bluuebunny/crossref_metadata_2025 huggingface dataset:
INNV-25. PATIENT CENTERED MULTI-DISCIPLINARY NEURO-ONCOLOGIC CARE AS DIRECTED BY NEW PATIENT STAKEHOLDERS
Authors: Hunt Rachel , Robin Adam , Scarpace Lisa , Gay Nestelynn , Lee Ian , Walbert Tobias , Snyder James
Published: December 2020

Multidisciplinary oncology care requires a team of experts which should include patient stakeholders. The Henry Ford Health System (HFHS) Hermelin Brain Tumor Center (BTC) patient and family advisory council (PFAC) recommended a focus group of patient stakeholders newly diagnosed with glioblastoma(GBM) to better understand this experience. Our PFAC, comprised primarily of long-term survivors and patient advocates, felt the perspective of newly diagnosed patients may not be adequately represented. We reviewed the BTC tumor board records, identified patients within six months from GBM diagnosis, and invited these patients and their advocates to participate in an in-person session held November 2019. The BTC Patient Resource Coordinator who is also a brain tumor survivor led the session. Predefined questions prompted discussion of their neuro-oncologic care experience. Patient perspectives and recommendations were disseminated to the BTC PFAC and health system leaders. Nine patients and ten caregivers participated. Key feedback included the need for improved communication in the peri-operative period (symptom presentation until pathology results consultation). Participants requested more information prior to surgery on what to expect after surgery and with a brain tumor diagnosis. The PFAC-developed BTC experience handbook was declared useful, but patients did not receive this book until 2-weeks after surgery. As a result, we ensured that patients received a copy of the handbook at the time of diagnosis. Additionally, the development of a brain tumor surgery “prehab” course is underway. Use of a focus group to obtain input from patients recently diagnosed with GBM provided valuable insight into their experience that can be used to align care pathways with patient needs. Feedback was used to improve the delivery of neuro-oncologic care and enhance patient communication. In the constantly evolving landscape of GBM diagnosis and treatment, it is important to remain attuned to our patients’ perspectives on the care we deliver.
INNV-28. TEMOZOLOMIDE IN RENAL DYSFUNCTION
Authors: Garzio Kayla , McElroy Kelly , Grossman Stuart , Holdhoff Matthias , Ozer Byram , Yankulina Olga
Published: December 2020

BACKGROUND

Temozolomide (TMZ) is a cytotoxic DNA alkylating agent. It is the only chemotherapy known to improve survival in patients with high grade astrocytomas. The active alkylating species, methylhydrazine, is not recovered in the urine and thus renal function is not expected to affect clearance of this agent. It has never been formally evaluated in adults with eGFR < 36 mL/min/1.73 m2, and it is often recommended to administer with caution, dose reduce, or withhold therapy. However, lacking other effective therapies, we have elected to administer TMZ at full dose to these patients. This IRB approved retrospective study was conducted to evaluate the safety of this practice.

METHODS

The primary endpoint was to characterize the incidence and severity of thrombocytopenia in patients with renal impairment defined as eGFR < 60 mL/min/1.73 m2 who received TMZ for the treatment of their high grade gliomas (HGG) or primary CNS lymphoma (PCNSL). Secondary endpoints included incidence and severity of neutropenia, lymphocytopenia, hepatotoxicity, and number of cycles administered. Medical records were reviewed for adult patients with HGG or PCNSL treated with TMZ from October 1, 2016-September 30, 2019.

RESULTS

Thirty-four patients met criteria for inclusion. Of the 7 patients with eGFR < 36 mL/min/1.73m2, 33/34 cycles (97%) were completed successfully without grade 3–4 thrombocytopenia. No patients experienced grade 3–4 neutropenia, and grade 3–4 lymphocytopenia occurred in 5 cycles (15%). One patient required discontinuation of TMZ 7 days prior to completion of radiation due to thrombocytopenia.

CONCLUSION

The side effect profile from TMZ administered to patients with eGFR < 36 mL/min/1.73 m2 appears to be similar to that of patients with normal renal function. This is not an unanticipated finding given what is known about the metabolism of the drug.
NCOG-17. PREDICTORS OF SURVIVAL IN ELDERLY PATIENTS UNDERGOING SURGERY FOR GBM
Authors: Voisin Mathew , Zadeh Gelareh
Published: December 2020

BACKGROUND

Despite the median age of diagnosis of GBM being 64 years old, there is only a paucity of studies on elderly patients with GBM. Furthermore, the majority of these studies examine treatment paradigms, and there is limited research on clinical and hospital factors on overall survival. The purpose of this study is to determine predictors of survival in elderly patients undergoing surgery for GBM.

METHODS

We searched our hospital brain tumour biobank database for all consecutive patients over a 14-year period from 2005 to 2018. All patients 65 years of age or older at time of surgery with a pathological diagnosis of de novo primary GBM were included. Kaplan-Meier survival curve and Cox proportional hazards model were constructed for overall survival vs age, sex, KPS, medical co-morbidities, extent of resection by surgeon, length of stay, postop complications, and discharge destination.

RESULTS

A total of 150 patients were included. The median age at time of surgery was 74 years old (range: 65-94). Median overall survival was 9.4 months (95% CI: 7.8-12.2). Variables associated with worse survival included longer length of stay (HR: 1.15, 95% CI: 1.02-1.30, p = 0.02), discharge destination other than home (HR: 1.91, 95% CI: 1.01-3.6, p = 0.04), and any postop complication (HR: 3.7, 95% CI: 1.87-7.3, p = < 0.001). The presence of any or multiple medical comorbidities was not associated with worse survival (p = 0.93 and 0.19, respectively).

CONCLUSIONS

The presence of medical comorbidities is not associated with worse survival in elderly patients undergoing surgery for GBM. In order to maximize survival in these patients, avoidance of postoperative complications is paramount, along with a short hospital stay and attempt to discharge these patients to their home.
NCOG-37. NATURAL LANGUAGE ASSESSMENT CORRELATES WITH HEALTH-RELATED QUALITY OF LIFE IN ADULT GLIOMA PATIENTS
Authors: Ammanuel Simon , Almeida Nyle , Kurteff Garret , Kakaizada Sofia , Molinaro Annette , Berger Mitchel , Chang Edward , Hervey-Jumper Shawn
Published: December 2020

PURPOSE

Impairments of speech are common in glioma patients and negatively impact health-related quality of life. The benchmark for clinical assessments is task-based measures that miss essential components of quality of life status. In this study, we test the hypothesis that variations in natural language (NL) correlate with health-related quality of life status.

MATERIALS AND METHODS

Natural language use was assessed using audio samples from 18 patients with newly diagnosed low- and high-grade gliomas collected unobtrusively. NL measures were correlated with the Quality of Life in Neurological Disorders (Neuro-QoL) outcomes at baseline. Spearman’s rank-order correlation was used to determine relationships between Neuro-QoL scores and NL measures.

RESULTS

Speech rate negatively correlated with functional domains of the Neuro-QoL (satisfaction with social roles: rho=-0.62, p=0.007; participate in social roles: rho=-0.74, p< 0.001;) while positively correlated with impairment domains(fatigue: rho=0.58, p=0.009).

CONCLUSIONS

Assessments of baseline natural language may be a useful tool in the context of treatment planning and monitoring outcomes.
NCOG-53. PREDICTORS OF ENDOCRINE OUTCOME AFTER ENDOSCOPIC TRANSSPHENOIDAL SURGERY FOR NON-FUNCTIONING PITUITARY ADENOMAS
Authors: Hwang Jenie , Yum Diane , Chicoine Michael , Dacey Ralph , Osbun Joshua , Rich Keith , Zipfel Gregory , Klatt-Cromwell Cristine , Mcjunkin Jonathan , Pipkorn Patrik , Schneider John , Silverstein Julie , Kim Albert
Published: December 2020

BACKGROUND

Although endoscopic transsphenoidal surgery (ETSS) is an established treatment for patients with nonfunctioning pituitary adenomas (NFPAs), data are limited regarding the rates and predictors of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS.

OBJECTIVE

To analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA.

METHODS

Among a cohort of 601 consecutive patients who underwent ETSS for NFPA between 2010 and 2018 at Washington University in Saint Louis, recovery or development of new hypopituitarism was retrospectively analyzed in 209 patients.

RESULTS

Preoperative endocrine deficits were observed in 59.8% of patients (125/209), and the deficit rates were 76.8% for male gonadal axis (86/112), 42.5% for thyroid axis, 25.8% for growth hormone axis, and 15.8% for cortisol axis. Recovery of preoperative pituitary deficit was noted in all four axes, with highest recovery in the cortisol axis with a 1-year cumulative recovery rate of 44.3%. New-onset postoperative hypopituitarism occurred most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Multivariate analyses revealed axis-specific predictors of postoperative recovery and de novo deficiency. Older age was a negative predictor for recovery of both male hypogonadism (P= 0.04) and adrenal insufficiency (P=0.046), and a larger tumor volume was a negative predictor for recovery of hypothyroidism (P=0.043). Although higher body mass index was generally associated with any new postoperative pituitary deficit (P=0.03), most predictors of new onset deficits also differed by hormone axis.

CONCLUSIONS

Dynamic changes in pituitary hormonal levels were observed in a significant fraction of patients following ETSS in NFPA patients. The specific hormonal axis dictated postoperative endocrine vulnerability, recovery, and predictors of recovery or loss of endocrine function.
NIMG-57. ASSOCIATION OF RADIOMICS BASED TUMOR SHAPE IRREGULARITY MEASURES AND GAMMA KNIFE DOSE PLANNING INDICES IN VESTIBULAR SCHWANNOMAS
Authors: Sümer Esra , Tek Ece , Şengöz Meriç , Pamir M Necmettiin , Dinçer Alp , Özcan Alpay , Özduman *Koray , Öztürk-Işık *Esin
Published: December 2020

Gamma knife radiosurgery (GKRS) delivers an unevenly distributed radiation dose to a tumor, with a sharp falloff outside the target. Although the dose inhomogeneity within a tumor is strongly influenced by its shape, routine GKRS dose planning does not account for it. We hypothesized that shape irregularity measures were correlated with treatment planning indices, and might provide insight during treatment planning. The aims of this study were to quantify the shape irregularity measures in vestibular schwannomas, estimate their correlations with core radiosurgical planning measures, and define the most predictive shape feature for dose effectiveness. METHODS: Four dose plan indices, which were the selectivity index (SI), gradient index (GI), efficiency index (EI), and Paddick’s conformity index (PCI) were estimated from the GKRS plans of 234 vestibular schwannomas. All dose plans were prepared using Gamma Plan 10.0 and above and all treatments were delivered using a perfexion/ICON platform. Three-dimensional (3D) tumor models were rendered using 3D Slicer Software from segmented T1-weighted MR images. Sixteen irregularity measures were calculated for each tumor using Radiomics in MATLAB. Spearman correlation coefficients (r) were computed to find associations of the dose plan indices with the irregularity descriptors. The most predictive shape feature for dose efficiency was identified using the least absolute shrinkage and selection operator (Lasso). RESULTS: The shape irregularity measures were negatively correlated with SI, EI, and PCI, and positively correlated with GI. Volumetric index of sphericity (VioS) had the highest correlations with SI (r = 0.63, p= 3.27E-23), GI (r= -0.58, p= 1.10E-19), EI (r = 0.69, p= 0.00), and PCI(r= 0.68, p = 6.73E-28), and Lasso feature selection identified VioS as the most important feature for predicting all dose plan indices. CONCLUSION: VioS provides a numerical quantification of tumor shape irregularity, and it is highly correlated with the GKRS dose planning indices. *indicates co-senior authors
NIMG-62. AMPHETAMINE-ASSOCIATED CNS VASCULITIS MASQUERADING AS TUMOUR
Authors: Shivaprasad Akhil , Qasim Muhammad , Langford Lauren , Fuller Gregory , El-Naggar Adel K , Vishwanathan Ashwin , Tremont-Lukats Ivo , Majd Nazanin
Published: December 2020

Amphetamine-associated CNS vasculitis is controversial. There are few reports but none as a tumor mimic to our knowledge. We describe a pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man presented with six weeks of progressive confusion and left-sided weakness. CT head reported a right thalamic mass with vasogenic edema. Laboratory tests were unremarkable except for cannabinoids and amphetamine in urine. MRI brain showed enhancement in right frontotemporal lobe, basal ganglia, and thalamus concerning for glioblastoma multiforme. After high-dose IV dexamethasone, an initial biopsy showed reactive gliosis, perivascular lymphocytic cuffing by CD3+, rare CD20+ cells and no infection. He continued to decline. MRI 22 days after admission showed increased T2/FLAIR hyperintensity, multifocal areas of enhancement, microhemorrhages, and ischemia. High-grade glioma, lymphoma and infectious encephalitis remained on differentials. Treatment included broad-spectrum antibiotics and acyclovir. Biopsy on 23rd day showed reactive gliosis with parenchymal macrophage infiltration and perivascular cuffing with mixed inflammatory infiltrates. CSF: slightly elevated WBCs (8/µL), elevated protein (139mg/dL), normal glucose, and no infection. MRI whole spine and CT body were unremarkable. The patient was transferred to MDACC 5.5 weeks after initial presentation. He was alert with expressive aphasia, right gaze preference, left hemiplegia, and right hemiparesis. He underwent a right anterior temporal lobectomy. Pathology showed extensive cortical laminar and white matter necrosis with macrophage infiltration and microglial activation. In areas of the preserved cortex, vasculocentric lymphocytic aggregates were present and reticulin staining showed lymphocytic infiltration of the vascular walls. Immunophenotyping (CD3, CD20) showed an almost pure T-cell population. The predominance of intramural T-lymphocytes reflected a vasculitic process. The final diagnosis was cerebral vasculitis with subacute infarction. The patient died six days later. The autopsy findings were identical to the previous resection without evidence of systemic inflammation.
PATH-27. CLINICAL, RADIOLOGIC AND PROGNOSTIC PROFILE OF IDH WILD TYPE DIFFUSE ASTROCYTOMA WITH MOLECULAR FEATURES OF GLIOBLASTOMA
Authors: Akintola Oluwatosin , Samore Wesley , Alvarez Maria Martinez-Lage , Gerstner Elizabeth
Published: December 2020

BACKGROUND

cIMPACT-NOW-3 recommends that IDH-wildtype diffuse astrocytic glioma Grade II or III with EGFR amplification, or combined whole chromosome 7 gain and whole chromosome 10 loss, or TERT promoter mutation should receive an integrated classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The aims of this study were: Outline the features of a cohort of patients with molecular glioblastoma according to the above criteria; Assess clinical and molecular factors that may inform prognosis; Determine if cIMPACT-NOW-3 recommendation changed clinical practice and clinical trial enrolment.

METHODS

61 patients diagnosed with IDH-wildtype diffuse astrocytic glioma Grade II or III and EGFR amp or mTERT or chromosome (+7/-10) between 2011 and 2019 at MGH were included in this single center retrospective cohort study. Data collected: sex, age, extent of surgery, functional status, histological grade, molecular diagnostics and treatment. Progression was defined using RANO criteria, progression was quantified in terms of months from the initial surgery. Survival was defined in terms of months from initial surgery to date of death or last known visit.

RESULTS

mOS was 16 months, mPFS was 9 months. 14 patients (23%) survived > 24 months, 7 ≥ 36 months (mOS 32 months; 9 deceased). The probability of survival in patients with markedly enhancing tumors was 0.5 at 3 months versus 0.5 at 11 months in non-enhancing tumors. The probability of survival in patients who underwent biopsy only was 0.5 at 5 months compared to 0.5 at 12 months in patients with maximally resected tumors. 1 patient was enrolled in a clinical trial at diagnosis. 6 were enrolled at time of recurrence.

CONCLUSIONS

mOS and pFS in the deceased patients was comparable to historical data on survival in IDH wild-type glioblastomas. Inclusion criteria in clinical trials have not reflected the cIMPACT-NOW-3 recommendation so far.
PATH-42. COMBINED NEXT GENERATION SEQUENCING AND IMMUNOHISTOCHEMISTRY IN THE DIFFERENTIAL DIAGNOSIS OF A PROGRESSIVE NEURONAL-GLIAL TUMOR: A COMPOSITE NEOPLASM
Authors: Kelly Nicholas M , Valyi-Nagy Tibor , Coleman Louis , Slavin Konstantin , Kpshy Matthew , Michals Edward , Arzbaecher Jean , Miller Clinton , Mohapatra Gayatry
Published: December 2020

BACKGROUND

Neuronal-Glial tumors (NGT) are rare neoplasms typically benign, and characterized by various admixtures of neuronal and glial components. Occasionally these tumors transform to higher grades and rarely develop other histologic features inconsistent with a neuroepithelial origin, raising the question of histogenesis. We present a case of World Health Organization (WHO) grade I ganglioglioma (GG) diagnosed in a 28 year old man whose tumor, over a period of 8 years, progressed to anaplastic ganglioglioma (AGG, WHO grade III) and ultimately AGG with high grade sarcomatoid features. The sarcomatoid component eventually outgrew the NGT components, resulting in the patient’s death. We used next generation sequencing (NGS) and immunohistochemistry to characterize the genetic changes associated with these events.

METHODS

Tissues representing NGT and sarcomatoid components were macrodissected from 6 samples representing the tumor during its evolution from low to higher grades. DNA and RNA were extracted from these samples and NGS performed using the Oncomine Comprehensive Panel. Whole exome sequencing was performed using DNA from the 6 tumor samples and adjacent non-neoplastic tissue.

RESULTS

The original tumor, WHO grade I ganglioglioma had a BRAF V600E mutation. Seven years later, the AGG component had the BRAF V600E, absent in the sarcomatoid component, which had a CDKN2A homozygous deletion. The following year, the sarcomatoid component appeared to predominate and had an additional PIK3CA activating mutation. The NGT component retained the original BRAF mutation but no others. Hierarchical clustering of genome-wide variants identified two distinct cell populations emerging over time: GG progressing to AGG and sarcomatoid tumor.

CONCLUSIONS

Based on these results, we propose two distinct tumor cell populations: GG/AGG and sarcomatoid component, evolving over time and resulting in what is commonly considered a collision tumor, two independent tumors adjacent to each other.
QOLP-02. PATIENT-REPORTED OUTCOMES FOLLOWING PERTUZUMAB PLUS HIGH-DOSE TRASTUZUMAB IN PATIENTS WITH HER2-POSITIVE METASTATIC BREAST CANCER (MBC) AND CENTRAL NERVOUS SYSTEM (CNS) PROGRESSION POST-RADIOTHERAPY
Authors: Kumthekar Priya , Sahebjam Solmaz , Pegram Mark , Ibrahim Nuhad , Sussell Jesse , Nicholas Alan , Fung Anita , Cheng Anna , Lin Nancy U
Published: December 2020

Effective therapies are needed for the treatment of patients with HER2-positive MBC who develop brain metastases. In the open-label, phase II PATRICIA study (NCT02536339), 40 patients with HER2-positive MBC with CNS metastases and CNS progression post-radiotherapy (median age 48 years [range, 34–69]; prior CNS treatment [whole brain radiotherapy 71%, stereotactic radiosurgery 59%, both 31%]) were enrolled to receive pertuzumab plus high-dose trastuzumab (6-mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Following a median (range) treatment duration of 4.5 (0.3–37.3) months, the CNS-confirmed objective response rate per Response Assessment in Neuro-Oncology Brain Metastases criteria (primary endpoint) was 11% (95% confidence interval: 3.03, 25.42), and the clinical benefit rate at 4 months was 68%, indicating sustained clinical stability. Patient-reported outcomes (PROs) were evaluated using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT), which includes sub-scales for symptom severity (average of 13 core symptom and 9 brain-tumor specific items) and symptom interference (average of 6 interference-with-life items representing overall symptom distress). Among 36 patients included in the PRO analyses, mean (standard deviation [SD]) symptom severity scores at baseline and weeks 12 and 28 were 1.65 (1.62), 2.24 (2.14), and 1.94 (2.55), respectively. Mean (SD) symptom interference scores at baseline and weeks 12 and 28 were 2.51 (2.63), 2.81 (3.39), and 1.76 (2.43), respectively. Mean (SD) changes in symptom severity and interferences scores from baseline to week 12 were 0.34 (1.54) and 0.33 (3.08), respectively. On average, patients who did not achieve stable disease or better in the CNS following treatment had worsened symptom severity and symptom interference scores over 12 weeks, while those with stable disease or better in the CNS exhibited stable or improving scores. Pertuzumab plus high-dose trastuzumab provided clinical benefit to the majority (68%) of patients in PATRICIA, without a decrement in quality of life.
RADT-10. SURVIVAL IN PATIENTS FULFILLING CCTG CE.7 ELIGIBILITY CRITERIA: EVALUATING INITIAL STEREOTACTIC RADIOSURGERY FOR 5-15 BRAIN METASTASES
Authors: Gurewitz Jason , Donahue Bernadine , Silverman Joshua S , Benjamin Carolina , Bernstein Kenneth , Kondziolka Douglas
Published: December 2020

INTRODUCTION

The suitability of stereotactic radiosurgery (SRS) in patients with 5-15 brain metastases (BM) is being evaluated in the ongoing CCTG CE.7 randomized trial testing SRS against HA-WBRT. Our study examines the survival of patients with 5-15 BM treated at initial SRS.

METHODS

Review of our Gamma Knife registry identified 163 patients who fulfilled CCTG CE.7 eligibility criteria.

RESULTS

92 females (56%) and 71 males (44%) with median age of 51.6 years (23-98.9) and primary diagnoses of lung (n = 108, 28 EGFR/ALK mutations), breast (n =14, 1 Her2+), melanoma (n = 27, 9 BRAF+), and 14 other were identified. 145 had active extracranial disease (89%); median KPS was 90 (50-100). Median number of tumors at first SRS was 8.2; 114 patients (70%) had 5-9 and 49 (30%) had 10-15 tumors. 73 patients (45%) had subsequent SRS to a median of 19 (6-84) cumulative subsequent tumors at a median time to 2nd treatment of 3.9 months (0.7-30.3). 32 patients (20%) had a 3rd SRS and 24 patients (15%) had 4 or more treatments. 16 patients (10%) received WBRT after initial SRS. 73 patients (45%) were alive at time of data analysis. Median OS from initial SRS for all patients was 15.5 months and was 15, 17.6, 13.4, and 8.7 months, for breast, lung, melanoma, and other respectively. Median OS with 5-9 metastases vs 10-15 metastases was 17.5 vs. 13.3 months (p=.15). Median OS with vs without subsequent SRS was 21.8 vs 8 months (p=.0013).

CONCLUSION

Patients with 5-15 BM treated with initial SRS can achieve survivals that compare favorably with or better than those of WBRT. These findings potentially challenge the assumption that such patients may be better candidates for HA-WBRT than upfront SRS. Our experience supports the ongoing efforts to prospectively evaluate upfront SRS in these patients.
RADT-36. PROSPECTIVELY ASSESSED TUMOR CONTROL AND TOXICITY OF BENIGN INTRACRANIAL PATHOLOGIES TREATED WITH AUTOMATED VMAT RADIOSURGERY – INITIAL 2 YEAR EXPERIENCE WITH FIRST 100 PATIENTS
Authors: Thomas Evan , Mullins Clarence , Bredel Markus , Dobelbower Michael , Willey Christopher , Spencer Sharon , Guthrie Barton , Riley Kristen , Markert James , Fiveash John , Boggs Drexell
Published: December 2020

BACKGROUND

HyperArc is a treatment planning technology that automates treatment planning and delivery of single-isocenter VMAT radiosurgery (SRS). The technique generates high quality, rapidly deliverable plans. It is unknown whether HyperArc is effective for commonly-encountered, benign, intracranial conditions managed with SRS. Under IRB-approved prospective registry, we collected data on treatment planning/delivery, and clinical outcomes of non-malignant conditions managed with single-fraction or fractionated SRS since deployment in October 2017.

METHODS

Patients received either single-fraction or fractionated SRS with HyperArc™ (Varian Medical Systems) between October 2017 & October 2019. Patients with < 3 months follow-up were censored. All patients treated received prescription dose to ≥ 99% of gross tumor volume without PTV expansion. All treatments were delivered on Varian Edge linac with 10MV flattening-filter free beam at 2400 MU/min with high-definition (2.5mm) multi-leaf collimator. Standard pathology-specific outcomes and toxicities were assessed. Significant CNS toxicity was defined as Grade 3 or higher event by CTCAE.

RESULTS

Total of 100 targets (min=0.13cc, max=58.9cc) were treated. 55 received single-fraction SRS (12-22Gy), two received 2-fraction fSRS boost (12Gy) following fractionated treatment, and 43 received 5-fraction fSRS (25-30Gy). The most common pathology was meningioma (n=55), followed by AVM (n=18), non-secretory pituitary adenoma (n=12), acoustic schwannoma (n=9), secretory pituitary adenoma (n=3), glomus tumor (n=2), pineocytoma (n=1), and paraganglioma (n=1). Follow-up ranged from 1.2 to 19.5 months (median 7.2). There were three local failures, all in atypical meningiomas. One patient in the cohort experienced ≥Gr3 toxicity. Each radiosurgery session used median of 3 arcs, with median treatment and beam-on time of 12.03 and 2.3 minutes. Plan quality was excellent; median RTOG conformity was 1.15, and median Paddick GI was 3.52.

CONCLUSION

Although HyperArc was developed for automated multiple-metastasis radiosurgery, we found it effective and efficient for benign intracranial indications too. Early clinical outcomes appear congruent with historical controls.
RADT-47. A MULTICENTER OBSERVATIONAL STUDY OF SURGICALLY TARGETED RADIATION THERAPY (START) USING IMPLANTED CS-131 SEEDS IN A COLLAGEN-BASED CARRIER TILE IN INTRACRANIAL BRAIN NEOPLASMS - PROTOCOL IN PROGRESS
Authors: Nakaji Peter , Brachman David , Misell Lisa
Published: December 2020

INTRODUCTION

Post-resection radiotherapy (RT) is the most effective adjuvant treatment for brain tumors. However, there is no current consensus as to the “best” type of post-resection RT, either at diagnosis or recurrence. The use of internally placed radiation (brachytherapy) allows immediate initiation of RT when residual tumor burden is minimal, which theoretically should lessen the risk of recurrence. Brachytherapy placement intraoperatively allows more precise identification of the tumor margins than by postoperative imaging. Traditional brachytherapy methods have several drawbacks, including uneven dose distribution, long operating room times, a need for expensive equipment, and/or frequent adverse events (AE). To address these issues, a device with Cs-131 radiation seeds in a resorbable collagen-based carrier tile (GammaTile, GT Medical Technologies, Tempe AZ) was developed and is described as Surgically Targeted Radiation Therapy or STaRT. The device has demonstrated excellent safety and local control in early commercial use.

OBJECTIVE

The objectives of this registry study are to evaluate real-world clinical outcomes and patient reported outcomes that measure the effectiveness and safety of STaRT.

METHOD

Patients (N=600) with surgically resected (R) brain tumors of any pathology who have undergone STaRT are eligible. Accrual to start at 20+ sites in Q3 2020. Data collected includes local control, overall survival, QOL, neurocognition, functional decline, and surgical and radiation associated AE’s. Data will be collected at 1, 3, 6, 9, and 12 months, then every 6 months through 5 years.

RESULT

Data will be used to benchmark clinical outcomes of STaRT therapy and allow for comparisons to existing standard-of-care treatments.

CONCLUSION

This will be the first observational registry study of R+STaRT, delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. The outcome measures captured will allow for evaluation of the potential risks and benefits of this treatment approach for patients in a real-world setting.
RBIO-04. NEW THERAPEUTIC DELIVERY METHODS FOR TUMOR-TREATING FIELDS FOR HIGHER EFFICACY
Authors: Carlson Kristen , Bomzon Zeev , Arle Jeffrey
Published: December 2020

Tumor-treating fields (TTFields) are the fourth modality of glioblastoma (GBM) treatment and in conjunction with chemotherapy can increase overall survival of GBM patients up to 60 months. However, in vitro and in animal models TTFields show 100% efficacy on a variety of tumor cell types including GBM cells when field strength is 4 V/cm, versus ~2 V/cm that is the clinical delivery target, TTFields are delivered transcranially. TTFields finite element modeling studies, supported by similar transcranial electric stimulation studies, show that the principal obstacle to delivering 4 V/cm is the electrically resistive skull. Our modeling shows the biophysics is more complicated than these findings. For instance, electrically-conductive cerebrospinal fluid regions surrounding the grey matter and in ventricles shunt electric current from anode to cathode, hindering delivery of the current required to produce 4 V/cm at the tumor/peritumor target. Thus, we consider two new delivery methods for TTFields. First, the transcranial array can be made more focal and directional, following modeling and development of electrode arrays used in spinal cord and deep brain stimulation. Our finite element modeling shows that similarly-designed TTFields electrode arrays can deliver field strength focally to a tumor target approaching 4 V/cm. Second, pre- or post-resection, TTFields can be delivered via electrode arrays surgically placed in the tumor or tumor resection cavity (intra-tumoral delivery), circumventing the resistive skull and CSF shunting effects. Such intra-tumoral arrays can deliver 4 V/cm to the tumor/peritumor region, opening up the potential to replicate clinically the 100% efficacy of TTFields in vitro and in animal models. Thus, new TTFields delivery may lead to unlimited survival of GMB patients via a side-effect free treatment modality.
RTID-07. HUMAN PLACENTAL HEMATOPOIETIC STEM CELL DERIVED NATURAL KILLER CELLS (CYNK-001) FOR TREATMENT OF RECURRENT GLIOBLASTOMA
Authors: Majd Nazanin , Rizk Maha , Ericson Solveig , Grzegorzewski Kris , Koppisetti Sharmila , Zhu Junhong , Kang Lin , He Shawn , Mahlakoiv Tanel , van Der Touw William , Zhang Xiaokui , Habboubi Nassir , Hariri Robert , Hunter Kathy , Alfaro-Munoz Kristin , Heimberger Amy , de Groot John , Chi Linda , Srour Samer
Published: December 2020

Glioblastoma (GBM) is the most aggressive primary brain tumor with dismal prognosis. Recent advances of immunotherapy in cancer have sparked interest in the use of cell therapy for treatment of GBM. Active transfer of Natural Killer (NK) cells is of particular interest in GBM because NK cells are capable of exerting anti-tumor cytotoxicity without the need for antigen presentation and sensitization, processes that are impaired in GBM. CYNK-001 is an allogeneic, off-the-shelf product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells manufactured by Celularity. Here, we demonstrate in vitro cytotoxicity of CYNK-001 against several GBM lines and its in vivo anti-tumor activity in a U87MG orthotopic mouse model via intracranial administration resulting in 94.5% maximum reduction in tumor volume. We have developed a phase I window-of-opportunity trial of CYNK-001 in recurrent GBM via intravenous (IV) and intratumoral (IT) routes. In the IV cohort, subjects receive cyclophosphamide for lymphodepletion followed by 3-doses of IV CYNK-001 weekly. In the IT cohort, subjects undergo placement of an IT catheter with an ommaya reservoir followed by 3-doses of IT CYNK-001 weekly. Patients are monitored for 28-days after last infusion for toxicity. Once maximum safe dose (MSD) is determined, patients undergo IV or IT treatments at MSD followed by surgical resection and the tumor tissue will be analyzed for NK cell engraftment and persistence. We will utilize a 3 + 3 dose de-escalation design (maximum n=36). Primary endpoint is safety and feasibility. Secondary endpoints are overall response rate, duration of response, time to progression, progression free survival and overall survival. Main eligibility criteria include age ≥18, KPS ≥60, GBM at first or second relapse with a measurable lesion on ≤2mg dexamethasone. This is the first clinical trial to investigate CYNK-001 in GBM and will lay the foundation for future NK cell therapy in solid tumors.
STEM-29. THE HISTONE VARIANT macroH2A2 ORCHESTRATES AN ACTIONABLE CHROMATIN PROGRAM OF STEMNESS IN GLIOBLASTOMA
Authors: Nikolic Ana , Bobyn Anna , Ellestad Katrina , Lun Xueqing , Johnston Michael , Gafuik Christopher , Zemp Franz , Ninkovic Nicoletta , Berger Daniel , Brownsey Duncan , Dirks Peter , Derksen Darren , Senger Donna , Chan Jennifer , Mahoney Douglas , Gallo Marco
Published: December 2020

Glioblastoma cells with the crucial stemness property of self-renewal constitute therapy-resistant reservoirs that seed tumor relapse. Effective targeting of these cells in clinical settings has been hampered by their relative quiescence, which invalidates the cell replication bias of most current treatments. Furthermore, although their dependence on specific chromatin and transcriptional states for the maintenance of stemness programs has been proposed as a vulnerability, these nuclear programs have been challenging to target pharmaceutically. Therefore the identification of targetable chromatin paradigms regulating self-renewal would represent a significant advancement for this incurable malignancy. Here we report a new role for the histone variant macroH2A2 in modulating a targetable epigenetic network of stemness in glioblastoma. By integrating transcriptomic, bulk and single-cell epigenomic datasets we generated from patient-derived models and surgical specimens, we show that macroH2A2 represses a transcriptional network of stemness through direct regulation of chromatin accessibility at enhancer elements. Functional assays in vitro and in vivo further showcase that macroH2A2 antagonizes self-renewal and stemness in glioblastoma preclinical models. In agreement with our experimental findings, high expression of macroH2A2 is a positive prognostic factor in clinical glioblastoma cohorts. Reasoning that increasing macroH2A2 levels could be an effective strategy to repress stemness programs and ameliorate patient outcome, we embarked on a screen to identify compounds that could elevate macroH2A2 levels. We report that an inhibitor of the chromatin remodeler Menin increases macroH2A2 levels, which in turn repress self-renewal. Additionally, we provide evidence that Menin inhibition induces viral mimicry programs and the demise of glioblastoma cells. Menin inhibition is being tested in clinical trials for blood malignancies (NCT04067336). Our preclinical work therefore reveals a novel and central role for macroH2A2 in an epigenetic network of stemness and suggests new clinical approaches for glioblastoma.
SURG-09. EXTRAOPERATIVE CORTICAL MAPPING VIA IMPLANTED SUBDURAL AND DEPTH ELECTRODES FOR MAXIMIZING ELOQUENT AREA GLIOMA RESECTION
Authors: Fountas Konstantinos , Paschalis Thanasis , Kapsalaki Eftychia
Published: December 2020

OBJECTIVE

Aggressive, even supramarginal, resection without compromising the neurological status of the patient remains a great challenge in the management of glioma cases. Accurate cortical and subcortical functional mapping allows more radical glioma resection. Numerous imaging, electrophysiological, and hybrid methodologies have been employed in the cortical mapping of patients with gliomas in eloquent areas. Despite the recent advances of these non-invasive modalities, direct electrical cortical and subcortical stimulation and mapping through an awake craniotomy remains the gold standard for maximal glioma resection and preservation of eloquent cortex functions. Extraoperative stimulation and mapping via implanted subdural and/or depth electrodes may be a valid alternative mapping method in these cases that an awake procedure is not feasible. The role of this mapping method is examined in our current study.

MATERIAL & METHODS

In a retrospective study, 51 patients undergoing extraoperative stimulation and mapping for glioma resection were included. The demographic data, the clinical characteristics, the stimulation parameters and complications, the extent of resection, the perioperative complications, and the tumor histological grade were analyzed. Shapiro-Wilk test, as well as uni- and multi-variate regression analysis was used for our statistical analysis.

RESULTS

The mean age of our participants was 58 (SD: 9.4) years. The location of the glioma was on the left side in 80.4%, while the frontal lobe was affected in 51.0%. Extraoperative cortical and subcortical stimulation and mapping was successful in 94.1%. The median stimulation procedure was 2.0 hours, while the median implantation time was 72 hours. Stimulation-induced seizures occurred in 13.7%, while CSF leakage in 5.9% of our cases. The mean extent of resection was 91.6%, while transient dysphasia occurred in 21.6%, and transient hemiparesis in 5.9% of our cases.

CONCLUSIONS

Extraoperative stimulation and mapping constitutes a valid alternative mapping option in glioma patients, who cannot undergo an awake craniotomy.
SURG-33. ROLE OF SURGERY IN TREATING EPSTEIN-BARR VIRUS-ASSOCIATED SMOOTH MUSCLE TUMOR (EBV-SMT) WITH CENTRAL NERVOUS SYSTEM INVASION: A SYSTEMIC REVIEW
Authors: Chen Ko-Ting , Lau Ka-Wei , Hsu Yu-Wei , Lin Yin-Ting
Published: December 2020

Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor that almost exclusively occurs in immunocompromised hosts. The term unknown malignant potential once used interchangeably to describe EBV-SMT and the less invasive clinical behavior than leiomyosarcoma indicate an indolent growth pattern of EBV-SMT. Nevertheless, an EBV-SMT with CNS invasion would result in neurological deficits which may jeopardize patients’ survival.We provide a systemic review of literature under PRISMA guideline on the clinical features, treatment modalities, role of surgery intervention and outcomes of all 65 reported EBV- SMTs with central nervous system (CNS) invasion. Over 95% of the reported cases were immunocompromised, while human immunodeficiency virus infection and post- organ transplantation being the most commonly associated underlying causes (near 90%). A 76.0% 1-year survival rate and 59.6% 5-year survival rate confirms the indolent and non-deadly nature of EBV-SMT even with CNS invasion. An immune survey and reconstruction should be conducted for every patient with CNS EBV-SMT. Surgical resection is mostly adopted as primary treatment to acquire diagnosis and relieve compressive effect. A total resection of tumor may be beneficial if tumor was symptomatic and had intracranial invasion
TAMI-23. NEUTROPHIL-TRIGGERED FERROPTOSIS PROMOTES TUMOR NECROSIS IN GLIOBLASTOMA PROGRESSION
Authors: Yee Patricia , Wei Yiju , Kim Soo Yeon , Lu Tong , Lawson Cynthia , Tang Miaolu , Liu Zhijun , Anderson Benjamin , Young Megan , Thamburaj Krishnamoorthy , Aregawi Dawit , Glantz Michael , Zacharia Brad , Specht Charles , Wang Hong-Gang , Li Wei
Published: December 2020

Tumor necrosis indicates poor prognoses in many cancers, including glioblastomas (GBMs). Although thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscured by lack of animal models recapitulating the extent of necrosis in human GBMs. The molecular and clinical heterogeneity of GBMs adds further complexity. Not all GBMs contain necrosis. Mesenchymal (MES)-GBM, the subtype correlated with worst prognosis and highest treatment resistance, is most closely associated with necrosis. MES-GBM exhibits hyperactivity of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in human GBMs predicts short survival. To elucidate mechanisms driving GBM necrosis, we devised a novel orthotopic mouse model recapitulating human MES-GBM phenotypically and histopathologically by expressing a constitutively-active TAZ mutant (TAZ4SA) in three human GBM cell lines (LN229, U87, and LN18) lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter than mice implanted with GBMvector or mutant TAZ unable to bind its downstream effector, TEAD (GBM4SA-S51A). Extensive (≥30% of tumor volume) necrosis was present in GBM4SA mice but not GBMvector or GBM4SA-S51A. In GBM4SA tumors, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse tumors killed co-cultured tumor cells. Neutrophils induce iron-dependent accumulation of lipid hydroperoxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibiting myeloperoxidase suppresses neutrophil-induced tumor cytotoxicity. Intratumoral glutathione peroxidase 4 (GPX4) overexpression or acyl-CoA synthetase 4 (ACSL4) depletion diminishes necrosis and aggressiveness of tumors. Human GBM analysis indicates neutrophils and ferroptosis are associated with necrosis and predict poor survival. Together, we propose that certain tumor damage(s) during early tumor progression (i.e. ischemia) recruits neutrophils to damaged tissue and results in a positive feedback loop, amplifying GBM necrosis development. We show GBM necrosis involves neutrophil-triggered ferroptosis and reveal an unprecedented pro-tumorigenic role of ferroptosis.
TAMI-31. MACROPHAGE M1 INVASION PREDICTS POOR PROGNOSIS OF GLIOMA AND REVEALS A STRATEGY FOR GLIOBLASTOMA THERAPY
Authors: Zhou Zhaoming , Wen Lei , Shan Changguo , Lai Mingyao , Zhou Cheng , Cai Linbo
Published: December 2020

BACKGROUND

Glioma is one of the most malignant tumors in the central neural system, due to a lack of efficient immune therapy targets. Here we explored the transcriptional information of gliomas with the aim to discover novel biomarkers for glioma classifying in the aspects of prognosis and immune therapy targets prediction.

METHODS

We explored the gene expression data from the Chinese Glioma Genome Atlas (CGGA). The extracellular matrix (ECM) and immune cells abundance of gliomas were evaluated on the transcriptional level by the ECM score and cell infiltration enrichment score.

RESULTS

Based on top differentially expressed genes (DEGs), ECM scores showed significantly differences between various grades (WHO II, III, and IV) of gliomas (p values < 0.0001). Cell infiltration enrichment scores of macrophages, macrophages M1, and monocytes showed positively correlated with the ECM scores by the linear regression analysis (r = 0.51, 0.54, and 0.62, respectively; p values < 0.0001). Variation-partitioning analysis indicated that macrophages, macrophages M1, and monocytes played dominant roles in the variances between WHO II, WHO III, and WHO IV gliomas. Survival association analysis showed that patients with higher infiltration of macrophages, macrophages M1, and monocytes shared shorter overall survival (OS). OS of glioblastoma (GBM) were determined to be shorter in high macrophages M1 enrichment group (p < 0.0001). Univariate and multivariate analysis of clinical characteristics with OS in GBM cohort demonstrated that macrophages M1 enrichment score was an independent survival risk factor for GBM patients. Further subgroup survival association analysis showed that the higher M1 macrophages enrichment score was associated with higher OS in IDH wildtype GBM patients (p = 0.011).

CONCLUSIONS

This study demonstrates Macrophages M1 infiltration level as a poor prognostic factor for glioma and suggests macrophages M1 could be the potential immune therapy targets for IDH-wild-type GBM patients.
TAMI-62. ANGIOGENESIS INHIBITORS STRONGLY SYNERGIZE WITH THERAPEUTICS TARGETING TUMOR METABOLISM
Authors: Khadka Sunada , Lin Yu-Hsi , Ackroyd Jeffrey , Arthur Kenisha , Barekatain Yasaman , Poral Anton , Tran Theresa , Georgiou Dimitra , de Groot John , Huse Jason , Asara John , Muller Florian
Published: December 2020

Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their demise. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit some degree of metabolic stress, this is stress is not sufficient to induce significant cancer cell death. We posit that the full potential of angiogenesis inhibition can be realized by the combination of angiogenesis inhibition with emerging tumor metabolism targeting therapies. Because tumors under angiogenesis inhibition are already in a state of nutrient stress, the effects of metabolically targeted therapies such as amino acid depletion (e.g. asparginase, methionine restriction), inhibitors of stress adaption (AMPK and GCN2 inhibitors) or energy metabolism (e.g. IACS-010759, Metformin, POMHEX) stand to dramatically increase in potency whilst remaining selective for (angiogenic) tumor versus (non-angiogenic) normal tissue. Here, we provide proof-of-principal for this thesis. First, we performed metabolomic profiling of angiogenesis-inhibited tumors, which corroborates as state of nutrient stress in angiogenesis-inhibited tumors. Second, we demonstrate dramatic anti-neoplastic synergy (effectively curing of xenografted tumor-bearing mice, irrespective of initial tumor size), without enhanced adverse toxicities, between the OxPhos inhibitor IACS-010759 and the angiogenesis tyrosine kinase inhibitor, Tivozanib. The same results were recapitulated with the anti-VEGFA antibody, Avastin, and the OxPhos inhibitor could be substituted with the Enolase inhibitor HEX, with similar effects. The synergy was observed in a broad range of tumor types, even those without clear genetic susceptibilities. Together, these results suggest that Angiogenesis inhibitors synergize broadly with cancer therapies targeting metabolism, allowing the realization of the full potential of these previously disappointing drugs. Our results warrant systematic combination clinical trials between angiogenesis inhibitors and established, as well as emerging anti-metabolic cancer therapies.