bluuebunny/crossref_metadata_2025 huggingface dataset:
ACTR-17. DIAGNOSTIC UTILITY OF SERUM microRNA CLASSIFICATION IN DIFFUSE GLIOMA
Authors: Ohno Makoto , Matsuzaki Juntaro , Kawauchi Junpei , Aoki Yoshiaki , Miura Junichiro , Takizawa Satoko , Kato Ken , Sakamoto Hiromi , Matsushita Yuko , Takahashi Masamichi , Miyakita Yasuji , Ichimura Koichi , Narita Yoshitaka , Ochiya Takahiro
Published: November 2019

To improve clinical outcomes, a less invasive screening test for detection of diffuse glioma is needed. The purpose of this study is to establish models using serum microRNAs (miRNAs) to distinguish between diffuse glioma patients from non-cancer controls (Glioma Index) and between glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastatic brain tumors (Meta) (3-Tumor Index). A total of 580 patients, including 266 with brain or spinal tumors and 314 non-cancer controls, were analyzed. Non-cancer control samples were collected from the National Cancer Center Biobank and members of the general population undergoing routine health examinations. Expression of serum 2565 miRNAs was assessed in each sample, and the expression profiles were compared between diffuse glioma patients and non-cancer controls, and between GBM, PCNSL, and Meta. Diagnostic models were established using a training set, and diagnostic performance was confirmed in validation and exploratory sets and area under the receiver operating curve (AUC), sensitivity, specificity, and accuracy were used to evaluate their diagnostic performances. The Glioma Index was constructed using three miRNAs. The AUC was 99%, with sensitivity of 95% and specificity of 97% in the validation set. The Glioma Index classified 93% of PCNSL, 89% of Meta, 91% of benign brain tumors, and 0% of spinal tumors as positive in the exploratory set. The 3-Tumor Index was constructed using 48 miRNAs and had an accuracy of 0.80 in the validation set, positively detecting 94.1% of GBM, 80% of Meta, and 50% of PCNSL. In conclusion, we developed novel serum miRNA discriminant models to detect diffuse glioma from non-cancer control and to discriminate tumor histology. These models could serve as less invasive screening tools or complementary diagnostic tools, thereby decreasing neurosurgical risks.
ACTR-18. A PHASE IB/II CLINICAL TRIAL OF DODECAFLUOROPENTANE EMULSION (DDFPE) AS A RADIOSENSITIZER IN GLIOBLASTOMA
Authors: Lickliter Jason , Ruben Jeremy , Jennens Ross , Kichenadasse Ganessan , Gzell Cecelia , Mason Ralph , Carmody Raymond , Becker Jennifer , Stea Baldassarre , Zhou Heling , Sellenger Michael , Longacre Olivia , Graham Kaitlin , Unger Evan
Published: November 2019

BACKGROUND

Tumor hypoxia decreases the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). The purpose of this study was to evaluate the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response.

METHODS

With ethics approval and informed consent, 11 adult GBM patients were enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) within 5–30 minutes prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) while breathing supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To evaluate the reversal of tumor hypoxia, patients underwent oxygen-sensitive (TOLD) MRI before and after DDFPe administration. Patients were also studied with serial MRI scans per standard of care and followed for survival.

RESULTS

The non-serious adverse events considered by the investigator to be possibly, probably, or definitely related to DDFPe administration included fatigue (n=4), headache (n=2) and decrease in platelet count (n=2). Serious adverse events included two patients with symptomatic radiation necrosis: one patient at each of dose levels 0.1 and 0.17 mL/kg. Enrollment continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. Historically, the average overall survival for GBM patients is about 14.6 months. The median overall survival for the study was 591 days, or 19.4 months. According to independent review of the serial MR images, the median time to progression was 555 days, or 18 months, compared to a historical control of 6.9 months. TOLD MRI showed a trend in improved tumor oxygenation.

CONCLUSION

Although small, this trial shows that DDFPe used as a radiosensitizer appears to be safe and may provide some survival benefit. The FDA has allowed a Phase II clinical trial to assess its effectiveness.
ACTR-31. THE USE OF TTFIELDS FOR NEWLY DIAGNOSED GBM PATIENTS IN GERMANY IN ROUTINE CLINICAL CARE (TIGER: TTFIELDS IN GERMANY IN ROUTINE CLINICAL CARE)
Authors: Bähr Oliver , Tabatabai Ghazaleh , Fietkau Rainer , Goldbrunner Roland , Glas Martin
Published: November 2019

OBJECTIVE

Survival for the most common brain tumor, glioblastoma (GBM), has not improved since 2005, despite numerous phase 3 trials. The phase 3 EF-14 trial demonstrated significantly improved overall, progression-free and long-term survival in newly diagnosed GBM (ndGBM) patients by addition of TTFields to adjuvant temozolomide chemotherapy. As there is very high interest among prescribing physicians from all disciplines to further evaluate these effects in routine clinical care, the aim of the TIGER study is to assess safety and efficacy of TTFields in routine care and reasons for patients refusing TTFields treatment, quality of life, treatment duration and compliance.

METHODS

The TIGER study is a multi-centre, prospective, non-interventional study in Germany (NCT03258021). All ndGBM patients who are eligible for TTFields therapy are asked for consent for study-participation and comprehensively introduced to the therapy to allow them to make a conscious positive or negative therapy decision. At baseline and 2–4 months after treatment start, demographic data, the QoL and reasons for therapy decision are evaluated utilizing the EORTC-QLQ-C30/BN-20 and TTFields questionnaire. Inclusion of 1000 patients is planned (500 with positive/negative treatment decision, respectively) with a follow-up period of 18 months.

RESULTS

At the last data cut-off (May 2019), 497 patients have made a decision regarding treatment with TTFields. Within this population, 84% of patients decided to undergo TTFields therapy. The median age of patients included in the trial is currently 58.3 years (19–85). 91% of patients report that the prospect of treatment success considerably or strongly affects treatment decision. Most recent data will be presented at the meeting.

CONCLUSION

Systematic and prospective data assessment for using TTFields in routine clinical care including patient’s therapy decision can be evaluated in TIGER. Additionally, the study supports the analysis of treatment duration and usage rate, which could drive future assessment of TTFields treatment duration.
ACTR-33. INFIGRATINIB (BGJ398) IN PATIENTS WITH RECURRENT GLIOMAS WITH FIBROBLAST GROWTH FACTOR RECEPTOR (FGFR) ALTERATIONS: A MULTICENTER PHASE II STUDY
Authors: Lassman Andrew , Sepúlveda-Sánchez Juan , Cloughesy Timothy , Gil-Gil Juan , Puduvalli Vinay , Raizer Jeffrey , De Vos Filip , Wen Patrick , Butowski Nicholas , Clement Paul , Groves Morris , Belda-Iniesta Cristobal , Steward Keith , Rowsey Steven , Ye Yining , Roth Patrick
Published: November 2019

INTRODUCTION

FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion is predictive of response to FGFR tyrosine kinase inhibitors pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor with anti-tumor activity in several solid tumors with FGFR genetic alterations.

METHODS

Open-label phase II trial of adults with recurrent high-grade gliomas following failure of initial therapy (NCT01975701). Tumors harbored FGFR1-TACC1 or FGFR3-TACC3 fusions, activating mutations in FGFR1, 2 or 3, or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg d1–21 q28d. Prophylaxis for hyperphosphatemia was recommended. Primary endpoint: 6-month progression-free survival (6mPFS) rate by RANO (locally assessed); goal of >40%.

RESULTS

As of Sep 2017, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥ 2 prior regimens) were treated; 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All had FGFR1 or FGFR3 gene alterations; 4 had >1 gene alteration. Estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). Best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. Most common (>15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions/reductions (most commonly hyperphosphatemia).

CONCLUSIONS

Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes; analysis of biomarker data is ongoing.
ACTR-40. PHASE 2 SAFETY AND EFFICACY OF AR-67 (7-T-BUTYLDIMETHYLSILTYL-10-HYDROXYCAMPTOTHECIN) IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME (GBM) OR GLIOSARCOMA
Authors: Kumthekar Priya , Raizer Jeffrey , Cavaliere Robert , Devoe Craig , Jensen Randy , Stieber Volker , Runk Tina , Grewal Jai , Brownell Elise , Zukiwski Alex , Proniuk Stefan , Arnold Susanne , Vredenburgh James
Published: November 2019

BACKGROUND

AR-67 (formerly DB-67) is a novel 3rd generation camptothecin with improved safety and lipophilicity than current drugs in this class. Safety and efficacy of AR-67 were evaluated in a Phase 2 study in recurrent GBM/gliosarcoma in adult patients.

METHODS

AR-67 (7.5 mg/m2) was administered once daily by IV infusion for 5 consecutive days on a 21-day cycle. Cohort 1 patients (N=31/46 enrolled) had not received (or had not recently failed) bevacizumab. Cohort 2 patients (N=13/46 enrolled) had failed bevacizumab within 90 days before screening. Cohort assignments for 2/46 patients were undetermined. Tumor response was assessed ≥14d after every second cycle and before every third cycle using MRI. Primary endpoints were 6-month PFS (Cohort 1), and 2-month PFS (Cohort 2).

RESULTS

45/46 patients received ≥ one dose of AR-67; one patient (Cohort 1) died prior to dosing. Efficacy: 6/30 (Cohort 1) and 2/13 (Cohort 2) treated patients achieved the primary endpoints of 6- and 2-month PFS, respectively. Across the study, PR was the best overall response in 3/45 treated patients, all in Cohort 1. SD was the best overall disease response in 7/45 treated patients (5 in Cohort 1 and 2 in Cohort2). Safety: AR-67 was well tolerated; 17 patients (38%) exhibited serious adverse events (SAEs) including headache and Grade 4/5 muscular weakness (2.2%). Most TEAEs were mild/moderate in intensity and Grade 1–3 intoxicity. Notably absent was Grade 4 diarrhea, a hallmark of other approved camptothecin chemotherapies.

CONCLUSIONS

AR-67 was well tolerated and exhibited a safety profile consistent with or better than currently approved camptothecins. 6/30 treated patients in Cohort 1 and 2/13 patients in Cohort 2 achieved the primary endpoints of 6- and 2-month PFS, respectively. PR was the best overall response in 3/45 treated patients and SD was the best overall response in 7/45 patients.
ACTR-41. AN ARGUMENT THAT MORE ADJUVANT TEMOZOLOMIDE THERAPY IS BETTER FOR GLIOMA PATIENTS
Authors: Levin Victor , Patel Alyssa , Le Amy , Thomas Piia , Scott Peak
Published: November 2019

Current guidelines for adjuvant temozolomide (TMZ) treatment of glioma patients advocates 6 to 12 monthly cycles. Is that best? Will patients who receive > 12 cycles live longer? To find out, we conducted a 10-year (2006–2016) chart review of 1300 glioma patients treated at NorCal Kaiser Permanente facilities to determine the impact of dose-week (AUC) quartiles and duration of TMZ therapy quartiles on median overall survival (mOS) in new low- and mid-grade gliomas (Group A) and glioblastoma (Group B) patients. Group A had 357 patients with WHO grade II and III astrocytic and oligodendroglial tumors; Group B had 943 patients with glioblastoma. The median AUC in Group A was 337 mg/m2 (IQR 129, 1095) and the median weeks of TMZ 15 (IQR 1, 42). In Group B, median AUC was 210 mg/m2 (IQR 79,581) and median weeks of TMZ 24 (IQR 9. 45). Based on quartile ranking of AUC, a higher AUC was found to be associated with longer mOS in Group A and B. In Group A, for increasing AUC quartiles, mOS was 134, 146, 369, and 397 weeks (p=0.0014); for Group B, mOs were 30, 48, 74, and 117 weeks (p< 0.0001). Based on increasing quartiles for TMZ treatment duration for quartiles 2–4, Group A patient mOS increased from 122 weeks to 431 weeks (p = ns) and Group B patients, increased mOS from 51 to 143 weeks (p< 0.0001). This retrospective analysis of 10-years of neuro-oncology practice brings into question limiting TMZ dose in WHO grade 2–3 glioma and WHO grade 4 glioblastoma patients as higher dose toleration and longer duration of treatment appears to be associated with longer mOS in both groups. Or does it show that patients who do well elect to take TMZ longer and maybe these findings reflect reverse causality?
ACTR-42. PI3K/mTOR PATHWAY ACTIVATION SELECTED PHASE II STUDY OF EVEROLIMUS (RAD001) WITH AND WITHOUT TEMOZOLOMIDE IN THE TREATMENT OF ADULT PATIENTS WITH SUPRATENTORIAL LOW-GRADE GLIOMA [NCT NCT02023905]
Authors: Taylor Jennie , Molinaro Annette , Rodriguez Almaraz Eduardo , Downey Ciara , Phillips Joanna , Ann Oberheim-Bush Nancy , Butowski Nicholas , Chang Susan , Berger Mitchel , Prados Michael , Haas-Kogan Daphne , Clarke Jennifer
Published: November 2019

Functional activation of the PI3K/AKT/mTOR pathway is seen in ~50% of low-grade gliomas and correlates with worse survival. Everolimus is a selective inhibitor of mTOR that targets mTOR-raptor signaling, halting proliferation and indirectly inhibiting angiogenesis. This phase 2 study evaluated the efficacy of everolimus in untreated grade II diffuse glioma. Patients were stratified by 1p19q status and PI3K pathway activation (via phosphorylation of PRAS-40) into three arms: 1) 1p19q intact, PRAS-40 phosphorylated received everolimus monotherapy; 2) 1p19q intact, PRAS-40 not phosphorylated received everolimus with temozolomide; and 3) 1p19q co-deleted received everolimus monotherapy. Primary outcome was landmark PFS-33 months for Arms 1 and 2; and PFS-38 months for Arm 3 (null hypothesis 50% for all arms individually). Key eligibility criteria included central pathology confirmation, no prior treatment, and initiation of everolimus within 120 days of most recent tissue sampling. From 05/2014 to 07/2018, 27 patients were enrolled – 16 into Arm 1; 2 into Arm 2; and 9 into Arm 3. Median age at enrollment was 38 years (range 21 – 65); median KPS 90 (range 70 – 100) and a majority were male (74%). Although follow-up is not complete, as of 05/2019 11 of 16 patients had progressed prior to 33 months in Arm 1, and 5 of 9 patients had progressed prior to 38 months in Arm 3. Toxicity was as expected with frequent grade 1/2 AEs of diarrhea, rash, and mucositis. Headache was the most common grade 3 AE and was seen in three cases. The study was closed prematurely secondary to slow accrual and loss of drug support. Updated survival data as well as results of secondary and exploratory analyses will be reported. In summary, everolimus was well tolerated in previously untreated low-grade gliomas. However, it failed to meet primary outcome of extending PFS in this population.
ACTR-47. PHASE-III TRIAL OF STANDARD CHEMOTHERAPY VS. CHEMOTHERAPY GUIDED BY CANCER STEM CELL TEST IN RECURRENT GLIOBLASTOMA (NCT03632135)
Authors: Ranjan Tulika , Aregawi Dawit , Lu-Emerson Christine , Schroeder Jason , Anderson Mark , Chaudhary Rekha
Published: November 2019

Stupp treatment protocol for patients with glioblastoma (GBM) has improved the median overall survival to 14.6 months. However, no investigations have defined effective strategies against recurrence and the prognosis of recurrent GBM patients remains poor. Personalized medicine with assay-guided treatment targeting chemotherapy resistant cancer stem cells (CSCs) alongside the bulk tumor cells is a new paradigm in cancer treatment that may result in improved patient’s outcome. We are using ChemoID, a CLIA and CAP certified CSC cytotoxicity assay for predicting response to chemotherapeutic agents. Our prospective analysis of 61 GBM patients demonstrated that ChemoID-guided treatment significantly improved tumor response. For every 5% increase in cell kill of CSCs by assay-guided chemotherapy, 12-month patient response (non-recurrence of cancer) increased 2.5-fold, OR=2.3 (p=0.01). We also found that median recurrence time was 20-months versus 3-months for patients with a positive (>40% cell kill) CSC test versus negative, whereas median recurrence time was 13-months versus 4-months for patients with a positive (>55% cell kill) bulk test versus negative. We are conducting a multi-institutional phase-III clinical trial (NCT03632135) to determine the clinical validity of the ChemoID assay as a predictor of clinical response in recurrent GBM. The study has been designed as a parallel group controlled clinical trial and the participants are randomized to either standard of care chemotherapy chosen by the physician or ChemoID-guided therapy. Response to therapy will be measured by MRI imaging using RANO criteria. Primary endpoint of median overall survival (OS) and secondary endpoints of OS at 6, 9, and 12 months, median progression free survival (PFS), PFS at 4, 6, 9, and 12 months, objective tumor response, time to recurrence, and quality of life will be measured. Trial is open and currently 22 subjects have been enrolled. Interim analysis of the trial will be conducted in approximately 12 months.
ACTR-49. INITIAL EXPERIENCE WITH SCALP PRESERVATION AND RADIATION PLUS CONCURRENT ALTERNATING ELECTRIC TUMOR-TREATING FIELDS (SPARE) FOR GLIOBLASTOMA PATIENTS
Authors: Song Andrew , Ly Michele , Bar-Ad Voichita , Werner-Wasik Maria , Glass Jon , Martinez Nina , Andrews David , Judy Kevin , Evans James , Farrell Christopher , Shi Wenyin
Published: November 2019

INTRODUCTION

Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with electric tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-preserving radiation with concurrent TTFields.

METHODS

We conducted a single arm pilot study. Adult patients (≥ 18 years old) with KPS ≥ 60 with newly diagnosed glioblastoma were included. All patients received concurrent scalp-preserving radiation (60 Gy in 30 fractions), standard temozolomide (75 mg/m2 daily), and TTFields (200 kHz; ≥ 18 hr daily). Maintenance therapy included standard temozolomide and TTFields. Radiation treatment was delivered through TTFields arrays. Our primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma.

RESULTS

Here we report the first seven patients on the trial. Five were male, and 2 female, with median age 58 y/o (range 49–73). Median KPS was 90. Median follow-up was 5.2 months (range 1.4–11.2). MGMT status was unmethylated for 6 patients, and one unknown, and no IDH mutations. Four (57.1%) received gross total resection and three (42.9%) had subtotal resection. All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. There was no related Grade 3 or higher toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in all patients, however, limited to Grade 1 or 2 which resolved spontaneously or responded to topical medications. All patients were alive at time of writing. Two (28.6%) patients had progression, of which one (at 9 months) continued TTFields and temozolomide with bevacizumab, while the other (at 4 months) discontinued TTFields and underwent re-resection with bevacizumab.

CONCLUSIONS

Concurrent TTFields with scalp-preserving chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.
SURG-03. THERAPEUTIC VALUE OF SURGICAL RESECTION OF BRAIN METASTASES: A RETROSPECTIVE ANALYSIS OF 147 CASES
Authors: Mou Yonggao , Duan Hao , He Zhenqiang , Guo Chengcheng , Jiang Xiaobing
Published: November 2019

OBJECTIVE

Brain metastases are the most common malignant tumors of the central nervous system. In patients with brain metastases with surgical indications, total surgical resection is the most effective treatment for prolonging patient survival and relieving neurological symptoms. In this study, the clinical data of 147 patients in a single group underwent microsurgery of brain metastases were retrospectively analyzed to investigate the therapeutic value of microsurgery in patients with brain metastases.

METHODS

From January 2000 to December 2017, patients who underwent microsurgical removal of brain metastases from the Department of Neurosurgery in Sun Yat-sen University Cancer Center were retrospectively analyzed. The clinical and pathological features and prognosis of the patients were collected and analyzed. The characteristics of brain metastases were analyzed through surgical recording and videos.

RESULTS

A total of 147 patients were enrolled, including 86 males and 61 females. The average age was 54.4 years, of which 125 were younger than 65 years old. 137 people with KPS ≥ 70. 95.9% (141 patients) had an RPA grade of I-II, of which 51 (34.7%) were RPA class I and 90 (61.2%) were RPA class II. 90.5% (133 patients) were single brain metastases. 71.5% (105 cases) of patients with metastases are located in the cerebral area. The distribution of primary lesions suggested that the lung cancer was the most, reaching 62.6%; followed by breast source (10.9%). The surgical video analysis suggest that most brain metastatic lesions have obvious supplying vessels, relatively clear boundaries with a pseudo-capsule structure. The 5-year OS of all patients reached 15% with a median survival of 42.3 months.

CONCLUSION

The brain metastases have clear blood supplying vessels and relatively clear boundaries that favors gross total resection. Surgical treatment is associated with better prognosis in patients with brain metastases.
SURG-06. FOLLOWING INTRAOPERATIVE TUMOR-FREE PRINCIPLES IS AN EFFECTIVE APPROACH TO IMPROVE SURVIVAL OF PATIENTS WITH GLIOBLASTOMA
Authors: Mou Yonggao , Fuad Al-Nahari , Duan Hao , He Zhenqiang , Zhang Guanhua , Zhang Xiangheng , Sai Ke , Ke Chao , Zhang Ji , Jiang Xiaobing , Lin Fuhua , Chen Zhenghe , Chen Yinsheng
Published: November 2019

The intraoperative tumor-free principles refer to the operation techniques that must be carried out to prevent the exfoliation and planting of tumor cells during the operation, so as to prevent local recurrence and distant metastasis. Following the intraoperative tumor-free principles has been valued in resection of extracranial solid tumors. However, the significance of intraoperative tumor-free principles for brain tumors is still unclear. We retrospectively analyzed 106 patients with primary glioblastoma who underwent resection following the intraoperative tumor-free principles from 2010 to 2016. By February 28, 2019, 11 (10.4%) patients were lost to follow-up. The median overall survival (OS) was 20.2 months, and the 1-, 3-, and 5-year survival rates were 71%, 30%, and 26%, respectively. For patients with complete tumor resection, the median OS was 24.8 months, and the 1-, 3-, and 5-year survival rates were 80%, 38%, and 36%, respectively. Patients who received postoperative Stupp regimen had a median OS of 74.1 months, and the 1-, 3-, and 5-year survival rates were 82%, 51%, and 51%, respectively. A total of 36 patients had complete tumor resection followed by Stupp regimen. Their 1-, 3-, and 5-year survival rates were 94%, 68%, and 68%, respectively. Median OS was not reached. The patient with the longest OS had survived for 108 months and was still alive. In summary, the OS of patients in this study was relatively longer than that reported in most previous literatures, which suggests that following the intraoperative tumor-free principles in resection of GBM can benefit patient survival.
SURG-09. CHANGING PARADIGMS IN THE MANAGEMENT OF CEREBRAL METASTASES
Authors: Telemi Edvin , Snyder James , Lee Ian , Robin Adam
Published: November 2019

INTRODUCTION

Paradigms in the management of cerebral metastases (CM) are evolving, in part due to the expanded use of laser interstitial thermal therapy or LITT in lesion ablation, with treatment of CM comprising up to 34% of all LITT cases. Currently, CM are treated with LITT largely in the setting of disease progression after initial therapy with focused radiation with no standard for performing biopsy prior to LITT. In this study we aim to assess the significance of the pathology of the lesion at the time of LITT on survival.

METHODS

We conducted a retrospective review of our institution’s LITT/brain tumor database and identified patients who underwent LITT with concurrent biopsy. For deceased patients, we identified cause of death if secondary to neurologic causes defined as death either due to direct intracranial disease progression leading to rapid neurologic decline or due to progressive neurologic decline without significant extracranial disease burden.

RESULTS

We identified 16 progressive CM lesions in 15 adults treated with LITT with concurrent biopsy, predominantly with non-small cell lung cancer. The mean age at LITT was 62, median follow-up was 8.5 months and thirteen of fifteen patients had previous focused radiation therapy. Eleven of sixteen lesions demonstrated radiation necrosis(RN) without tumor and 5 with tumor progression(TP). The mean survival in patients with RN was 548 days compared with 285 days in patients with TP (p=0.15). Of the 9 deceased, 2 of 5 patients with RN and 3 of 4 patients with TP died of neurologic causes.

CONCLUSIONS

Although statistically not significant due to the small sample size, this preliminary analysis suggests that clinically significant differences in survival and cause of death may exist between patients with RN and TP. Further evaluation with implications for treatment, prognosis and the expectant management of the patient with CM is warranted.
SURG-11. PATTERNS OF RECURRENCES OF OLFACTORY NEUROBLASTOMA AFTER SURGICAL RESECTION
Authors: Hee Chang Jong , Hyung Moon Ju , Hyun Kim Eui , Sung Lee Kyu , Suh Chang-Ok
Published: November 2019

INTRODUCTION

Patterns of failure in patients with olfactory neuroblastoma (ONB) according to two surgical approaches, craniofacial resection (CFR) and endoscopic surgery (ENDO), have yet to be analyzed.

METHODS

We retrospectively reviewed 30 patients with surgically treated ONB between January 1995 and October 2018. Sixteen (53.3%) patients underwent CFR (9 CFR alone, 7 ENDO-assisted CFR) and 14 (46.7%) underwent ENDO. Twenty-one (70.0%) patients underwent post-operative radiotherapy (RT).

RESULTS

At a median follow-up of 53.8 months (range 10.4–195.3), the 5-year progression-free survival (PFS) and 10-year overall survival were 37.3% and 57.5%, respectively. Patients with adjuvant RT had a 5-year PFS of 46.7%, whereas those treated with surgery alone had a 5-year PFS of 19.4% (p = 0.01). Locoregional failure (LRF) occurred in ten patients (median 59.6 months after initial diagnosis; range 12.7–59.7). Neck node metastasis occurred in 23.3% (7 of 30). Five patients with ENDO showed LRF and underwent proper subsequent treatments with either surgery or adjuvant RT. Approximately 31.3% patients (five patients) in the CFR group experienced distant metastasis in the intracranial dura region (median 116.4 months after initial diagnosis; range 2.6–142.4). Three of four patients who developed LRF after CFR developed dura-based metastasis.

CONCLUSIONS

Both dura-based and neck node metastasis in the delayed phase were distinct patterns of failure in ONB. Patterns of recurrence differed based on surgical approach; dura-based metastases were common after CFR. LRF was the distinct failure pattern in ENDO, but could be successfully salvaged. Treatment outcome was improved considerably with RT following surgical resection.
SURG-16. SUPRATOTAL VERSUS GROSS TOTAL RESECTION OF GLIOBLASTOMA: A SYSTEMATIC REVIEW
Authors: Jackson Christina , Choi John , Price Carrie , Bettegowda Chetan , Lim Michael , Gallia Gary , Weingart Jon , Brem Henry , Mukherjee Debraj
Published: November 2019

INTRODUCTION

Due to the infiltrative nature of glioblastoma(GBM) outside of the contrast enhancing region in the peritumoral zone, there is increasing movement to perform supratotal resections (SpTR) by extending the edge of resection beyond the contrast enhancing portion of the tumor. However, there is currently no consensus on the potential survival benefit of SpTR in GBM as compared to gross total resection (GTR).

METHODS

Therefore, we performed a systematic review using PRISMA guidelines and performed a comprehensive literature search on Pubmed, EMBASE, The Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov, from inception to August 16, 2018, to identify articles comparing overall survival (OS) after SpTR versus GTR. Furthermore, we assessed study quality using the Oxford Centre for Evidence-Based Medicine guidelines.

RESULTS

We identified 8902 unique citations, of which 11 articles and 2 abstracts met study inclusion criteria. 925 patients underwent SpTR out of a total of 2137 patients. 9 of the 13 studies demonstrated improved survival with SpTR compared to GTR (median improvement in OS of 10.5 months), with no significant difference in post-operative complication rate. Conversely, one abstract found worsened outcomes with SpTR compared to GTR (median decrease in OS of 4 months). However, overall study quality was poor, with 12 of the 13 studies of level IV evidence and one study of level IIIb evidence. We were unable to perform a meta-analysis due to significant clinical and methodological heterogeneity amongst the studies (e.g. differences in adjuvant therapy and lack of standardization of definition of supratotal resection).

CONCLUSIONS

Our systematic review indicates that SpTR may be associated with improved OS compared to GTR for GBM. However, this is limited by poor study quality and significant clinical and methodological heterogeneity amongst the studies. There is need for prospective clinical trials to further establish standardized guidelines for SpTR in GBM.
ACTR-61. A RANDOMIZED PHASE 2 TRIAL OF CEDIRANIB IN COMBINATION WITH OLAPARIB VERSUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Arrillaga-Romany Isabel , Sahebjam Solmaz , Picconi David , Campian Jian , Giglio Pierre , Drappatz Jan , Aiken Robert , Villano John , Lee Eudocia , Welch Mary , Ellingson Benjamin , Ney Douglas , Becker Kevin , Muzikansky Alona , Das Biswajit , Swisher Elizabeth , Nixon Andrew , Karlovich Chris , Mickey Williams P , Percy Ivy S , Batchelor Tracy , Gerstner Elizabeth
Published: November 2019

BACKGROUND

Like most proliferating tumors, GBM relies heavily on accurate DNA repair for maintenance of genome stability. Dysfunction in repair of both single and double strand DNA breaks by PARP inhibition and impairment of homologous recombination, respectively, would be synthetically lethal. In this study we combined the PARP inhibitor olaparib with cediranib, a pan VEGF receptor inhibitor. Cediranib may mediate disruption in the homologous recombination pathway through its antiangiogenic properties.

METHODS

Through the Experimental Therapeutics Clinical Trials Network, we performed an open-label randomized phase II study of bevacizumab (BEV)- naive adult patients with first or second recurrence of glioblastoma after radiation and temozolomide. Patients were randomized 1:1 to receive either olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily or BEV 10 mg/kg IV every 2 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included safety and overall survival. Exploratory objectives included blood, tissue and imaging-based biomarkers of response to treatment.

RESULTS

Seventy patients were enrolled. Median age was 60.5 years (range: 19–79), 39% females, median KPS was 90 (range: 60–100). Baseline characteristics were well balanced. With a data cut-off of 5/2/2019, PFS6 was 14% [95% CI 4–30%] in the cediranib/olaparib arm vs 30.9% [95% CI 12.7–51.2%] in the BEV arm. Median OS was 247 days in the cediranib/olaparib arm vs 201 days in the BEV arm, HR 0.816, 95% CI (0.431, 1.546). Related grade 3, 4 or 5 toxicity was experienced in 29% vs 12% of patients for the cediranib/olaparib vs BEV arm.

CONCLUSION

Treatment with cediranib/olaparib failed to increase PFS and OS in patients with recurrent GBM. Blood, tissue and imaging correlates will be presented to help understand why this treatment combination was unsuccessful.
TMIC-03. UPREGULATION OF THE NLRC4 INFLAMMASOME CONTRIBUTES TO POOR PROGNOSIS IN GLIOMA PATIENTS
Authors: Lim Jaejoon , Park Youngjoon , Kim Minjun , Ahn Juwon , Kwack KyuBum , Cho Kyunggi
Published: November 2019

Inflammation in tumor microenvironments is implicated in the pathogenesis of tumor development. In particular, inflammasomes, which modulate innate immune functions, are linked to tumor growth and anticancer responses. However, the role of the NLRC4 inflammasome in gliomas remains unclear. Here, we investigated whether the upregulation of the NLRC4 inflammasome is associated with the clinical prognosis of gliomas. We analyzed the protein expression and localization of NLRC4 in glioma tissues from 11 patients by immunohistochemistry. We examined the interaction between the expression of NLRC4 and clinical prognosis via a Kaplan-Meier survival analysis. The level of NLRC4 protein was increased in brain tissues, specifically, in astrocytes, from glioma patients. NLRC4 expression was associated with a poor prognosis in glioma patients, and the upregulation of NLRC4 in astrocytomas was associated with poor survival. Furthermore, hierarchical clustering of data from the Cancer Genome Atlas dataset showed that NLRC4 was highly expressed in gliomas relative to that in a normal healthy group. Our results suggest that the upregulation of the NLRC4 inflammasome contributes to a poor prognosis for gliomas and presents a potential therapeutic target and diagnostic marker.
TMIC-19. H+ EXTRUSION PROTEIN NA/H EXCHANGER IN METABOLIC POLARIZATION OF GLIOMA-ASSOCIATED MICROGLIA/MACROPHAGES AND TUMOR IMMUNITY
Authors: Nabiul Hasan Md , Guan Xiudong , Ahuja Avani , Castro Maria , Kohanbash Gary , Sun Dandan
Published: November 2019

Immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) attributes to poor efficacy of chemotherapy and/or immunotherapy. We recently reported that SLC9A1 gene expression (Na/H exchanger 1, NHE1) in GBM tumor correlates with increased macrophage tumor infiltration and worsened patient survival. Temozolomide (TMZ) monotherapy, the standard care therapy for GBM, stimulates NHE1 protein expression in mouse syngeneic glioma models. We speculate that in response to TMZ therapy, NHE1 promotes immunosuppressive TME development via deregulation of glucose metabolism and anti-tumor function of immune cells. CD57BL/6 mice bearing GL26 glioma tumor were treated with NHE1 inhibitor HOE-642 (H, 0.3 mg/kg/day), TMZ (T, 2.5 mg/kg/day), and/or anti-PD-1 (10 mg/kg/day) monotherapy or in combination. The T+H+anti-PD-1 combination therapy increased glucose uptake (2-NBDG) and mitochondrial mass (mitotracker fluorescent intensity) of tumor infiltrating CD8+ T-cells by ~2-fold compared to the monotherapies. This suggests that NHE1 protein is involved in metabolic transformation of T-cells and affects their responses to chemo and/or immunotherapy. Furthermore, we detected that specific deletion of Nhe1 in Cx3Cr1CreErT2r+/-;Nhe1f/f mice (Nhe1 KO) alters activation of glioma-associated microglia/macrophages (GAM) and T-cells in response to TMZ therapy. TMZ monotherapy stimulated macrophage (CD11b+CD45hi) infiltration by ~2.5-fold in Cx3Cr1CreErT2-/-;Nhe1f/f (Nhe1 Con) mice bearing SB28-GFP glioma tumor with abundant proinflammatory CD16/32+ GAMs. In contrast, TMZ treated Nhe1 KO mice displayed ~3-fold reduction in tumor infiltrating GAMs with nearly abolished Ym-1+ tolerogenic macrophages, ~3-fold reduction of tumor-promoting CD4+CD25+FoxP3+ regulatory T-cells (Treg) and increased CD8+/Treg ratio by ~2-fold than the Nhe1 Con mice. Importantly, TMZ followed by anti-PD-1 therapy prolonged survival of Nhe1 KO mice but not Nhe1 Con mice. Taken together, our study suggests that NHE1 is involved in transformation of GAMs and PD-1 check point activation of T-cells. Blocking NHE1 function in combination with TMZ and anti-PD-1 may restore glucose metabolism of immune cells necessary for their anti-tumor function.
TMIC-22. IDENTIFICATION OF CANCER-ASSOCIATED FIBROBLASTS IN GLIOBLASTOMA and Defining Their Protumoral Effects
Authors: Rick Jonathan , Nguyen Alan , Chandra Ankush , Wadhwa Harsh , Shah Sumedh , Wang Lin , Lau Darryl , Safaee Michael , Ordaz Angel , Yagnik Garima , Diaz Aaron , Aghi Manish
Published: November 2019

While cancer-associated fibroblasts (CAFs) and their pro-tumoral effects have been demonstrated in systemic cancers, CAFs had been presumed absent in glioblastoma given the lack of normal fibroblasts in the healthy brain. Here, we show that 5–26% (mean=12%) of cells in human glioblastomas express CAF markers α-SMA or PDGFR-β, morphologically resemble fibroblasts, and transcriptomically resemble by RNA-seq CAFs from other cancers. Glioblastoma CAFs were chemotactically attracted to glioblastoma-initiating stem cells (P=0.02). While glioblastoma CAFs did not affect differentiated glioblastoma cell proliferation (P=0.4), CAFs increased glioblastoma stem cell proliferation (P=0.002) and expression of glioblastoma stem cell-associated genes (P< 0.001). To identify mediators of CAF/glioblastoma stem cell interactions, we created a resource of inferred crosstalk by mapping the expression of receptors to that of their cognate ligands/agonists, using our RNA-seq results from glioblastoma CAFs and stem cells, revealing PDGF-β/PDGFR and osteopontin/CD44 to mediate stem cell recruitment of CAFs and CAF enrichment of stem cells, as confirmed by blocking antibodies (P=0.02–0.03). CAFs also render the glioblastoma microenvironment more pro-tumoral by promoting M2 polarization of tumor-associated macrophages (P=0.01), an effect we found to arise from unique CAF production of the EDA splice variant of fibronectin binding toll-like receptor 4 (TLR4), a known EDA receptor expressed by macrophages (P=0.02). In patient glioblastomas, CAFs were enriched 3-fold in the subventricular zone (SVZ) (P=0.04) which houses the neural stem cells that generate glioblastoma stem cells. SVZs from epilepsy cases or autopsies of glioblastoma-containing brains without ventricular involvement lacked CAFs. Depleting CAFs in xenografts derived from neurosphere-containing glioblastoma stem cells slowed their growth in vivo (P< 0.001). These findings are among the first to identify and profile glioblastoma CAFs. CAF recruitment by glioblastoma stem cells and creation of a pro-tumoral microenvironment in the perivascular niche housing glioblastoma stem cells, particularly in the SVZ, makes them an intriguing therapeutic target.
ACTR-64. PHASE 2 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF PI3K/mTOR INHIBITOR GDC-0084 IN GBM PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE (MGMT) PROMOTER STATUS
Authors: Wen Patrick , DeGroot John , Battiste James , Goldlust Samuel , Garner James , Simpson Jeremy , Kijlstra Jelle , Olivero Alan , Cloughesy Timothy
Published: November 2019

BACKGROUND

GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR). GDC-0084 crosses the blood-brain barrier and achieves a brain / plasma ratio of approximately 1.0. GDC-0084 was given as once daily dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established PI3K/mTOR inhibitor class-effects. The MTD identified was 45mg once daily.

METHODS

The current study is conducted in the newly diagnosed GBM patient with unmethylated MGMT promotor status upon completion of standard adjuvant XRT/TMZ. It has a 2-part design: an open-label, dose-escalation phase to assess the safety, tolerability, MTD (Part 1, followed by an expansion cohort (Part 2) commencing once MTD is established. Dose-escalation started at 60mg, and progressed in 15mg increments, per standard 3 + 3 rules. Part 2 recruits 20 patients, who are randomized to take GDC-0084 at the identified MTD, in fed and fasted states.

RESULTS

Part 1 of the study is complete. There were no DLTs among 3 pts treated at the 60mg. Among 6 pts treated at 75mg, DLTs were identified as hyperglycaemia (symptomatic) and oral mucositis. Adverse effects seen were generally modest, manageable and consistent with the PI3K-class. PK parameters are in line with phase 1 data. Part 2 recruitment is ongoing.

CONCLUSION

GDC-0084 displays a safety profile consistent with previous data in recurrent high-grade glioma but appears better tolerated in the newly diagnosed GBM setting. An MTD of 60mg is identified.
TMIC-32. PARALLEL SINGLE CELL NUCLEOSOME OCCUPANCY AND RNA SEQUENCING ON RECURRENT GBM
Authors: Shireman Jack , Gauchat Eric , Eckart Heather , Park Cheol , Basu Anindita , Pott Sebastian , Ahmed Atique
Published: November 2019

Nearly all patients diagnosed with Glioblastoma (GBM) will experience a fatal recurrence of the tumor. Thought to be in part driven by immense tumor heterogeneity it is important to explore the small subpopulations of tumor cells with in depth single cell sequencing pre and post therapy in order to understand recurrence. To this end, we created an experimental in vivo pipeline that allows us profile not only gene expression changes during therapy, but also epigenetic shifts due to methylation across the genome at the single cell level from a single tumor. Single Cell NomE-Seq libraries were created and correctly identified characteristic CTCF binding regions within DNase1 hypersensitivity regions when compared back to representative encode data sets. Primary tumors analyzed by single cell RNA sequencing showed enrichment for on average 5 significant principle components (St. Dev >2 verified by Elbow Plot). Comparatively, recurrent temozolomide (TMZ) exposed tumors averaged 10 significant principle components (St. Dev >2 verified by Elbow Plot) suggesting TMZ therapy causes tumors to diversify their gene expression profiles. For direct comparison samples were merged into a continuous data set and dimensional analysis with TSNE reduction (15 dimensions used) identified 6 unique clusters, with one cluster being over-represented by cells from recurrent, TMZ exposed mice. Gene Ontology analysis on expression values contained within in this cluster demonstrated significant enrichment for ribosome biogenesis/ribosomal structure, (p=2.87e-17) and mRNA catabolic processes (p=2.47e-30). Further, comparison to a similar data set gathered using cells in vitro culture conditions demonstrates superior intraturmoral heterogeneity from cells isolated freshly from the brains of mice as opposed to tissue culture, indicating the effectiveness of our model for assaying heterogeneity. Ultimately, these data illuminate possible new mechanisms for TMZ induced ribosomal modifications underlying intraturmoral heterogeneity in GBM and provide an expandable technique for further experimentation.
TMIC-35. IDH1 MUTATION IN GLIOMA REPROGRAMS EARLY MYELOID DIFFERENTIATION IN THE BONE MARROW (BM) TO PRODUCE NON-IMUNESUPPRESSIVE NEUTROPHILS
Authors: Alghamri Mahmoud , Castro Maria , Lowenstein Pedro , Kamran Neha , Kadiyala Padma , Avvari Ruthvik , Zhang Li
Published: November 2019

Gliomas are the most common primary brain tumors; patients exhibit a poor prognosis. Mutations in isocitrate dehydrogenase (mIDH) are present in most patients with lower grade glioma (LGG), and are correlated with better prognosis and survival. We postulated that mIDH1 induces epigenetic reprogramming leading to alteration in immune cells’ function. To examine the role of mIDH1 in the tumor immune microenvironment (TME), we generated LGG glioma models using the sleeping beauty system (Koschmann et al., 2016, Nunez et al., 2019). We show that mIDH1 gliomas exhibit increased levels of CD11b+ Gr1+ myeloid derived suppressor cells in the tumor, BM, circulation and spleen of mice. We found that mIDH1 modifies the cytokines’ repertoire in the glioma microenvironment altering the phenotype and function of the tumor infiltrating CD45+/CD11b+/Gr-1+ myeloid cells, rendering them non-immunosuppressive. Production of these cells results from activation of the granulocytic differentiation program in the BM. This novel mechanism is mediated by tumor-derived granulocyte-colony stimulating factor (G-CSF) which elicits expansion and differentiation of hematopoietic stem cells, skewing hematopoiesis towards the immature myeloid lineage. Moreover, mIDH1 glioma derived G-CSF causes mobilization of hematopoietic stem cells (HSCs) and myeloid progenitors (MPs) from BM to spleen. Blocking G-CSF in mIDH1 bearing mice significantly restored HSCs, and MPs frequencies in the spleen to levels encountered in wtIDH1 glioma. Interestingly, blocking G-CSF restored the inhibitory function of the granulocytic CD11b+ Gr-1+ in mIDH1, and shortened the median survival (MS) of mIDH1 bearing mice to the same MS encountered in wtIDH1 glioma. Our results provide insights into novel epigenetic alterations triggered by mIDH1 which regulate myeloid cells’ heterogeneity and immunosuppression; a feature that can be harnessed to develop novel immunotherapeutic strategies.