bluuebunny/crossref_metadata_2025_split huggingface dataset:
SURG-20. USEFULNESS OF PHOTODYNAMIC THERAPY (PDT) WITH TALAPORFIN SODIUM FOR GLIOBLASTOMA
Authors: Sasayama Takashi , Tanaka Kazuhiro , Nagashima Hiroaki , Fujita Yuichi , Yamanishi Shunsuke 
Published: November 2023

Abstract

BACKGROUND
Photodynamic therapy (PDT) with talaporfin sodium uses the toxicity of singlet oxygen generated by a reaction between a photosensitizer in tumor cells and light with a specific wavelength. PDT was introduced in our hospital in April 2017. We retrospectively analyzed the glioblastoma (GBM) patients treated with PDT and compared with the patients who did not receive PDT.

MATERIAL AND METHODS
From April 2015 to March 2023, total 145 patients with GBM were treated in our hospital. Among them, patients of recurrence, IDH mutant, biopsy and no chemo/radiotherapy were excluded. The patients’ characteristics, adverse event, changes of the MR image, recurrence pattern, outcome of the patients were analyzed. In addition, survival time of the patients between the PDT group and the non-PDT group was compared.

RESULTS
A total of 80 GBM patients were analyzed. Forty-four patients received PDT. 4 patients had adverse event; cyst formation, venous infarction, brain swelling, and delirium. In most of the patients, linear high signals of 5-7 mm on DWI were detected at the surface of the resected cavity and matched the PDT-irradiated area from 1 day after PDT. All hyperintense signal on DWI disappeared in about 30 days without any neurological deterioration. Sixty-seven patients had recurrence (PDT group; 33 cases, non-PDT group; 34 cases). Recurrence pattern of distant/dissemination were significantly increased in the PDT group compared with the non-PDT group. The PDT group tended to have longer survival in both OS (p = 0.08) and PFS(p = 0.07) than the non-PDT group. In multivariate analysis for OS, age and MGMT promotor methylation were significant prognostic factors, but not PDT.

CONCLUSION
PDT was safety and useful for GBM. However, the PDT group had significantly more distant/disseminated recurrences than the non-PDT group. We need to analyze more cases to clarify efficacy and recurrence patterns.
SURG-22. MECHANISMS OF BBB PERMEABILITY CHANGES TRIGGERED BY LASER THERAPY
Authors: Cleary Ryan , Kim Albert 
Published: November 2023

Abstract
The blood-brain barrier (BBB) severely limits access of systemically delivered drugs to the brain and brain tumors. Laser interstitial thermal therapy (LITT) has previously been shown to increase BBB permeability in both patients and in mice. The exact mechanisms of LITT-induced BBB permeability changes and their temporal features have yet to be elucidated. To answer this question, we used an established mouse model of LITT to evaluate changes in endothelial cell tight junction integrity and transcytosis over time in normal brain and demonstrate changes in transcytosis in human GBM tumor samples. Mean vesicular density (MVD) was calculated using electron microscopy to evaluate transcytosis. Immunohistochemistry (IHC) was used to assess tight junction integrity (Claudin 5 area/CD31 area) and Mfsd2a levels (Mfsd2a area/CD31 area) along endothelial cells in the laser penumbra. Tight junction integrity decreased 2.5 fold 3 days after LITT, with continued decrease 14 days post-LITT. Mean vesicular density (MVD) in endothelial cells within the laser penumbra increased 3-4 fold compared to sham treated mice, with a peak increase 14 days after LITT before returning to baseline levels 21 days after treatment. These changes in transcytosis correlated with a significant decrease in the intensity of Mfsd2a IHC in the laser penumbra at day 14. Finally, we found similar low levels of transcytosis in non-enhancing and enhancing human GBM tumor samples, confirming that transcytosis is potentially targetable to manipulate BBB permeability. CONCLUSION: Disruptions in tight junction integrity continue up to 14 days after LITT, while LITT-induced increases in transcytosis occur in a delayed fashion, peaking 14 days after laser treatment. Increased transcytosis is inversely correlated with decreased Mfsd2a expression, suggesting a role for Mfsd2a in regulation of LITT-induced BBB changes. Importantly, baseline levels of transcytosis in human GBM appear to be low, such that transcytosis could be targeted to increase BBB permeability.
SURG-32. EFFICACY OF LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR BIOPSY-PROVEN RADIATION NECROSIS IN RADIOGRAPHICALLY RECURRENT BRAIN METASTASES
Authors: Strowd Roy , Chan Michael , Tatter Steven , Chiang Veronica , Fecci Peter , Prabhu Sujit , Hadjipanayis Constantinos , Kirkpatrick John , Sun David , Sinicrope Kaylyn , Mohammadi Alireza , Sevak Parag , Abram Steven , Kim Albert , Leuthardt Eric , Chao Samuel , Phillips John , Lacroix Michel , Williams Brian , Placantonakis Dimitris , Silverman Joshua , Baumgartner James , Piccioni David , Laxton Adrian 
Published: November 2023

Abstract

BACKGROUND
Evidence is growing for the efficacy of laser interstitial thermal therapy (LITT) for radiation necrosis (RN) following stereotactic radiosurgery (SRS) for patients with brain metastases. Questions remain regarding local control, symptom control, and concurrent use of therapies.

METHODS
Demographics, intraprocedural data, safety, Karnofsky performance status (KPS) and survival data were prospectively collected from the LAANTERN multi-center registry (NCT02392078) then analyzed on patients consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 U.S. centers. Data was monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan Meier estimated survival.

RESULTS
Ninety patients met inclusion criteria. Median hospitalization time was 32.5hrs. Median time to corticosteroid cessation after LITT was 13 days (range 0 - 1229) and cumulative incidence of lesional progression was 19% at 1-year. Median post-procedure overall-survival was 2.6 years [1.7, NR] and 77% at one year as estimated by Kaplan Meier. Median KPS remained 80 through 2-year follow-up. Seizure prevalence improved from 34.4% pre-procedure to 12% 1-month post-LITT and 7.9% at 3-months. There was no significant difference in risk of radiographic progression in total and near-total ablations (91% or greater ablative coverage) versus sub-total ablations (&lt; 90%). Lesion size was not a significant predictor of future radiographic progression.

CONCLUSIONS
LITT is an effective, minimally invasive, safe treatment for RN, in terms of both local control and symptom management. LITT is effective in the management of lesion-related seizures in addition to averting expected neurological death. LITT facilitates ongoing systemic therapy (particularly immunotherapy) by enabling the rapid cessation of corticosteroids. Effective management options for RN could facilitate the more aggressive use of combined systemic and radiotherapeutic treatment options for brain metastases patients in order to avoid failure due to tumor recurrence and extend survival.
SURG-46. PRIMARY MALIGNANT MELANOMA, AN ATYPICAL PRESENTATION IN THE CERVICAL SPINE
Authors: Kamabu Larrey , Kataka Louange Maha , Galukande Moses , Lekuya Hervé Monka 
Published: November 2023

Abstract
Few studies have documented the occurrences of melanomas in the cervical spine. one percent of all malignant melanoma cases are primary melanoma of the central nervous system, which is extremely uncommon and nonspecific. We aimed to report a case of uncommon presentation of primary melanoma in the cervical spine. This a 59-year-old, male who presented with a 2-year history of anterior neck swelling, severe pain and tingling sensation in the left shoulder and arm which worsened in the previous 6 months. He developed weakness and paresthesia in the left upper arm and progressive gait disturbance of the left lower limb. Physical examination revealed masses in the left cervical and right submandibular region. There was left upper and lower extremities hemiparesis and hemi hypoesthesia. MRI showed hyperintense lesion on T1WI and hypointense on T2WI originating from the cervical spine and involving the vertebral bodies and paravertebral soft tissues. The patient underwent surgery, a black tumor was extracted, and histology revealed malignant melanoma. This case is presented in order to highlight the significance of and challenges associated with making a preoperative diagnosis of primary cervical melanoma with atypical radiological characteristics. Patients with extradural lesions that show hyperintensity on T1 weighted images and hypo intensity on T2-weighted images should have spinal melanoma examined as a possible differential diagnosis.
TMET-07. METABOLIC RISK FACTORS AND OUTCOMES IN PATIENTS WITH GLIOBLASTOMA
Authors: Aboubechara John Paul , Aboud Orwa 
Published: November 2023

Abstract
A growing body of evidence is beginning to implicate mutations in genes underlying cellular metabolism in the etiology of glioblastoma. The metabolic syndrome has been found to increase the risk of developing various systemic cancers, but it is not known how often the metabolic syndrome occurs in patients with glioblastoma or how it affects their clinical outcomes. Therefore, the purpose of this study is to test the hypothesis that the metabolic syndrome is a risk factor for developing glioblastoma and is associated with worse survival outcomes. A retrospective cohort study was conducted, consisting of patients at a single institution. Clinical records from 40 patients with glioblastoma IDH wild type were reviewed as part of this interim analysis—with plans to analyze 80 patients by study completion. Records included the patient’s diagnosis, progression free survival, overall survival, treatment, tumor molecular characteristics, blood pressure, body mass index, medications, and laboratory data. Our results demonstrate a trend that patients with the metabolic syndrome have worse overall survival compared to those who do not (16.7 months vs 8.1 months; p=0.069). Interestingly, hypertension (p=0.007), hyperglycemia (p = 0.044), and dyslipidemia (p = 0.041) were negatively associated with survival, while BMI was not. Furthermore, there was a significant negative association between overall survival and the number of metabolic risk factors that patients accumulate (i.e. BMI, HTN, etc.) (p=0.0038). However, our results demonstrate the prevalence of metabolic syndrome in GBM patients to be 30%, which is less than that of the general population, 35%. These interim results suggest that the metabolic syndrome is associated with worse survival in patients with glioblastoma IDH wild type, but that it is not a risk factor in the development of this cancer. These results support other work that has implicated metabolic dysregulation in the pathogenesis of glioblastoma.
TMET-08. ELONGATION CONTROL OF MRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA ADAPTATION TO NUTRIENT DEPRIVATION
Authors: Delaidelli Alberto , Yao Betty , Burwag Fares , de Santis Jessica Oliveira , Huang Yue Zhou , Zhang Haifeng , Negri Gian Luca , Hughes Christopher , Leprivier Gabriel , Sorensen Poul 
Published: November 2023

Abstract
Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We performed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p&lt; 0.05). Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.
TMET-14. PROBING TCA CYCLE ACTIVITY IN H3WT AND H3K27M-ALTERED DIFFUSE MIDLINE GLIOMAS
Authors: Ijare Omkar , Roberson Jackson , Kumar Sushmita , Ramamurthy Rishith , Baskin David S , Pichumani Kumar 
Published: November 2023

Abstract
DMG has high levels of α-ketoglutarate (α-KG), causing histone hypomethylation and promoting tumor growth. Therefore, targeting α-KG production in DMG tumors may be of therapeutic value. α-KG is synthesized in the tricarboxylic acid cycle (TCA) cycle via oxidation of multiple nutrients including glucose and glutamine. Hence, probing mitochondrial metabolism in DMG with the goal of altering α-KG levels will lead to new therapies to treat DMG. Here, we examine glucose and glutamine metabolism in H3WT and H3K27M-altered patient-derived DMG cells (Dr. Monje’s lab) using GC-MS based metabolic flux analysis. Both cells were grown as neurospheres in tumor stem medium. Neurospheres were treated with 11.0 mM [U-13C]glucose or 4.0 mM [U-13C]glutamine. The 13C-isotopomer analysis revealed that H3K27M-altered cells produced higher levels of (M+3) pyruvate (14.05 ± 5.37% vs. 7.15 ± 2.98%), and (M+3) lactate (9.46 ± 6.48 % vs.3.87 ± 1.80 %) compared to the H3WT. Whereas, the glucose derived (M+2) citrate in the TCA cycle was similar in both cases (15.81 ± 2.91% vs. 16.76 ± 4.15%). This data shows that both types of DMG possess similar TCA cycle activity leading to the synthesis of α-KG, which we measured through glutamate 13C labeling. Next, we probed [U-13C]glutamine metabolism in these two types of DMG cells as glutamine is another major source of α-KG synthesis . Both cell lines showed higher levels of glutamine-derived M+5 α-KG (34.62 ± 2.12 % vs. 42.17 ± 5.05%). Interestingly, H3K27M-altered DMG showed higher flux via reductive carboxylation generating M+5 citrate when compared to M+4 citrate produced via canonical glutamine metabolism in the TCA cycle (citrate M+5: 7.13 ± 2.14% vs. 4.33 ± 1.68%; citrate M+4: 4.04 ± 1.06% vs. 7.85 ± 1.52%). Therefore, inhibiting synthesis of α-KG in H3 K27M-altered DMGs would be of therapeutic interest in the treatment of both DMG subtypes.
TMIC-12. RAB27 REGULATION OF VASCULAR WALL INTEGRITY MEDIATES T-CELL INFILTERATION IN GLIOBLASTOMA
Authors: Adnani Lata , Meehan Brian , Rak Janusz 
Published: November 2023

Abstract
Endothelial secretome exerts a potent influence on the phenotype of cancer cells and immune microenvironment. Recently, we have reported that glioblastoma stem cells acquire a more aggressive mesenchymal state under influence of vascular endothelial cell derived extracellular vesicles (EVs). Since Rab27, GTPases involved in multiple aspects of EV (exosome) biogenesis, has been implicated in control of angiogenic pathways through regulation of VEGFR1 turnover and possibly other mechanisms, we interrogated the role of Rab27 in the function of normal and glioblastoma associated brain microvasculature. Using mice with disrupted Rab27a and Rab27b isoforms, we documented that these proteins control development and stability of the brain vasculature including pathological angiogenesis in glioblastoma. Thus, relative to wild-type C57bl/6 (WT) and double heterozygous Rab27a+/-;Rab27b+/- (dHET) mice, animals with Rab27a/b double knock-out (Rab27a/b-dKO) exhibit reduced microvascular density in brain cortices. When neoangiogensis was induced following orthotopic inoculation of mouse glioma cells (GL261), multiple morphological anomalies were observed in the tumour vasculature relative to tumours established in control mice. Moreover, vascular permeability of tumours in Rab27a/b-dKO mice markedly exceeded that of similar tumours in wild type or heterozygous controls resulting in augmented T-cell infiltration into the otherwise ‘cold’ brain tumor microenvironment. Our results suggest that key switches in the cellular secretome, such as Rab27a and Rab27b, may impact endothelial membrane dynamic and intercellular interactions capabilities, whereby they may play a critical role in ensuring the stability and sustained cellular barrier function of the vasculature during brain tumour progression. Therapeutic implications of these findings are being explored.
TMIC-39. PERIVASCULAR CONTAINMENT OF T CELLS IN IDH-MUTANT ASTROCYTOMA ASSOCIATES WITH HIGH ABUNDANCE OF GEMISTOCYTIC TUMOR CELLS AND IMMUNE STIMULATORY MICROGLIA
Authors: van Hijfte Levi , Geurts Marjolein , de Heer Iris , Vallentgoed Wies , Balcioglu Emrah , Debets Reno , French Pim 
Published: November 2023

Abstract
Isocitrate dehydrogenase mutant (IDHmt) astrocytoma is considered a T cell-deficient tumor, yet little is known regarding the underlying mechanism that drives T cell exclusion. To this end, we have systematically characterized the IDHmt astrocytoma immune microenvironment. We used multiplex immunofluorescence stainings (n=75; 1293 regions), bulk (n=152) and single nucleus RNA-sequencing (snRNAseq) (n=8) alongside spatial proteomics and RNA sequencing (n=12; 72 regions of interest) on samples from one patient cohort from the Erasmus Medical Center in the Netherlands, enabling integrative spatially resolved multi-omics analysis. We identified three spatially distinct T cell distributions in IDHmt astrocytoma: perivascular accumulation of T cells (T cell cuffs); presence of T cells in the tumor stroma; and absence of T cells. T cells were most frequently present in cuffs. Notably, T cell cuffs were characterized by a high abundance of a histologically distinct tumor cell type called gemistocytes. Conversely, we find gemistocyte high regions to be enriched for T cell cuffs, B cells and tumor associated macrophages (TAMs). Gemistocyte high tumors have an increased expression of immune cell migration and activation programs. SnRNAseq demonstrates that these programs originate from TAMs and T cells. Interestingly, we find that gemistocytic tumor cells form a transcriptionally distinct tumor cell sub-cluster of the astrocyte-like tumor cell state that expresses CD44. Spatial transcriptomics consequently confirmed that gemistocytes co-occurred with a population of immune stimulatory microglia that expresses the CD44-ligand Secreted Phosphoprotein 1 (SPP1), the chemo-attractants CCL3, CCL4 and CCL4L2, and markers for reactive microglia. In summary, we systematically uncovered a previously unrecognized cellular network between T cells, gemistocytic tumor cells and a subpopulation of immune-stimulatory microglia. This spatially confined population of TAMs, together with gemistocytic tumor cells, harbors signatures associated with astrogliosis, a CNS-specific mechanism of T cell exclusion, and thus may explain the perivascular confinement of T cells.
TMIC-49. AUTOMATIC SEGMENTATION OF DISTINCT GLIOBLASTOMA HALLMARKS ON DIGITIZED H&E SLIDES VIA DEEP LEARNING: CURATION OF A LARGE MULTI-INSTITUTIONAL COHORT
Authors: Sandino Alvaro , Becerra David S , Sandino Nelly J , Romero Eduardo , Tiwari Pallavi 
Published: November 2023

Abstract

PURPOSE
Glioblastoma (GBM) is a heterogeneous brain tumor. Standard treatment constitutes surgery, chemo-radiation, and chemotherapy. After surgery, the resected tissue is analyzed under a microscope by neuropathologists to identify distinct histological hallmarks. However, visual analysis of GBM pathological features on Hematoxylin and Eosin (H&E)-stained slides is subjective, time-consuming, and more importantly, requires wide expertise. We present a hierarchical deep learning-strategy to automatically segment distinct GBM hallmarks that first distinguishes necrosis (NE) from cellular tumor (CT), and subsequently, segments regions of microvascular proliferation (MV) and pseudo-palisading cell patterns (PC) within the CT region, on digitized H&E slides.

METHODS
We employed n=541 publicly available studies including IvyGap (n=41), and TCGA (n=500). For the IvyGap cohort, expert-driven segmentations of CT, NE, MV and PC were available. We randomly employed n=21 slides from 4 patients for training, n=5 slides from 2 cases for validation, and n=2 slides from 2 cases for testing. We employed an EfficientNet model using ~600 patches of 224×224 pixels of NE and CT sampled for every slide. For semantic segmentation of MV and PC, we separately trained two EfficientNet-UNet models trained on ~200 squared-patches of 1792 and 896 pixels size, respectively.

RESULTS
Our hierarchical deep learning model on the IvyGap cohort achieved an accuracy of 96%, with an area under the curve (AUC) of 98% for distinguishing necrosis from non-necrotic (i.e. CT) regions. For segmenting PC and MV within the non-necrotic regions, our DL models achieve a dice score of 0.69 and 0.77, respectively. Additionally, the segmentation results for each of the pathological attributes were also generated and vetted for the TCGA cohort.

CONCLUSION
We developed a hierarchical model for automatic segmentation of NE, CT, and MP and PC in H&E-stained Glioblastoma images which could reduce cost, time, and effort in annotating these pathological phenotypes, for quantifying the GBM micro-environment.
TMIC-55. TURNING ENEMY INTO ALLY: HIJACK BRAIN TUMOR CELLS TO BREAK DOWN THE BLOOD-TUMOR BARRIER
Authors: Bahrampour Shahrzad , Huang Xi 
Published: November 2023

Abstract
A major obstacle in brain cancer treatment is the blood-tumor barrier (BTB), which limits the delivery of a vast majority of therapeutic agents. Medulloblastoma (MB), the most common pediatric malignant brain tumor, consists of four subgroups (WNT, SHH, Group 3, Group 4). Increasing BTB permeability of non-WNT MB is essential for effectively treating patients by overcoming this drug delivery impediment. Since the BTB is exposed to biofluids such as blood and brain interstitial fluid, which present dynamic osmotic challenges, we hypothesized that cell volume regulation plays a crucial role in BTB integrity. Using a genetically engineered mouse model of SHH MB, we show that tumor-specific knockout of volume-regulated ion channel, Lrrc8a, significantly increases BTB permeability and enhances the therapeutic response of MB-bearing mice to vismodegib, an FDA-approved antagonist of the SHH pathway. Lrrc8a-deficient tumor cells develop ectopic contact with blood vessels, permitting tumor cell-derived Tgfβ2 to activate Tgfβ signaling in endothelial cells. Consequently, endothelial cells in Lrrc8a knockout MB lose endothelial characteristics and gain mesenchymal features, indicative of Tgfβ signaling-induced endothelial-mesenchymal transition (EndMT). Furthermore, tumor-specific LRRC8A knockdown enhances BTB permeability in a xenograft human Group 3 MB model. Collectively, our findings establish Lrrc8a/LRRC8A as a therapeutic target to increase the therapy response of MB and provide evidence that inducing EndMT could be a strategy for enhancing BTB permeability to treat brain cancer.