cells had significantly lower H-Ferritin (FTH1) expression when co-cultured with male BMDMs (Fold change: 0.789, P = 0.0045). However, this decrease in ferritin didn’t result in a decrease in cellular LIP. We discovered that there was an increase in secreted ferritin in the GL261 culture media. Further experiments with Fe57-loaded GBM cells showed that this increase in secreted ferritin correlated with increased iron release from the GL261 cells. These results indicate that tumor-associated macrophages may regulate tumor iron homeostasis by inducing ferritin-bound iron release from GBM cells in a sex-biased manner.
TMET-17. LIPID METABOLIC HETEROGENEITY OF GLIOMA CELLULAR STATES REVEALS ENVIRONMENTAL DEPENDENCIES
Authors: Bayley Nicholas , Minami Jenna , Tse Christopher , Zhu Henan , Salinas Jennifer , Andrasz Cassidy , Yan Weihong , Cadet Dimitri , Borujerdpur Amir , Williams Kevin , Bhaduri Aparna , Bensinger Steven , Liau Linda , Cloughesy Timothy , Graeber Thomas , Nathanson David
Published: November 2024

Malignant growth and survival of cancer is supported through reprogrammed lipid metabolism. In gliomas, genetic alterations can drive lipid metabolic dysregulation revealing therapeutic opportunities to exploit lipid metabolic vulnerabilities within genetically defined subsets of glioma tumors. However, it remains unclear whether inter- and intra-tumoral transcriptomic heterogeneity in gliomas relates to distinct lipid programs and potential dependencies. Here we set out to characterize pan-glioma lipid metabolic heterogeneity through genomic, transcriptomic, and lipidomic profiling of a large and diverse cohort of patient tumor samples. We define key axes of lipid metabolic variability across gliomas and identify relationships between lipid metabolic gene expression programs and glioma lipidomic profiles. Intriguingly, intersection of lipid gene expression signatures with single cell RNA sequencing revealed patterns of lipid metabolic heterogeneity that distinguish neurodevelopmental cellular states of gliomas, mirroring patterns of lipid metabolic diversity across cell types within the normal brain. Consequently, tumors with opposing cellular state enrichment have distinct lipid metabolism and environmental dependencies. Tumors enriched for Radial Glia-like states have high capacity for de novo fatty acid synthesis while tumors enriched for oligodendrocyte progenitor-like states are dependent on exogenous sources of lipids for survival and growth. These findings connect inter- and intra-tumoral heterogeneity of cellular states to variability in lipid metabolic reprogramming to reveal future avenues for precision medicine.
TMET-24. MULTI-OMIC CHARACTERIZATION OF THE TEMPORAL METABOLIC ADAPTATIONS UNDERPINNING THERAPY RESISTANCE AND TUMOR RECURRENCE IN GLIOBLASTOMA
Authors: Martell Emma , Kuzmychova Helgi , Senthil Harshal , Kaul Esha , Chawla Ujala , Banerji Versha , Anderson Christopher M , Venugopal Chitra , Miller Donald , Werbowetski-Ogilvie Tamra E , Singh Sheila K , Sharif Tanveer
Published: November 2024

Therapy resistance and tumor recurrence are barriers to achieving long-term survival in cancer patients, particularly evident in glioblastoma (GBM), known for its dismal 5-year survival rate below 10%. Despite aggressive treatment regimens, including maximal resection, alkylating chemotherapy, and radiation, the majority of GBM patients experience relapse within 7-9 months post-initial intervention. Recurrent GBM poses surgical challenges and resists subsequent treatments, leading to an almost universally fatal outcome and an average survival of 12-18 months. Metabolic networks can serve as ancient stress-protection mechanisms that operate independently of genomic changes, offering an initial line of defense against exogenous pressures. Although the role of metabolism in cancer has gained prominence, our understanding of the metabolic adaptations following chemoradiotherapy and their contributions to therapy resistance and tumor recurrence in highly aggressive GBM tumors remains incomplete. We postulate that metabolic adaptations play a pivotal role in facilitating therapy resistance and GBM recurrence. Exploring the metabolic dependencies of these persistent cells may unveil vulnerabilities for therapeutic exploitation to counteract chemoradiotherapy resistance. We established clinically relevant patient-derived in vitro and in vivo models mirroring the standard GBM treatment protocol. Using state-of-the-art single-cell and bulk multi-omics technologies, we profiled the temporal transcriptomic and metabolomic adaptations from therapy-naïve primary GBM to chemoradiotherapy-resistant recurrent tumors. Our findings revealed unique metabolic transitions that occurred during chemoradiotherapy treatment in GBM cells that were conserved in vitro and in vivo across ten genetically diverse GBM patients. In a pre-clinical animal trial, a novel metabolism-targeting combinatorial treatment regimen prevented the emergence of recurrent tumors and significantly prolonged survival compared to chemoradiotherapy alone. Altogether, our results uncover distinct metabolic adaptations mediating therapy resistance and tumor recurrence in GBM. These findings emphasize the need to consider metabolic flexibility and dependencies for effective therapeutic strategies, offering potential avenues to overcome chemoresistance in recurrent GBM tumors.
TMET-35. UPREGULATION OF THE URIDINE SALVAGE PATHWAY IN MESENCHYMAL GLIOBLASTOMA STEM-LIKE CELLS
Authors: Baljinnyam Tuvshintugs , Sowers Mark L , Chang-Gu Bruce , Tang Hui , Herring Jason L , Zhang Kangling , Sowers Lawrence C
Published: November 2024

Glioblastoma is a heterogenous tumor comprised of multiple molecular subtypes of cancer cells and cancer stem-like cells. Of particular importance are the cancer stem-like cell niche population as they are believed to be more resistant to existing therapies and re-seed the tumor following initial response to standard-of-care treatment. To better understand glioblastoma stem-like cells we completed an untargeted proteomic analysis of 35 patient derived glioblastoma stem cell lines. This revealed an increase in several important proteins involved in the uridine salvage pathway, in the mesenchymal subtype. A subset of these proteins, including ecto-5’-nucleotidase (NT5E/CD73), uridine phosphorylase (UPP1), phosphoglucomutase-2-like-1 (PGM2L1), nicotinamide phosphoribosyltransferase (NAMPT), and nicotinamide N-methyltransferase (NNMT), suggest an augmented pathway for utilization of UMP and uridine as a fuel source and to replenish NAD+. Uridine and UMP are present in human serum and are enriched in the tumor microenvironment, providing a sustainable resource to resupply the tumor. The upregulation of this pathway was validated in established cell lines and orthogonal patient-derived xenograft cell lines not included in the proteomics study. Further work is underway to selectively inhibit or exploit this pathway with small molecule inhibitors.
TMET-36. INCREASED METHIONINE CYCLE DRIVES PYRIMIDINE METABOLISM IN LETHAL PEDIATRIC EPENDYMOMAS
Authors: Yadav Navneesh , Manuvel Antony Michealraj Kulandai
Published: November 2024

Supratentorial ependymomas (ST-EPN) are pediatric brain tumors found in the cerebral hemisphere, driven by the oncogenic fusion of ZFTA with RELA. Other than surgery and radiotherapy, these tumors do not have effective therapeutic options. Recurrent ST-EPN tumors are highly aggressive and hard to treat, which makes these tumors lethal. To understand the disease mechanism and potentially identify or develop therapeutic targets, we established patient-derived models and interrogated the genetic and metabolic dependencies using cutting-edge, near-genome-wide genetic screening and metabolomic tools. Our integrative transcriptomics and metabolic analysis identify that the ZFTA-RELA fusion drives methionine metabolic reprogramming in the cancer stem cells to regulate permissive epigenetic status and pyrimidine nucleotide synthesis to fuel tumor growth. Limiting methionine or inhibiting MAT2A, a rate-limiting enzyme of methionine metabolism in ST-EPN cells, results in profound cell cycle arrest and make the cells vulnerable to pyrimidine inhibitors compared to other pediatric brain tumors. Thus, for treatment, along with radiotherapy, blocking the methionine cycle by using the methionine limited diet or in combination with pyrimidine metabolism inhibitors can be a novel therapeutic strategy against the aggressive paediatric ST-EPN tumors.
TMET-38. BIOCHEMICAL CHARACTERIZATION OF PSAMMOMATOUS MENINGIOMA USING MAGNETIC RESONANCE SPECTROSCOPY
Authors: Ijare Omkar B , Powell Suzanne Z , Baskin David S , Pichumani Kumar
Published: November 2024

Psammomatous meningioma is a histologic subtype of meningioma and is presented as a highly calcified intracranial or spinal lesion. Although computed tomography (CT) and short/zero echo-time MRI techniques can detect calcification in tumors, a complete biochemical profile of psammomatous meningiomas is not known. Here, we compare the metabolomic profiles of common meningiomas (WHO grade-I and grade-II) and a psammomatous meningioma using ex vivo proton magnetic resonance spectroscopy (1H MRS). The tumor specimens were collected from meningioma patients undergoing surgery for the resection of the tumor mass. Tumor samples were extracted in 5% perchloric acid, centrifuged, supernatants were vacuum dried and reconstituted in D2O containing 1.0 mM sodium 2,2-dimethyl- 2-silapentane-5-sulfonate-d₆ (DSS-d6, internal standard). Previously, we have identified the following metabolites in grade-I and grade-II meningioma tumors: leucine, isoleucine, valine, lactate, alanine, acetate, glutamate, succinate, glutamine, aspartate, creatine, phosphocreatine, phosphocholine, glycerophosphocholine, myo-inositol, scyllo-inositol, taurine, hypotaurine, glycine, phosphoethanolamine, and glucose. In the current study, psammomatous meningioma also showed the presence of all the above metabolites; however, the levels of these metabolites were lower concentrations compared to the grade-I and grade-II meningiomas, except for lactate. In addition to the above-mentioned metabolites, psammomatous meningioma showed the presence of citrate which was not detected in other meningioma subtypes. Citrate is a major component of bone and the presence of citrate (~614 µM/g, tissue) in psammomatous meningioma could be due to the calcification occurring in these tumors. Surgical pathology report of resected tissue specimen showed clusters and small whorls of meningothelial cells with scattered calcifications, consistent with psammomatous meningioma (WHO grade-I; Ki-67 = 3%). In conclusion, detection of citrate by 1H MRS in meningiomas can be helpful in the differential diagnosis of psammomatous meningiomas.
TMIC-04. SPATIAL SEQUENCING OF MEDULLOBLASTOMA REVEALS BIOLOGICAL NICHES CORRELATED WITH HIGH-RISK FEATURES AND RELAPSE
Authors: Michaud Marina , Chien Franklin , Bakhtia Mojtaba , Snuderl Matija , Schroff Chanel , Schneiderjan Matthew , MacDonald Tobey , Bhasin Manoj
Published: November 2024

Medulloblastoma (MB) defines a heterogeneous set of neuroepithelial cancers of the posterior fossa. The MB tumor microenvironment (MB-TME) influences tumor progression and therapy response and has emerged as a growing target for novel therapeutic approaches. Prior single-cell analysis has characterized the MB-TME composition but does not reveal the spatial orientation of components. To address this gap, we performed 10X Visium spatial sequencing on sixteen pediatric MB samples obtained at surgical resection with samples representing the four molecular subtypes (WNT, N=1; SHH, N=6; Group 3, N=2; Group 4, N=5) and two matching samples at diagnosis and relapse. Spatial voxel clustering yielded clusters corresponding to malignant, immune, and stromal components of the TME, including tumor-associated astrocytes (TAAs), macrophages (TAMs), and vascular endothelium. Ten distinct clusters emerged representing malignant cell states, defined primarily by programs of cell cycle progression and neuronal differentiation. Notably, these MB cell clusters were differentially abundant between the MB subgroups, highlighting heterogeneity between disease subtypes. Moreover, examining the patterns of cellular spatial distribution in high-risk (HR) patients revealed dense regions of quiescent MB progenitors, while standard-risk patients showed greater heterogeneity within their TME. Proximity-dependent intercellular signaling further highlighted increased signaling by TAAs and vascular endothelium with decreased heat shock response signaling in HR patients. Comparing samples from relapse to diagnosis, TAMs, TAAs, and vascular endothelium were found to constitute a greater proportion of the TME. Subsequent niche-dependent gene expression and pathway analysis for TAAs localized near tumor vasculature in relapsed samples revealed increased expression of metastasis-associated pathways. Collectively, the results of our study enable new insight into the heterogeneity of the MB-TME, with close spatial association of quiescent MB progenitors correlating with high-risk clinical features. Quiescent MB progenitors have been documented to confer resistance through cellular dormancy, and identifying its molecular drivers may reveal potential targets for anticancer therapy.
TMIC-11. THE EFFECTIVENESS OF VALPROIC ACID IN COMBINATION WITH TEMOZOLOMIDE FOR TREATMENT OF HIGH-GRADE GLIOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Sharma Eshita , Ahmed Aisha Rizwan , Łajczak Paweł , Chatterjee Anoushka , Jagodzinski Maks , Rajab Numa , Sahin Oguz Kagan , Chawla Dikshit , Fagbamila Oluwaseun , Silva Yasmin , Petry Iago Nathan Simon , Fagundes Walter
Published: November 2024

BACKGROUND

High-grade gliomas (HGGs) rapidly progress with a high recurrence rate and poor prognosis despite standard multimodal treatment. Valproic acid (VPA), a histone deacetylase inhibitor, sensitizes HGG to radiochemotherapy along with having potential anti-cancer mechanisms and augmenting the growth inhibitory effect of Temozolomide (TMZ). This study explores the effectiveness of VPA in combination with TMZ for treating patients with HGG.

METHODS

A comprehensive literature search was performed on PubMed, Scopus, Embase, and Web of Science databases and identified relevant studies (case-control, cohort, RCTs) comparing the synergistic effect of VPA during TMZ to TMZ without VPA. We investigated median overall survival (OS), Progression-free survival (PFS), and baseline MGMT methylation status to evaluate this relationship.

RESULTS

Our systematic review encompassed 9 studies involving 4,097 patients with HGGs (seven cohorts, one case-control, and one RCT). The pooled analysis of median OS demonstrated no statistical significance difference between VPA during TMZ and TMZ alone (MD=-3.97; 95%CI=-8.43-0.49; p=0.08). However, sub-analysis showed a statistically significant effect in studies with sample size <100 (MD=-5.06; 95%CI=-9.32,-0.80; p<0.02), and 100-200 (MD=-7.07; 95%CI=-13.15,-1.00; p<0.02), and those conducted before 2015 (MD=-5.62, 95%CI=-9.08,-2.17, p<0.01). On meta-regression analysis, no statistical significance (RC=0.82,95% CI=0.39,-2.03, p=0.18) was observed, indicating that the study year is not associated with the intervention. A separate analysis of 3 studies also showed no significant variance in the baseline percentage of patients without MGMT methylation (log OR=-0.35, 95%CI=-1.02,-0.32, p=0.30) when administering VPA during TMZ treatment (n=67) compared to TMZ alone (n=409). Additionally, VPA during TMZ does not significantly affect PFS (MD=-3.54; 95% CI=-10.18-3.10, p=0.30) compared to TMZ alone.

CONCLUSIONS

The concurrent use of VPA with TMZ shows no significant effect on OS and PFS, nor does it show any variance in the baseline MGMT methylation status compared to TMZ alone. However, smaller sample sizes show a significant effect. Thus, our findings emphasize the imperative for additional research aimed at refining clinical outcomes.
TMIC-13. INTEGRATING SNRNASEQ AND SPATIAL TRANSCRIPTOME (ST) SHOWS DIVERSE TRANSCRIPTOMIC LANDSCAPE FOR TUMOR MICROENVIRONMENT (TME) IN INTRACRANIAL GERMINOMAS
Authors: Lin Na , Liu Anthony Pak-Yin , Ka-Wai Li Kay , Wong Queenie Hoi-Wing , Yang Rui Ryan , Chan Danny Tat-Ming , Ding Xiaofan , Ng Ho-Keung
Published: November 2024

The incidence of intracranial germ cell tumors is 5-8 times higher in East Asia and histologically, germinoma is well known to show intense lymphocytic infiltrates. In spite of germinoma’s well known immune infiltration, there have only been a few studies on its tumor micro-environment (TME). There has been no study using the recent and comprehensive techniques of single nucleus sequencing or spatial transcriptomics to study its TME. In this study, we studied snRNAseq (Chromium 10X) of FFPE tissues of 24 intracranial germinomas, and spatial transcriptomes (STs) (Visium Spatial) from fresh tissues from ten matched cases. For the TME, in contrast to common belief, macrophages and fibroblasts were equally represented as T- and NK-cells as immune cells. Clinical stage correlated with a lesser proportion of fibroblasts and T- and NK-cells. There was no correlation with proportion of tumor cells with either focal vs bifocal disease or clinical stage. Common gene modules (non-negative matrix factorization) were epithelial-mesenchymal transition (complete and partial), cell cycle and immune cells. Cell interaction analysis showed strong interaction between germ cells and macrophages involving CXCL, MIF and MK pathways. By ligand-receptor analysis, MIF combined with CD74 might promote tumor development. For ten cases, we studied STs with fresh tissues and integrated the results with snRNSeq, deconvoluting the spots for ST using snRNAseq cell types as reference (SPOTight) and achieved integrated single cell expression atlases of the STs (Seurat package). STs revealed a similar CNV plot pattern as those derived from snRNAseqs. Multimodal Intersection Analysis integrated significant genes based on snRNAseq and different regions’ significant genes based on STs. There was correlation between the expression of the four gene modules for tumor and immune cells for cell neighborhood. In conclusion, we showed in details the heterogenous expression landscape of TME of germinomas.
TMIC-22. MYELOID CELLS INDUCE IMMUNOSUPPRESSION AND HYPORESPONSIVENESS OF CHIMERIC ANTIGEN RECEPTOR T CELLS IN THE NEURONAL MICROENVIRONMENT OF GLIOBLASTOMA
Authors: Zhang Junyi , von Ehr Jasmin , Look Thomas , Benotmane Jasim Kada , Neidert Nicolas , Kueckelhaus Jan , Weiss Tobias , Heiland Dieter Henrik , Abubakar Yabo Yahaya
Published: November 2024

Chimeric antigen receptor T (CART)-cell therapy has shown little success in glioblastoma and other solid tumors, unlike in hematologic malignancies. The immunosuppressive milieu and intratumoral heterogeneity are some obstacles limiting the effectiveness of CART-cell therapy in glioblastoma. Our goal in this study is to investigate how CART-cell transcriptional adaptations and cellular interactions in the glioblastoma microenvironment drive T-cell hyporesponsiveness. Using a human neocortical slice model, we performed physically interacting cell sequencing (PIC-seq) to investigate the transcriptional diversity of NKG2D CAR-T cells and control T-cells in the glioblastoma ecosystem. Through the integration of spatially resolved T-cell receptors sequencing and PIC-seq, we investigated the cellular and receptor-ligand interactions in CART-treated glioblastoma cells. Gene regulatory networks were reconstructed to identify key transcriptional regulators of CD8 CART-cell dysfunction. We used in-silico perturbation to understand transcriptional drivers that could potentially enhance the cytotoxic response of CAR-Ts. Primary patient-derived glioma cells were inoculated into human neocortical slices from surgical access tissue specimens. After 3 days of tumor growth, slices were treated with NKG2D CARTs or control T-cells. We observed that after 2 days of anti-tumor T-cell response in the CART group, tumor growth did not differ between conditions. After 7 days of treatment, PIC-seq was used to profile CARTs (tomato+) and tumor cells (GFP+) as well as physically connected cells (+/+). We identified a transcriptional shift towards T-cell exhaustion in CART cells compared to T-cells lacking the NKG2D construct. This transcriptional phenotype was driven by myeloid-CART and myeloid-tumor interaction. We identified that tumor-associated macrophages with enhanced phagocytic function in proximity to mesenchymal-like tumor cells located within hypoxic niches are the main drivers of T-cell dysfunction. Gene regulatory network analysis demonstrated that MAF and BACH2 are key transcriptional regulators of CART-cell function. Myeloid-tumor and myeloid-T-cell interactions promote an immunosuppressive microenvironment and hyporesponsive T-cells in glioblastoma. Our data has the potential to catalyze the re-engineering and optimization of CART-cell therapies with sustained cytotoxic effect against glioblastoma.