bluuebunny/crossref_metadata_2025_split huggingface dataset:
STEM-28. TARGETING KIF11 TO RADIOSENSITIZE GLIOBLASTOMA
Authors: Zalenski Abigail , Montgomery Miranda , De Kuntal , Grubb Treg , Venere Monica 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common primary brain tumor, and is incredibly lethal, with less than 10% of patients surviving more than 5 years after diagnosis. These tumors are routinely treated with radiotherapy, although we and others have shown that there is a subpopulation of GBM cells, called cancer stem-like cells (CSCs), that are radio-resistant, and do not respond to this standard therapy. We aim to overcome the radio-resistance of GBM CSCs by using radiotherapy in combination with a KIF11 inhibitor. We previously reported that the mitotic kinesin KIF11, required for bipolar spindle formation during mitosis, is elevated in GBM and portends poor prognosis. We also demonstrated that invasiveness and self-renewal of CSCs could be targeted with ispinesib, a small molecule inhibitor to KIF11. Furthermore, survival of mice bearing orthotopic glioblastoma was prolonged with KIF11 inhibition, although tumor burden increased with cessation of treatment. To combat tumor recurrence after treatment cessation, we proposed to use a KIF11 inhibitor with radiotherapy. KIF11 inhibitors will arrest cells in G2/M, where they are most sensitive to radiotherapy. By enriching CSCs in G2/M, we hypothesized that we would overcome CSC radio-resistance to decrease CSC viability and improve survival. We first tested the efficacy of combining a KIF11 inhibitor and irradiation in vitro. We found that using combination therapy to treat CSCs significantly decreased CSC survival over vehicle or either treatment used as a monotherapy. We then investigated the effects of combination therapy in vivo. Using a KIF11 inhibitor combined with irradiation increased survival of mice bearing orthotopic glioblastoma. Our results suggest that targeting KIF11 in combination with radiotherapy is a promising technique to overcome the radio-resistance of CSCs, and holds potential to significantly improve treatment outcomes and extend survival of patients with GBM.
SURG-01. OPTIMALTTF-1: FINAL RESULTS OF A PHASE 1 STUDY: FIRST GLIOBLASTOMA RECURRENCE EXAMINING TARGETED SKULL REMODELING SURGERY TO ENHANCE TUMOR TREATING FIELDS STRENGTH
Authors: Korshøj Anders , Mikic Nikola , Lukacova Slavka , Christian Sørensen Jens , Hansen Frederik , Thielscher Axel , Cortnum Søren , Guldberg Trine , Ramshad-Lassen Yasmin , Rahbek Christian , Severinsen Kåre , von Oettingen Gorm 
Published: November 2019

Abstract

BACKGROUND
OptimalTTF-1(open-label phase-1) combines Tumor Treating Fields(TTFields) treatment with targeted skull-remodeling surgery(SR-surgery) aiming to enhance the electric field strength in the tumor(NCT02893137). SR-surgery aims to reduce the electrical impedance of the skull. Pre-clinical modeling indicates that SR-surgery increases the electric field strength. The final analysis examined toxicity and efficacy of TTFields combined with SR-surgery and best-choice-chemotherapy in first glioblastoma recurrence(rGBM).

METHODS
18 patients were screened and 15 (4F/11M) enrolled between Dec2016 and Mar2019. The primary endpoint was frequency of serious adverse events (CTCAEv4.0) and secondary endpoints were overall survival (OS) and progression-free survival (PFS). Eligible patients were ≥18-years, had focal supratentorial rGBM, KPS≥70, and a minimum calculated increase in TTFields strength of ≥25% after SR-surgery. At the time-of-analysis patients were censored for time-to-event endpoints.

RESULTS
Baseline data(median (range)) demonstrated a patient age of 57(39;67), skull defect area=10.6 cm2(7;37), increase in the TTFields strength by 43%(25;59). All tumors were IDH-wt and 4 had MGMT-promoter methylation. In total, 4 patients were excluded from the study prior to TTFields initiation (consent withdrawal, radionecrosis/non-recurrence, postoperative infection and neurodeficit), 11 patients (2F/9M) underwent treatment. Treatment compliance was 90%(48;98), mean treatment duration and follow-up was 6.8 months(2.3;20.4) and 10 months respectively. Grade 1–2 AEs included, headache 60% CI95%=[32;84], fatigue 53%, CI95%=[27;79], skin rash 47%, CI95%=[21;73], and nausea 40%, CI95%=[16;68]. No grade 3 SAEs were related to the intervention (6 seizures, 1 headache, 1 fatigue, 1 TIA, 1 post-op infection, 1 diarrhea and 1 DVT). Efficacy outcomes were PFS6=64%, CI95%=[35;85], PFS=8.8 months, CI95%=[6.2;13.2], OS=15.0 months, CI95%=[9.6;16.2], and OS12=64%, CI95%=[35;85].

CONCLUSION
Targeted SR-surgery combined with TTFields is safe and does not induce additional toxicity. Furthermore, it potentially increases overall survival in rGBM. A phase 2 clinical trial is currently being planned.
SURG-05. EXPERIENCE PROFILING OF FLUORESCENCE-GUIDED SURGERY FOR GLIOMAS
Authors: Young Ji So , Eun Lee Chae , Chowdhury Tamrin , Wook Kim Jin , Park Chul-Kee 
Published: November 2019

Abstract
Numerous studies reported a usefulness of 5-ALA fluorescence-guided surgery (FGS) in high grade gliomas. However, fluorescence pattern and intensity is variable among gliomas. In this study, we report our extensive experiences of FGS in various gliomas focusing on epidemiological data of fluorescence pattern. A total of 827 histologically proven glioma patients out of 900 brain tumor patients who had undergone FGS using 5-ALA during the period of 8.5 years between July 2010 and January 2019 were analyzed. Indication for FGS in glioma surgery harbored any evidence of possible high-grade foci at presumed gliomas in preoperative magnetic resonance images (MRI). Among the 827 gliomas, the number of cases corresponding to 2016 World Health Organization (WHO) grade IV, III, II, and I are 528 (58.7%), 193 (21.4%), 87 (9.7%) and 19 (2.1%), respectively. In terms of fluorescence rate, grade IV gliomas showed positive fluorescence in 95.4% of cases including strong intensity in 85.6%. Grade III gliomas showed fluorescence in about half of cases (55.0%), while 45.0% of cases did not show any fluorescence. Anaplastic oligodendroglioma had more positive rate (63.9%) than anaplastic astrocytoma (46.2%). Both grade II and I gliomas still showed positive fluorescence in about one-fourths of cases (24.1% and 26.3%, respectively). Among them ependymoma and pilocytic astrocytoma were fluorescence-prone tumors. This epidemiological data of 5-ALA fluorescence in various grades of gliomas provides fundamental reference to clinical application of FGS using 5-ALA in glioma surgery.
SURG-08. SURGICAL OUTCOMES OF PITUITARY ADENOMAS TREATED WITH TRANSSPHENOIDAL SURGERY: A SINGLE INSTITUTION’S EXPERIENCE
Authors: Beom Seo Young , Kim Oh-Lyong 
Published: November 2019

Abstract
We retrospectively analyzed surgical outcomes of transsphenoidal surgery for pituitary adenomas. A total of 366 consecutive patients undergoing transsphenoidal surgery for a pituitary adenoma from December 1990 through May 2017 were included in this study. The most common tumor type was nonfunctioning pituitary adenoma (NFPA) (63.7%), followed by prolactin-secreting adenoma (20.5%), growth hormone-secreting adenoma (13.4%), adrenocorticotropin-secreting adenoma (2.2%), and thyrotropin-secreting adenoma (0.2%). This cohort study consisted of 164 male and 202 female patients. The median patients age was 48 years. The median follow-up duration was 63 months. Gross-total resection (GTR) was achieved in 83.7% of patients with a NFPA, 76% of prolactin-secreting adenomas, 71.4% of growth hormone-secreting adenomas, 75% of adrenocorticotropin-secreting adenomas, 100% of thyrotropin-secreting adenomas. There were 326 macroadenomas (69.1%). Surgical outcome was better in patients with microadenomas than in patients with macroadenomas (100% and 77.9%, respectively). Improvement of visual disturbances occurred in 148 (93.7%) of the 158 cases. Hormonal impairment by pituitary adenoma was improved in 105 (87.5%) of the 120 cases. There were 24 (8.2%) cases of recurrence after GTR; 17 patients underwent second surgery, 5 patients received radiotherapy, and the others continued conservative treatment. The median time interval between TSA and recurrence was 56 months. Postoperative cerebrospinal fluid leakage occurred in seven (1.9%) of 366 patients. Transsphenoidal surgery is an effective and safe treatment modality for most patients with pituitary adenoma.
SURG-20. IDENTIFICATION OF INFILTRATIVE CANCER CELLS AT THE GLIOMA RESECTION CAVITY MARGIN USING STIMULATED RAMAN SCATTERING MICROSCOPY
Authors: Morshed Ramin , Pekmezci Melike , Young Jacob , Aghi Manish , McDermott Mike , Theodosopoulos Philip , Berger Mitchel , Hervey-Jumper Shawn 
Published: November 2019

Abstract

INTRODUCTION
Microscopic residual disease at the tumor margin is the primary barrier to complete resection which impacts outcome. Stimulated Raman scattering microscopy (SRM) has proven effective to classify CNS tumor tissue and detect tumor cells within grossly normal post mortem glioma specimens. In this study, we use SRM for detection of residual glioma cells within the resection cavity margins.

METHODS
Patients with gliomas undergoing surgical resection were included. Margin samples were taken after the primary surgeon determined the resection cavity wall to be grossly normal and were analyzed using (1) true H&E, (2) SRM pseudo H&E, (3) immunohistochemical stains (IHC) for IDH1-R132H or p53. The sections were scored on a scale of 0–3 by a neuropathologist blinded to the corresponding results from each modality (0=no definite tumor cells; 1=rare tumor cells; 2=moderate tumor cells with preserved neuropil; 3 = abundant tumor cells). Positive and negative predictive values and Spearman correlation coefficients were calculated.

RESULTS
Ninety-one margin samples from 19 patients were included. Tumors were WHO grade II (29.7%), III (38.5%), and IV (31.8%). There was a strong correlation between SRM and H&E (Spearman correlation (r) = 0.76), SRM and IHC (r=0.81), and H&E and IHC scores (r=0.91). PPV of SRM score of 3 was 100%. The presence of tumor cells on SRM (scores 1–3) strongly correlated with the presence of tumor cells on H&E (PPV = 95%) and IHC (PPV = 91%). The absence of tumor cells on SRM correlated with absence of tumor on H&E and IHC only 10% and 50% (NPV) of the time, respectively.

CONCLUSIONS
The PPV of utilizing SRM to detect residual glioma cells in grossly normal resection cavity margins is high however the NPV is low. SRM may have utility as a rapid point-of-care intraoperative tool for identification of infiltrative glioma within resection cavity margins.
SURG-28. RADIOFREQUENCY ABLATION AS AN ADJUNCT FOR PAIN AND TUMOR CONTROL IN SPINAL METASTATIC DISEASE
Authors: Urbisci Tony , Thomas Bryan , Tran Nam 
Published: November 2019

Abstract

BACKGROUND
The spine, particularly the thoracolumbar region is a common site for metastatic spread from a variety of primary cancer types. Radiofrequency ablation (RFA) of these lesions has proven efficacious for pain control, but the addition of adjunctive radiation therapy (XRT) remains the standard of care for pain palliation and to prevent tumor progression.

OBJECTIVE
This study aims to investigate RFA as a standalone intervention to treat and prevent the progression of metastatic vertebral lesions. Study Design: Single center retrospective review of patients receiving RFA for vertebral metastatic lesions between 2013 and 2016. Twenty-nine spinal lesions in nineteen patients were treated with RFA followed by vertebral augmentation. Primary tumors were from prostate, renal cell, breast, lung, laryngeal, multiple myeloma, cervix, thyroid, and colon. The treated levels were then followed with either MRI, PET CT, or CT at varying intervals per the primary oncologist. We compared the duration between the procedure and either first imaging evidence of tumor progression at the treated level or patient death between patients that underwent RFA alone or with the addition of adjunctive XRT.

RESULTS
Our comparison shows no significant difference (p < 0.357) between the time to progression between the group that received RFA alone and the group that received RFA in conjunction with XRT.

CONCLUSION
Radiofrequency ablation is a safely and effectively used in the treatment of vertebral metastatic osseous lesions. Although the sample size is small, and the patient population is heterogenous, there is supporting evidence that targeted RFA is as effective in preventing local tumor progression as the procedure combined with XRT.
SURG-29. LASER INTERSTITIAL THERMAL THERAPY COMPARED TO CRANIOTOMY FOR TREATMENT OF RECURRENT GLIOBLASTOMA
Authors: Palejwala Ali , O’connor Kyle , Glenn Chad , Sughrue Michael 
Published: November 2019

Abstract
There have been publications that propose the use of laser interstitial thermal therapy (LITT) as a viable alternative to craniotomy for the treatment of glioblastoma (GBM). The aim of this study was to retrospectively compare outcomes after LITT versus craniotomy for patients with recurrent GBM. To adequately match the cohorts, we included only pre-treatment tumor volumes of under 15 cc. We retrospectively collected data on all patients presenting with recurrent GBM, with a recurrence volume under 15 cc. These patients were either treated with LITT or craniotomy by the senior author. Data included demographics, tumor location and volume, tumor markers, perioperative complications, re-initiation of adjuvant chemotherapy, and long-term follow up data. We performed 23 LITT treatments and 34 craniotomies for recurrent GBM in patients that met selection criteria. There was no significant difference in the patients’ age, tumor volume (6.38 for craniotomy versus 5.765 cc for LITT), location, and post-procedure KPS. Patients that underwent LITT had significantly reduced inpatient stays in comparison to craniotomy (1.7 versus 4.2 days). They also had less perioperative complications (13.0% versus 32.3% for craniotomy). It was found that 28 out of the 34 patients that underwent craniotomy were able to undergo adjuvant therapy; in comparison, 15 out of the 23 patients who underwent LITT had undergone adjuvant therapy. Of these patient’s that underwent adjuvant therapy, 87% of patients were able to receive bevacizumab or a clinical trial versus 42% after craniotomy. Progression-free survival (PFS) and overall survival (OS) after procedure were similar for LITT versus craniotomy, respectively: % PFS-survival at 6 months = 23.5% versus 21.7%. Overall survival did not significantly differ at 9 months versus 9.9 months respectively. LITT appears to be safe and may be as efficacious as craniotomy in achieving progression free survival for small to moderate volume recurrent GBM.
SURG-34. CLINICAL PREDICTORS OF TUMOR RECURRENCE AFTER PITUITARY ADENOMA RESECTION
Authors: Jackson Christina , Vo Chau , Daniels Marcus , Chaichana Kaisorn 
Published: November 2019

Abstract

INTRODUCTION
Repeat surgery after tumor recurrence after pituitary adenoma resection can be challenging due to formation of scar tissue and loss of surgical landmarks, which can lead to increased rates of postoperative complications. Identification of clinical predictors of tumor recurrence would allow for appropriate stratification of patients to optimize preoperative counseling and postoperative management.

METHODS
We conducted a retrospective review of 349 patients who underwent pituitary adenoma resection at Johns Hopkins Hospital between 2003 and 2017. We used unadjusted and adjusted logistic regression to identify predictors of tumor recurrence. Factors which were associated with tumor recurrence in univariable models (p< 0.1), were included in our multivariable model. Factors that remained significantly associated with tumor recurrence (p< 0.05) in our multivariable model were considered predictors of recurrence.

RESULTS
59 (16.9%) patients developed tumor recurrence at the time of our study. Patients who had surgery through one nare, transcranial surgery, visual field deficit, larger tumor volume, bilateral cavernous sinus invasion, carotid artery invasion, and postoperative cerebral spinal fluid (CSF) leak were more likely to have tumor recurrence. Conversely, patients who are younger in age, had sphenoid packing, and gross total resection were less likely to have tumor recurrence. In our multivariable model, only age (adjusted odds ratio[aOR]: 0.96), surgery through one nare (aOR: 2.05), gross total resection(aOR: 0.21), and presence of CSF leak(aOR: 4.43) remained significantly associated with tumor recurrence.

CONCLUSIONS
We identified several predictors of tumor recurrence after pituitary adenoma resection. Notably, having gross total resection of the primary tumor had the most significant protective effect on tumor recurrence. Given the increased complication associated with repeat surgery, gross total resection should be attempted in all patients, if feasible. Patients with other predictors of tumor recurrence should be monitored more frequently to allow for early detection of recurrence to optimize treatment strategies.
TMIC-01. THE DYSTROGLYCAN RECEPTOR MAINTAINS GLIOMA STEM CELLS IN THE VASCULAR NICHE
Authors: Day Bryan , Lathia Justin , Bruce Zara , Ensbey Kathleen , Chieh Lim Yi , Jamieson Paul , D’Souza Rochelle , Akgul Seckin , Offenhauser Carolin , Baumgartner Ulrich , Smith Fiona , Li Yuchen , Jurd Courtney , Stringer Brett , Robertson Thomas , Jeffree Rosalind , Johns Terrance , Bhat Krishna , Rich Jeremy , Campbell Kevin , Boyd Andrew 
Published: November 2019

Abstract
Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding alpha (α) subunit of the dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the vascular niche. Glycosylated αDG is also expressed highly on the most aggressive mesenchymal-like GBM tumour tissue. Furthermore, we found that DG acts to maintain a de-differentiated stem cell-like phenotype via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor not only as a structural element but also as a critical factor in the maintenance of GSCs in the GBM vascular niche.
TMIC-02. JUNCTIONAL ADHESION MOLECULE-A (JAM-A) DEFICIENCY DRIVES SEX-SPECIFIC DIFFERENCES IN GLIOBLASTOMA PROGRESSION VIA DIFFERENTIAL MICROGLIA RESPONSES IN THE TUMOR MICROENVIRONMENT
Authors: Turaga Soumya , Silver Daniel , Paouri Evi , Bayik Defne , Peng Sen , Connor James , Barnholtz-Sloan Jill , Rubin Joshua , Berens Michael , Davalos Dimitrios , Lathia Justin 
Published: November 2019

Abstract
Despite the male preponderance for developing glioblastoma (GBM) and better survival outcomes in females, current treatment paradigms do not account for biological sex as a biological or clinical variable. Sex-specific molecular alterations that drive tumor cell growth and therapy response have been documented, however, sex-specific extrinsic differences in the tumor microenvironment have yet to be identified. Based on well-established sex-specific gene signatures and functional differences in microglia, we interrogated influences of male and female microglia in driving GBM growth. Specifically, manipulation of JAM-A expression, a tight junction protein on microglia, was exploited as a paradigm for determining effects on in vivo syngeneic GBM mouse models. Male and female JAM-A KO mice that received orthotopic injection of syngeneic GBM cells presented differential overall survival distinct from their wildtype counterparts. Wild-type male mice phenocopied human males, presenting shorter overall survival than females, this trend was reversed in JAM-A KO mice. Compared to the other genotypes, female JAM-A KO mice presented the greatest number of phagocytic, tumor-promoting, activated microglia. RNA-sequencing of tumors from JAM-A KO and WT mice revealed that female JAM-A KO mice had increased expression of Ifi202b (interferon activated gene 202b), a member of the Activity-regulated Inhibitor of Death (AID) gene family that contributes to mitochondrial resistance to cellular stress. Ifi202b has a role in sex-specific inflammatory diseases, which is consistent with our observation. Female KO microglia had enhanced Ifi202b expression, along with the secretion of Ifi202b associated cytokines, including interleukin-6. Treatment of wild-type female microglia with a JAM-A function blocking antibody demonstrated an increase in Ifi202b levels, confirming direct regulation of Ifi202b expression by neutralizing JAM-A. While cell intrinsic, sex-specific differences have been reported in GBM, our findings demonstrate that differences in the GBM tumor microenvironment also drive sexually dimorphic tumor growth.
TMIC-11. ENHANCED B7-H4 EXPRESSION IN GLIOMAS WITH LOW PD-L1 EXPRESSION IDENTIFIES COLD TUMORS
Authors: Chen Di , Li Gaopeng , Ji Chunxia , Lu Qiqi , Qi Ying , Tang Chao , Xiong Ji , Hu Jian , Hoon Dave S B , Zhang Yan , Yao Yu , Zhou Liangfu 
Published: November 2019

Abstract
The expression profiles of different immune checkpoint molecules are promising for triaging personalized targeted immunotherapy. Gliomas have been shown as potential targets for immune checkpoint inhibitors. Our study was performed to determine co-expression levels of two major B7 immune molecules PD-L1 and B7-H4 in gliomas in which both have demonstrated to inhibit anti-tumor host immunity. We assessed tumor issues from primary gliomas stage II–IV(n=505) by immunohistochemistry (IHC) for protein levels of both PD-L1 and B7-H4. Gene co-expression analysis assessing clusters based on extent of PD-L1/B7-H4 classifier genes expression were investigated in two transcriptome datasets (TCGA and CGGA) to validate IHC expression profiles. Here, we found that 61% and 54% of patient samples were positive for PD-L1 and B7-H4 respectively, whereby high-expression of either protein was limited to 23% and 20% respectively. Co-expression of PD-L1 and B7-H4 in high levels was limited to 2%. Comparable results were seen in RNA-seq datasets when PD-L1 mRNA expression level corelated negatively with B7-H4. Gene co-expression modules clustered in each grade gliomas without Double-High modules (glioma cluster with high mRNA expression of both PD-L1 and B7-H4 classifier genes) also verified restricted co-expression pattern. B7-H4 mRNA expression level had negative correlation with extent of immune cell infiltration, including tumor-infiltrating lymphocytes (TILs), and High-B7-H4 module gliomas (high B7-H4 but low PD-L1 classifier genes expression) were related to a cold tumor with less TILs. The majority of gliomas express PD-L1 or B7-H4, however, co-expression of both at high levels is minimal. The High-B7-H4 module was significantly lacking in TILs, suggesting that B7-H4 might inhibit T cell trafficking into the central nervous system (CNS). This study demonstrates that PD-L1 expression alone is not fully informative in gliomas for immune targeted or active-specific immunotherapy, and PD-L1 and B7-H4 probably inhibit different aspects of the T cell functions.