bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-32. PROGNOSTIC IMPLICATIONS OF SIZE OF PITUITARY MACROADENOMAS: A COMPARATIVE ANALYSIS OF GIANT ADENOMAS WITH NON-GIANT MACROADENOMAS
Authors: Ghazi Sanam Mir , Tariq Muhammad Bilal , Hashmi Fauzan Alam , Tanwir Asra , Khan Ahsan Ali , Shamim Muhammad Shahzad , Angez Meher , Enam Syed Ather 
Published: November 2021

Abstract

BACKGROUND
In this study we compared giant pituitary adenomas (GPAs) and non-giant pituitary macroadenomas (nGPAs) on the basis of presenting complaints, surgical procedures, tumor resections and outcomes.

METHODS
A retrospective analysis (2006-2017) of pituitary macroadenomas was performed where tumors were divided into two groups; tumors greater than 4 cm were classified as GPAs while macroadenomas smaller than 4 cm were termed as nGPAs. Both GPA and nGPA had 75 patients in each group.

RESULTS
The most common complaint of all patients was visual deterioration (77.3% of patients with nGPAs and 89.3% of patients with GPAs). Visual field defects were present in 55 patients (73.3%) in the nGPA group compared to 68 patients (90.7%) in the GPA group (p=0.006). The mean volume of nGPAs was 6.3 cm3 (range 0.45 cm3 to 22 cm3 while the mean volume of GPAs was 30.1 cm3 (range 10.8 cm3 to149.4 cm3) (p=0.001). The mean extent of resection was 88.9% for nGPAs whereas the mean extent of resection was 76.7% for GPAs (p=0.03). Craniotomy was required only in the GPA group (5 patients, 6.7%) (p=0.023). Tumor recurrence/progression was seen in 9.3% of patients with nGPAs and 44% of patients with GPAs (p=&lt; 0.001). Re-do surgery was required in 2.7% of nGPA cases (via transsphenoidal approach) and 32% of GPA cases; in this GPA subgroup, 22.7% patients required transsphenoidal surgeries while 9.3% patients required transcranial surgeries. Stereotactic radiosurgery in recurrence/progression accounted for 4% of nGPA patients and 22.7% of GPA patients. There were 3 mortalities, all in GPA group. Overall, nGPA group had better postoperative course as compared to GPA group.

CONCLUSION
The frequency of preoperative symptoms in GPAs is more significant and associated with lesser chances of gross total tumor resection, higher rates of recurrence, and worse postoperative course in comparison to nGPAs.
NCOG-46. WHITE MATTER TRACT INVOLVEMENT BY INTRA-AXIAL BRAIN TUMORS; DIAGNOSTIC & THERAPEUTIC IMPLICATIONS
Authors: Bakhshi Saqib Kamran , Quddusi Ayesha , Mahmood Danish , Waqas Muhammad , Shamim Muhammad Shahzad , Mubarak Fatima , Enam Syed Ather 
Published: November 2021

Abstract
Diffusion tensor imaging (DTI) is a relatively recent modality which aids in visualization of WMT and their relation to intracranial lesions. Despite almost two decades since the beginning of its use in tumor resection, there is still dearth of data on its diagnostic and prognostic value from low- and middle-income countries. We aimed to assess the pattern of involvement of white matter tracts (WMT) by intra-axial brain tumors on DTI. Secondary objectives were to evaluate implications of involvement of WMT on surgical resection, and post-operative functional outcome. This was a retrospective study of 77 consecutive patients, who underwent DTI guided surgery for brain tumors. The involvement of WMT by tumors on DTI was assessed by a radiologist (who was blind to the pathology) using the Witwer classification. The pathology was reported by histopathologists using WHO brain tumor classification. Karnofsky Performance Scale (KPS) was used for assessing patients’ neurological status at admission, and at follow-up. Forty-five (58.4%) out of 77 tumors reviewed, caused infiltration of WMT, whereas only 22 (28.6%) tumors caused displacement of WMT (p = 0.040). Among 32 cases of astrocytoma, involvement of WMTs was influenced by the grade of tumor (p = 0.012), as high-grade tumors caused infiltration (19; 59.4%), unlike low grade tumors which commonly caused displacement (2; 50%). Oligodendroglioma caused infiltration/disruption of WMTs in most cases, irrespective of the grade (19 out of 25 cases; 76%). At last follow-up, 27 (35.1%) patients showed improvement in KPS and 14 (18.2%) reported deterioration, while there was no change observed in 36 (46.8%) patients. Infiltration of WMTs was associated with poor functional outcome. We conclude that intra-axial brain tumors mostly cause infiltration of WMTs, particularly high-grade astrocytoma, and oligodendroglioma of any grade. Infiltration of WMTs is associated with poor functional outcome at follow-up.
NCOG-48. LONGITUDINAL ASSESSMENT OF SUBJECTIVE COGNITIVE FUNCTION IN A BRAIN TUMOR SAMPLE: IMPROVED CORRESPONDENCE WITH NEUROPSYCHOLOGICAL PERFORMANCE OVER TIME
Authors: Gardner Melissa , Zarrella Giuliana , Dietrich Jorg , Parsons Michael 
Published: November 2021

Abstract

INTRODUCTION
Estimates of subjective cognitive function (SCF) generally show minimal correlation with objective measures of neurocognitive function (NCF). Our group recently validated a new metric of SCF in neuro-oncology patients, creating the Cognitive Index of the Functional Assessment of Cancer Therapy-Brain (FACT-Br-CI). This study examines whether brain tumor (BT) patients evaluated on more than one occasion show improved relationship between SCF and NCF. We hypothesized that change scores in SCF and NCF across evaluation would be more highly correlated than SCF and NCF at either timepoint.

METHODS
A retrospective study of BT patients who completed two neuropsychological evaluations (baseline, follow-up) was conducted. NCF was measured by the clinical trial battery composite (CTBC), a mean of 6 commonly used neuropsychological test scores. SCF was measured by the FACT-Br-CI. Mood/Anxiety were measured by the Beck scales (BAI/BDI-II). Change over time on each metric was evaluated with paired t-test. Correlational analyses evaluated relationships between NCF, SCF, and mood within and between time points.

RESULTS
Twenty-nine patients (16 female; mean age=54.6y; mean education=15.5y) completed all CTBC measures and FACT-Br-CI, 28 of whom completed and BDI and/or BAI. On group analyses, there were no significant differences between baseline and follow-up on CTBC (t=-.53;p=ns) or FACT-Br-CI (t=-.98;p=ns). Correlations between CTBC and FACT-Br-CI were nonsignificant at baseline (r=.24;p=ns), but significant at follow-up (r=.56;p=0.002). Change scores over time were unrelated (r=-.104;p=ns). Similar to previous studies, the FACT-BR-CI correlated with the BDI-II at baseline (r=-.38;p=0.04) and follow-up (r=-.59;p&lt; 0.001) and with the BAI at follow-up (r=-.44;p=0.02).

CONCLUSION
In this small group of brain tumor patients seen for repeated neuropsychological evaluations, we found that agreement between SCF and NCF was much higher on their second than initial evaluation. These findings suggest that patients may develop enhanced awareness of their cognitive function from an initial evaluation that persists over time.
EXTH-01. SECOND GENERATION OF INDUCED NEURAL STEM CELLS TO MIGRATE AND KILL AS AN ADJUVANT TO RADIOTHERAPY IN NON-SMALL CELL LUNG CANCER METASTASIS
Authors: Mercer-Smith Alison , Thang Morrent , Buckley Andrew , Valdivia Alain , Jiang Wulin , Bell Noah , Kumar Rashmi , Bomba Hunter , Woodell Alex , Luo Daniel , Floyd Scott , Hingtgen Shawn 
Published: November 2021

Abstract
Non-small cell lung cancer (NSCLC) spread to the leptomeninges is devastating with a median survival of only a few months. Radiation is frequently offered for symptomatic relief but alone does not eliminate leptomeningeal metastases (LMM). With no standard-of-care for patients with LMM, new adjuvant therapies are desperately needed in order to combat this disease. Neural stem cells (NSCs) have shown remarkable promise as drug delivery vehicles in the treatment of brain tumors due to their inherent tumoritropic properties. Using a cell sphere culture-based system, we have transdifferentiated fibroblasts into a second-generation induced neural stem cell (hiNeuroS) secreting the cytotoxic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to allow for the possibility of readily available, autologous cell carriers. Herein, we provide evidence that hiNeuroS-TRAIL cells can migrate to and suppress growth of NSCLC metastases in combination with radiation. In vitro time-lapse motional analysis and in vivo post-mortem tissue analysis showed that hiNeuroS-TRAIL cells migrate to NSCLC tumors. In vitro co-cultures with isobologram analysis suggests that TRAIL and radiation together have a synergistic cytotoxic effect on NSCLC tumors. In an intratumoral injection model of hiNeuroS-TRAIL, mice treated with the combination therapy of hiNeuroS-TRAIL and 2 Gy together had a small fraction of the mean tumor volume (6.4%) of controls (100%) compared to monotherapies (107.3% radiation-only, 46.6% hiNeuroS-TRAIL only). Only combination-treated mice demonstrated a significant extension in survival, which amounted to a 42% extension compared to controls. In the LMM model with ICV-infused therapy, the combination-treated mice showed significantly smaller tumor volumes (2.0%) compared to control (100%) or 2 Gy (54.9%) treated mice. Mice treated with hiNeuroS-TRAIL-only also showed only 4.6% of the tumor volume of control mice. Combination-treated mice and hiNeuroS-TRAIL-treated mice both showed significant improvements in survival (36.6% and 46.3% median extension in survival, respectively compared to controls).
EXTH-02. AAV MEDIATED BRAIN DELIVERY OF AN ADCC-ENHANCED ANTIBODY OBVIATES XENOGRAFT GROWTH IN MOUSE MODELS OF HER2+ BREAST CANCER BRAIN METASTASIS
Authors: Laks Dan , Chen Kenny , Ren Xiaoqin , Shah Ishan , Hameedi Usman , Tocci Jenna , Fiore Timothy , Grant Kyle , Bales Kelly , Samuel Hasson 
Published: November 2021

Abstract

BACKGROUND
HER2+ tumors constitute approximately 20% of breast cancer patients and are characterized by overexpression of the growth factor receptor HER2 (ERBB2), a cell proliferation driver. Effective anti-HER2 therapies confer prolonged patient survival necessitating the need for transformative treatments targeting brain metastases, a major cause of mortality in ~30-50% of HER2+ metastatic breast cancer patients. HER2-directed antibody immunotherapy, while efficacious for peripheral disease, has limited central nervous system exposure (CNS). To overcome these challenges, we transduced CNS cells with a novel AAV vector carrying an anti-HER2 antibody payload.

METHODS
We assessed the biochemical equivalence and functional effectiveness of AAV vector-encoded antibodies using in vitro assays. After selecting promising vector-encoded antibody candidates, a novel, blood-brain barrier penetrant AAV capsid was administered via i.v. dosing to an orthotopic xenograft mouse model of HER2+ brain metastases. Bioluminescent imaging provided a longitudinal measure of brain tumor burden. At study termination, we measured antibody biodistribution in cerebrospinal fluid (CSF), serum, and brain homogenates with AlphaLISA assays.

RESULTS
Using HER2+ breast cancer cell lines, we determined that an antibody-dependent cell cytotoxicity (ADCC) enhanced anti-HER2 antibody was most effective and demonstrated that AAV-vector encoded forms of the antibody performed comparably to recombinant reference antibodies. Following i.v. administration of a HER2 antibody encoding AAV vector, we measured &gt;1 ug/mL of the antibody in CSF. Importantly, AAV-mediated expression of the ADCC-enhanced HER2-directed antibody significantly abrogated tumor growth in orthotopic xenograft models.

CONCLUSIONS
Peripheral administration of an AAV vector was able to transduce brain tissue such that efficacious levels of HER2-directed antibodies were produced. This strategy was successful at preventing tumor growth in our physiologically relevant model of breast cancer brain metastases. Such a treatment modality should be further evaluated in patient derived PDX models to validate translational efficacy for human patients.
EXTH-05. TUMOR TREATING FIELDS IN COMBINATION WITH THE TERT-INHIBITOR ERIBULIN HAVE SYNERGISTIC ANTIPROLIFERATIVE EFFECTS ON HUMAN GLIOBLASTOMA CELLS
Authors: Stein Marco , Beusker Piet , Goett Hanna , Kolodziej Malgorzata , Uhl Eberhard 
Published: November 2021

Abstract

OBJECTIVE
Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The optimal combination therapy for Tumor Treating Fields (TTFields) in glioblastoma (GBM) treatment is unknown. The aim of our study was to analyze, the effects of the TERT-inhibitor eribulin in combination with TTFields on human GBM cells.

METHODS
Human GBM cells of the established cell lines U87, A172 and U251, and two patient-derived cell lines, were treated with eribulin monotherapy, TTFields monotherapy, or both modalities together. After 72 hours of therapy, cell counts were measured and clonogenic assays were performed. Annexin staining and fluorescence-activated cell scanning (FACS) was used to analyze cell death.

RESULTS
Overall surviving fractions were 39.8±11.0% for eribulin monotherapy, 32.2±23.9% for TTFields monotherapy, and 10.9±9.9% for the combined treatment. Mean observed annexin positive fractions were 11.2±8.2% (control), 28.6±9.7% (eribulin), 34.8±8.1% (TTFields), and 78.1±13.5% (combination), respectively. The mean clonogenic fractions over all cell lines were 25.9±7.8% for eribulin and 46.4±12.9% for TTFields. For the combination therapy, a synergistic effect with a decreased mean of 3.6% clonogenic fractions was observed.

CONCLUSION
Eribulin increases cell death and reduces clonogenicity our experiments. Additionally, a synergistic effect of the combined treatment of TTFields and eribulin synergistic was observed. Eribulin in combination with TTFields could be a new effective therapy for GBM.
EXTH-13. LOCAL DELIVERY OF AN IL-15 SUPERAGONIST USING A REPLICATING RETROVIRUS SIGNIFICANTLY IMPROVES SURVIVAL AND LYMPHOCYTE INFILTRATION IN POORLY IMMUNOGENIC MURINE GLIOBLASTOMA MODELS
Authors: Haddad Alexander , Spatz Jordan , Montoya Megan , Collins Sara , Gill Sabraj , Wang Elaina , Chuntova Polly , Young Jacob , Kasahara Noriyuki , Aghi Manish K 
Published: November 2021

Abstract
Glioblastoma (GBM) leads to severe systemic and local immunosuppression, and immunotherapies have had limited clinical success. Here, we evaluated the treatment efficacy of RLI, a superagonist of T-cell activator IL-15, delivered to tumor cells using a tumor-selective retroviral replicating vector (RRV) in the syngeneic murine SB28 and Tu2449 GBM models, which are both engineered to be poorly immunogenic with low-mutational burden and known resistance to immunotherapy, and hence more accurate biomimetic models of human GBM. RRV-RLI replicated and spread effectively in cultured murine GBM cells with robust production of functional RLI (165.4 ± 5.3 ng/mL). Stereotactic injection of RRV-RLI into pre-established intracerebral SB28 tumors significantly reduced tumor growth on bioluminescent imaging, and increased median survival compared to control mice (55 vs. 19 days, p=0.002), leading to long-term survival in 12% of treated mice. In the Tu2449 model, imaging results showed complete eradication of intracerebral tumors after RRV-RLI treatment, with long-term survival (median not reached) in &gt; 85% of treated mice, compared to a median survival of 12.5 days in control mice (p=0.001). RRV-RLI treated tumors showed significantly increased CD8 T-cell infiltration, without altering immunosuppressive cell populations. Similarly, broad anti-tumor inflammatory changes, including increased expression of genes involved in T-cell activation and killing, were observed in the NanoString nCounter platform using a 770-gene panel representing various immune cell types. Notably, RLI was not detected in the blood of treated mice, and tumor-localized RRV-RLI gene delivery showed no adverse systemic immune effects in either model. In summary, RRV-mediated RLI immunotherapy results in immunostimulatory and pro-inflammatory changes to the tumor microenvironment and achieves a significant survival benefit in two poorly immunogenic syngeneic murine models of GBM. This tumor-localized immunomodulatory gene therapy has the potential to safely reverse the T-cell depleted immunophenotype of GBM.
EXTH-14. PRECLINICAL EVALUATION OF NOVEL CDK4/6 INHIBITOR GLR2007 IN GLIOBLASTOMA MODELS
Authors: Yin Lei , Yao Zhenglin , Wang Yue , Huang Ying-Hui , Mazuranic Michelle , Yin Ang 
Published: November 2021

Abstract
Glioblastoma multiforme (GBM) is characterized by a high frequency of cyclin-dependent kinase (CDK)4 and CDK6 pathway dysregulation. None of the approved CDK4/6 inhibitors are indicated for GBM. Poor blood–brain barrier (BBB) penetration is a potential factor limiting treatment efficacy in GBM. GLR2007 is an investigational CDK4/6 inhibitor with the potential for improved penetration across the BBB. These preclinical studies investigated the anti-tumor efficacy in GBM xenograft models and central nervous system distribution of GLR2007. In vivo evaluation of the anti-tumor efficacy of GLR2007 versus vehicle, abemaciclib, and/or palbociclib was performed in two BALB/c nude mouse GBM xenograft models. Efficacy was expressed as tumor growth inhibition (TGI, change in mean tumor volume from baseline as a percentage of change in vehicle group) or increased survival time. Following 21 days of treatment, TGI in BN2289 subcutaneous xenografts was 39.4% and 56.4% for 25 mg/kg and 50 mg/kg GLR2007 groups, respectively, 34.0% for 25 mg/kg palbociclib, and 24.9% for 25 mg/kg abemaciclib (p &lt; 0.001 in all groups vs vehicle control). In U87-luc orthotopic xenografts, compared with vehicle controls, median survival time was 50.0% (p = 0.0009) longer in the 12.5 mg/kg GLR2007 group, similar to the 150 mg/kg abemaciclib group (54.4%, p = 0.0002), and was 182.6% (p &lt; 0.0001) longer in mice treated with 50 mg/kg GLR2007. Quantitative whole-body autoradiography was used to determine the distribution of [14C]GLR2007 in Sprague Dawley rats following a single oral dose. Total radioactivity levels in the brain exceeded those in plasma by 2.3–4.5-fold from 2–6 h after dosing. These preclinical studies suggest the potential of GLR2007 for the treatment of GBM, supported by evidence that GLR2007 showed numerically greater anti-tumor efficacy than approved CDK4/6 inhibitors palbociclib and abemaciclib in GBM xenograft models, and evidence of substantial central nervous system distribution.
EXTH-21. MECHANISMS OF SYNERGISTIC GROWTH SUPPRESSION BY RADIOTHERAPY AND C-MET INHIBITION IN EXPERIMENTAL GLIOBLASTOMA
Authors: Silginer Manuela , Papa Eleanna , Szabo Emese , Vasella Flavio , Roth Patrick , Weiss Tobias , Weller Michael 
Published: November 2021

Abstract
Glioblastoma remains to be one of the most lethal solid cancers and novel therapies are urgently needed. There is increasing interest in the role of the HGF/MET pathway in the response of glioblastoma to radiotherapy. c-MET-mediated radioresistance may be partially induced via proinvasive and DNA damageresponse pathways and HGF may be involved in the regulation of immune responses. Here, we explored the role of the c-MET pathway in response to radiotherapy and investigated potential modes of action that mediate synergistic effects of MET pathway inhibition and irradiation in syngeneic murine glioma models in vitro and in vivo. Murine glioma cells express HGF and c-MET and respond with c-MET phosphorylation upon exposure to exogenous HGF. In vitro, glioma cell viability and proliferation are not affected by pharmacological or genetic c-MET pathway interference, and the c-MET inhibitor tepotinib fails to sensitize glioma cells to irradiation. Conversely, in vivo c-MET inhibition combined with focal radiotherapy synergistically prolongs survival in two syngeneic orthotopic glioma models compared with either treatment alone. Complementary studies demonstrated that synergy was lost when gliomas were established and treated in immunodeficient mice, and importantly, also when c-MET gene expression was disrupted in the tumor. Thus, synergistic suppression of experimental syngeneic glioma growth by irradiation and c-MET inhibition requires at least two mechanisms, expression of c-MET in the tumor and a functional immune system. In summary, our data suggest clinical evaluation of c-MET pathway inhibition in combination with radiotherapy in human glioblastoma.
EXTH-22. NEOADJUVANT IMMUNOTHERAPY WITH ANTI-PD1 ALTERS THE TUMOR MICROENVIRONMENT POST SURGERY IN A MODEL OF RECURRENT GLIOBLASTOMA
Authors: Hoang-Minh Lan , Doonan Bently , von Roemeling Christina , Yang Changlin , Shin David , Trivedi Vrunda , Karachi Aida , Wang Yu , Mitchell Duane 
Published: November 2021

Abstract

SIGNIFICANCE
New promising clinical trials for glioblastoma are evaluating the efficacy of neoadjuvant immunotherapy in the context of recurrent tumor surgery.

OBJECTIVE
We investigated the effects of neoadjuvant PD1 blockade on the glioma tumor microenvironment in a clinically relevant murine model of recurrent tumor.

RESULTS
Using an orthotopic mouse KR158 resection model of glioblastoma that we have established, we show that neoadjuvant anti-PD1 and surgery enhance animal survival and increase the recruitment of CD8+ and CD4+ T cells at recurrent tumor sites following bulk tumor resection compared to surgery followed by adjuvant immunotherapy. Transcriptome and spatial genomic analyses reveal alterations in immune exhaustion and activation pathway signaling after neoadjuvant anti-PD1treatment when compared with adjuvant anti-PD1-treatment or surgery alone.

CONCLUSIONS
These results provide insights into the effects of neoadjuvant PD1 blockade on the tumor microenvironment and uncover additional treatment targets.
EXTH-27. MOLECULAR CHARACTERIZATION AND PRECLINICAL DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITOR SPECIFIC FOR WILD-TYPE IDH1 FOR FERROPTOSIS INDUCTION IN GLIOBLASTOMA
Authors: Murnan Kevin , Tommasini-Ghelfi Serena , Hurley Lisa , Dussold Corey , Wahl Daniel , Stegh Alexander 
Published: November 2021

Abstract
Increased de novo synthesis, mobilization and uptake of fatty acids are required to provide sufficient lipids for membrane biogenesis in support of rapid tumor cell division and growth. In addition to their structural roles as components of the plasma membrane, fatty acid-derived lipids regulate ferroptotic cell death, a type of programmed cell death, when oxidized by iron-dependent lipoxygenase enzymes. De novo lipogenesis and the defense against oxidative lipid damage require large amounts of cytosolic NADPH. Our group has recently found that HGG up-regulate wild-type Isocitrate dehydrogenase 1 (referred to hereafter as ‘wt-IDH1high HGG’) to generate large quantities of cytosolic NADPH. RNAi-mediated knockdown of wt-IDH1, alone and in combination with radiation therapy (RT), slows the growth of patient-derived HGG xenografts, while overexpression of wt-IDH1 promotes intracranial HGG growth. Isotope tracer and liquid chromatography-based lipidomic studies indicated that wt-IDH1 supports the de novo biosynthesis of mono-unsaturated fatty acids (MUFAs) and promotes the incorporation of monounsaturated phospholipids into the plasma membrane, while displacing polyunsaturated fatty acid (PUFA) phospholipids. In addition, enhanced NADPH production in wt-IDH1high HGG increases glutathione (GSH) level, reduces reactive oxygen species (ROS), activates the phospholipid peroxidase glutathione peroxidase 4 (GPX4)-driven lipid repair pathway, and dampens the accumulation of PUFA-containing lipid peroxides, known executioners of ferroptosis. To pharmacologically target wt-IDH1,we have used and characterized wt-IDH1i-13, a first-in-class competitive α,β-unsaturated enone (AbbVie). wt-IDH1i-13 potently inhibits wt-IDH1 enzymatic activity, by covalently binding to the NADP+ binding pocket. Our data indicate that wt-IDH1i-13 promotes ferroptosis, which can be rescued by pre-treatment of cells with the peroxyl scavenger and ferroptosis inhibitor ferrostatin. wt-IDH1i-13 is brain-penetrant, and similar to genetic ablation, reduces progression and extends the survival of wt-IDH1high HGG bearing mice, alone and in combination with RT. These studies credential to wt-IDH1i-13 as a novel therapeutic modality for the treatment of wt-IDH1 gliomas.